WO2022261025A1 - Methods of treating cancer with a combination of sotorasib and trametinib - Google Patents

Methods of treating cancer with a combination of sotorasib and trametinib Download PDF

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WO2022261025A1
WO2022261025A1 PCT/US2022/032395 US2022032395W WO2022261025A1 WO 2022261025 A1 WO2022261025 A1 WO 2022261025A1 US 2022032395 W US2022032395 W US 2022032395W WO 2022261025 A1 WO2022261025 A1 WO 2022261025A1
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patient
sotorasib
cancer
trametinib
administering
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PCT/US2022/032395
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French (fr)
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Gregory Friberg
Haby HENARY
Brett E. Houk
Gataree Ngarmchamnanrith
Omar MATHER
Sandeep Dutta
Neelesh Soman
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Amgen Inc.
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Publication of WO2022261025A1 publication Critical patent/WO2022261025A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the rat sarcoma (RAS) proto-oncogene has been identified as an oncogenic driver of tumorigenesis in cancers, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • the RAS family consists of 3 closely related genes that express guanosine triphosphate (GTP)-ases responsible for regulating cellular proliferation and survival.
  • GTP guanosine triphosphate
  • the RAS proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS) can be mutationally activated at codons 12, 13, or 61, leading to human cancers.
  • KRAS being the most frequently mutated isoform in most cancers. While the role of KRAS mutations in human cancers has been known for decades, no anti-cancer therapies specifically targeting KRAS mutations have been successfully developed, until recently, largely because the protein had been considered intractable for inhibition by small molecules.
  • Described herein are methods of treating cancer comprising a KRAS G12C mutation in a patient comprising orally administering to the patient sotorasib and trametinib once daily, wherein the sotorasib and trametinib are administered to the patient in amounts effective to treat the cancer in the patient.
  • the methods further comprise administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient.
  • EGFR anti-epidermal growth factor receptor
  • the anti-EGFR antibody comprises a heavy chain variable region comprising heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.
  • the heavy chain variable region comprises the sequence of SEQ ID NO: 4 and the light chain variable region comprises the sequence of SEQ ID NO: 9.
  • the anti-EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10.
  • the anti-EGFR antibody is panitumumab.
  • the cancer is a solid tumor.
  • the cancer is non-small cell lung cancer, and in some cases, is metastatic or locally advanced.
  • the cancer is colorectal cancer.
  • the cancer is pancreatic cancer.
  • the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • Figure 1 shows the mean plasma concentration time profile after once daily oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1 , where N indicates number of observations across data points.
  • Figure 2 shows the mean plasma concentration time profile after once daily oral administration of 180, 360, 720, or 960 mg sotorasib on Day 8, where N indicates number of observations across data points.
  • kits for treating cancer comprising a KRAS G12C mutation in a patient comprising administering sotorasib and trametinib (a MEK inhibitor) to the patient in an amount effective to treat the cancer.
  • the methods further comprise administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient.
  • EGFR anti-epidermal growth factor receptor
  • the methods of treatment disclosed herein regarding administration of two or more therapeutics (e.g., sotorasib, trametinib) to a patient include concomitant administration of the therapeutics (e.g., within 1 hour, within 45 minutes, within 30 minutes, within 15 minutes, or within 10 minutes of each other), and sequential administration (e.g., administration separated by at least 1 hour, or at least two hours, or at least four hours, or at least six hours, or at least eight hours, or at least twelve hours, or at least 24 hours, or at least 2 days, or at least 3 days).
  • concomitant administration of the therapeutics e.g., within 1 hour, within 45 minutes, within 30 minutes, within 15 minutes, or within 10 minutes of each other
  • sequential administration e.g., administration separated by at least 1 hour, or at least two hours, or at least four hours, or at least six hours, or at least eight hours, or at least twelve hours, or at least 24 hours, or at least 2 days, or at least 3 days.
  • Sotorasib is a small molecule that irreversibly inhibits the KRAS G12C mutant protein. Sotorasib is also referred to as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1/W)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4- [(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-cf]pyrimidin-2(1/-/)-one and has the following structure: [0012] Sotorasib binds to the P2 pocket of KRAS adjacent to the mutant cysteine at position 12 and the nucleotide-binding pocket.
  • the inhibitor contains a thiol reactive portion which covalently modifies the cysteine residue and locks KRAS G12C in an inactive, guanosine diphosphate (GDP) bound conformation.
  • GDP guanosine diphosphate
  • RNA interference RNA interference
  • small molecule inhibition has previously demonstrated an inhibition of cell growth and induction of apoptosis in tumor cell lines and xenografts harboring KRAS mutations (including the KRAS G12C mutation) (Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016).
  • sotorasib have confirmed these in vitro findings and have likewise demonstrated inhibition of growth and regression of cells and tumors harboring KRAS G12C mutations (Canon et al., 2019). See also, LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 5/2021), which is herein incorporated by reference in its entirety.
  • Trametinib is a pyrido-pyrimidine derivative that is a potent and highly selective allosteric non competitive inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and kinase 2 (MEK2) activation and kinase activity (Gilmartin et al, 2011).
  • MEKINIST® mitogen-activated extracellular signal-regulated kinase 1
  • MEK2 extracellular signal-regulated kinase 2 activation and kinase activity
  • Trametinib has potent anti-proliferative activity against multiple cancer cell lines, but has minimal effect on normal, non-proliferating cells.
  • Trametinib is indicated, for example, as a monotherapy or in combination with dabrafenib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutation as detected by a Food and Drug Administration (FDA) approved test.
  • FDA Food and Drug Administration
  • Trametinib in combination with dabrafenib is also indicated in patients with metastatic non-small cell lung cancer with BRAF V600E mutation as detected by an FDA-approved test (Falchook et al, 2012, Flaherty et al, 2012). See also,
  • the methods further comprise administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient.
  • the anti-EGFR antibody comprises a heavy chain variable region comprising heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.
  • the heavy chain variable region comprises the sequence of SEQ ID NO: 4 and the light chain variable region comprises the sequence of SEQ ID NO: 9.
  • the anti-EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10.
  • the anti-EGFR antibody is panitumumab.
  • Panitumumab is a fully human immunoglobulin (lg)G2 monoclonal antibody to the epidermal growth factor receptor (EGFR). Panitumumab binds to the extracellular domain of EGFR, thus preventing its activation and intracellular signaling.
  • EGFR epidermal growth factor receptor
  • Panitumumab (VECTIBIX®) has been approved for the treatment of patients with wild-type RAS (in both KRAS and NRAS as determined by an FDA approved test for this use) metastatic colorectal cancer (mCRC) as first line therapy in combination with FOLFOX (leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin) and as monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin and irinotecan-containing chemotherapy.
  • the recommended dose is 6 mg/kg, administered as an IV infusion over 60 minutes (£ 1000 mg) or 90 minutes (> 1000 mg), Q2W. See also, VECTIBIX® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 6/2017)), which is herein incorporated by reference in its entirety.
  • the methods comprise administering sotorasib in an amount ranging from 240 mg to 960 mg. In some embodiments, the methods comprise administering 960 mg sotorasib to the patient once daily. In some embodiments, the methods comprise administering 240 mg to the patient once daily. In some embodiments, the methods comprise administering 480 mg to the patient twice daily. In some embodiments, the methods comprise administering 240 mg to the patient twice daily.
  • the methods comprise administering trametinib in an amount ranging from 0.5 mg - 2 mg (e.g., 0.5 mg, 0.6 mg, 0,7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.5 mg, 1.6 mg, 1.7 mg,
  • the methods comprise administering 1 mg trametinib to the patient. In some embodiments, the methods comprise 2 mg trametinib to the patient. In some embodiments, 0.5 mg trametinib to the patient.
  • the methods comprise orally administering 960 mg sotorasib and trametinib in an amount ranging from 0.5 mg - 2 mg (e.g., 0.5 mg, 0.6 mg, 0,7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1 .5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1 .9 mg, or 2 mg) once daily to the patient.
  • the methods comprise orally administering 960 mg sotorasib and 0.5 mg trametinib once daily to the patient.
  • the methods comprise orally administering 960 mg sotorasib and 1 mg trametinib once daily to the patient.
  • the methods comprise orally administering 960 mg sotorasib and 2 mg trametinib once daily to the patient.
  • the treatment cycle is at least 21 days. In some embodiments, the treatment cycle is 28 days or less. In some embodiments, the treatment cycle is between 21 and 28 days in length. In some embodiments, the treatment cycle is 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days or 28 days in length. In some embodiments, the treatment cycle is 28 days. In some embodiments, the patient is treated for one or more treatment cycles.
  • a patient can undergo two or more treatment cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more treatment cycles, or more specifically 1 to 20, 2 to 15, or 2 to 10 treatment cycles, depending upon the response of the patient to the treatment and the consideration of the attending clinician.
  • two or more treatment cycles e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more treatment cycles, or more specifically 1 to 20, 2 to 15, or 2 to 10 treatment cycles, depending upon the response of the patient to the treatment and the consideration of the attending clinician.
  • the methods described herein further comprise administering panitumumab to the patient once every two weeks.
  • the methods further comprise administering panitumumab in an amount ranging from 3.6 mg/kg to 6 mg/kg (e.g., 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/kg, 4.0 mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg, 4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg,
  • the methods further comprise administering 6 mg/kg panitumumab. In some embodiments, the methods further comprise administering 4.8 mg/kg panitumumab. In some embodiments, the methods further comprise administering 3.6 mg/kg panitumumab.
  • the methods described herein comprise administering (a) 960 mg sotorasib orally and trametinib in an amount ranging from 0.5 mg - 2 mg (e.g., 0.5 mg, 0.6 mg, 0,7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2 mg) once daily to the patient; and (b) panitumumab in an amount ranging from 3.6 mg/kg to 6 mg/kg (e.g., 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/kg, 4.0 mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg, 4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg,
  • the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and (b) 4.8 mg/kg panitumumab via IV administration every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and (b) 6 mg/kg panitumumab via IV administration every two weeks.
  • the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1.5 mg trametinib orally once daily; and (b) 6 mg/kg panitumumab via IV administration every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 2 mg trametinib orally once daily; and (b) 6 mg/kg IV panitumumab via IV administration every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and (b) 4.8 mg/kg panitumumab via IV administration every two weeks.
  • the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and (b) 3.6 mg/kg panitumumab via IV administration once every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and (b) 3.6 mg/kg panitumumab via IV administration once every two weeks.
  • sotorasib is administered with food. In various embodiments, sotorasib is administered without food. In various embodiments trametinib is administered at least 1 hour (e.g., 1 hour, 2 hours, 3 hours, and 4 hours) before a meal. In various embodiments, trametinib is administered at least 2 hours (e.g., 2 hours, 3 hours, 4 hours, and 5 hours) after a meal.
  • the patient is in further need of treatment with an acid-reducing agent.
  • Acid- reducing agents include, but are not limited to, a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), and a locally acting antacid.
  • PPI proton pump inhibitor
  • H2RA H2 receptor antagonist
  • the patient is further in need of treatment with a PPI or a H2RA.
  • Exemplary PPIs include, but are not limited to, omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole.
  • Exemplary H2RAs include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine, roxatidine and lafutidine.
  • Exemplary locally acting antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide.
  • the patient who is in further need of treatment with an acid reducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib.
  • the patient who is in further need of treatment with an acid-reducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib, but is administered a locally acting antacid in combination with sotorasib.
  • sotorasib is administered about 4 hours before or about 10 hours after a locally acting antacid.
  • the patient is in further need of treatment with a CYP3A4 inducer.
  • the patient is not administered a CYP3A4 inducer in combination with sotorasib.
  • Exemplary CYP3A4 inducers include, but are not limited to, barbiturates, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, and troglitazone.
  • the patient is not administered a strong CYP3A4 inducer in combination with sotorasib.
  • Exemplary strong CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates- inhibitors-and-inducers, accessed May 2021.
  • strong CYP3A4 inducers include, but are not limited to, rifampin, phenytoin, mitotane, carbamazepine, avasimibe, enzalutamide, rifapentine, St John's Wort extract, apalutamide, lumacaftor, and ivosidenib.
  • the patient is in further need of treatment with a CYP3A4 substrate.
  • the patient is not administered a CYP3A4 substrate in combination with sotorasib.
  • Exemplary CYP3A4 substrates include, but are not limited to, abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride,
  • CYP3A4 substrates with a narrow therapeutic index include but are not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, primozide, quinidine, tacrolimus, and sirolimus.
  • the patient is in further need of treatment with a P-glycoprotein (P-gp) substrate.
  • P-gp P-glycoprotein
  • the patient is not administered a P-gp substrate in combination with sotorasib.
  • P-gp substrates include, but are not limited to, dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine. See, e.g., www.fda.gov/drugs/drug-interactions- labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed May 2021 .
  • the patient is not administered a P-gp substrate in combination with sotorasib, wherein the P-gp substrate is a P-gp substrate with a narrow therapeutic index.
  • P-gp substrates with a narrow therapeutic index include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, and vincristine.
  • p-gp substrates with a narrow therapeutic index include, but are not limited to, digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, and vincristine.
  • the patient has a cancer that was determined to have one or more cells expressing the KRAS G12C mutant protein prior to administration of sotorasib as disclosed herein. Determination of KRAS G12C mutant protein can be assessed as described elsewhere in this disclosure.
  • the patient administered sotorasib in the methods described herein have been previously treated with a different anti-cancer therapy, e.g., at least one - such as one, or two, or three - other systemic cancer therapy.
  • the patient had previously been treated with one other systemic cancer therapy, such that the sotorasib therapy is a second line therapy.
  • the patient had previously been treated with two other systemic cancer therapies, such that the sotorasib therapy as provided herein is a third line therapy.
  • the prior systemic cancer therapy is a therapy with a KRAS G12C inhibitor.
  • the patient exhibits reduced sensitivity to a therapy with a KRAS G12C inhibitor.
  • the patient is resistant to a therapy with a KRAS G12C inhibitor.
  • KRAS G12C inhibitor is sotorasib, adagrasib, GDC-6036, D-1553, JDQ443, LY3484356, BI1823911, JAB-21822, RMC-6291, or APG-1842.
  • the KRAS G12C inhibitor is sotorasib.
  • the KRAS G12C inhibitor is adagrasib.
  • the therapy is monotherapy.
  • the therapy with a KRAS G12C inhibitor is sotorasib monotherapy.
  • the therapy with a KRAS G12C inhibitor is monotherapy with adagrasib.
  • sensitivity refers to the way a cancer reacts to a drug, e.g., sotorasib.
  • sensitivity means “responsive to treatment” and the concepts of “sensitivity” and “responsiveness” are positively associated in that a cancer or tumor that is responsive to a drug treatment is said to be sensitive to that drug.
  • Sensitivity in exemplary instances is defined according to Pelikan, Edward, Glossary of Terms and Symbols used in Pharmacology (Pharmacology and Experimental Therapeutics Department Glossary at Boston University School of Medicine), as the ability of a population, an individual or a tissue, relative to the abilities of others, to respond in a qualitatively normal fashion to a particular drug dose.
  • “Sensitivity” may be measured or described quantitatively in terms of the point of intersection of a dose-effect curve with the axis of abscissal values or a line parallel to it; such a point corresponds to the dose just required to produce a given degree of effect.
  • the “sensitivity” of a measuring system is defined as the lowest input (smallest dose) required producing a given degree of output (effect).
  • “sensitivity” is opposite to “resistance” and the concept of “resistance” is negatively associated with “sensitivity”. For example, a cancer that is resistant to a drug treatment is either not sensitive nor responsive to that drug or was initially sensitive to the drug and is no longer sensitive upon acquiring resistance; that drug is not or no longer an effective treatment for that tumor or cancer cell.
  • Prior systemic cancer therapies include, but are not limited to, chemotherapies and immunotherapies.
  • Specific contemplated prior systemic cancer therapies include, but are not limited to, anti-PD1 therapy, anti-PDL1 therapy, and platinum based chemotherapy.
  • Some examples of anti-PD1 therapy and anti-PDL1 therapies include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, tisielizumab, toripalimab, aspartalizumab, dostarlimab, retifanlimab, Heillimab, pidilizumab atezolizumab, avelumab, durvalumab, and zeluvalimab (AMG 404).
  • the anti-PD1 therapy includes, but is not limited to, balstilimab, budigalimab, cadonilimab, camrelizumab, cetrelimab, cemiplimab, dostarlimab, ezabenlimab, finotonlimab, nivolumab, penpulimab, pembrolizumab, pucotenlimab, retifanlimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, toripalimab, zeluvalimab (AMG 404), and zimberelimab.
  • the anti-PD1 therapy include, but is not limited to, cemiplimab, dostarlimab, pembrolizumab, or nivolumab. In some embodiments, the anti-PD1 therapy is pembrolizumab (KEYTRUDA®).
  • the anti-PD-L1 therapy includes, but is not limited to, adebrelimab, atezolizumab, avelumab, cosibelimab, durvalumab, envafolimab, erfonrilimab, garivulimab, lodapolimab, opucolimab, sugemalimab, socazolimab, and tagitanlimab.
  • the anti-PD-L1 therapy includes, but is not limited to, atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), and avelumab (BAVENCIO®).
  • platinum based chemotherapies include, but are not limited to, carboplatin, oxaliplatin, cisplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin, ProLindac, and aroplatin.
  • the patient has previously been administered a systemic cancer therapy that is a targeted therapy if the cancer was identified to have an actionable oncogenic driver mutation in the epidermal growth factor receptor gene ( EGFR ), anaplastic lymphoma kinase gene (ALK), and/or ROS proto-oncogene 1 (ROS1).
  • EGFR epidermal growth factor receptor gene
  • ALK anaplastic lymphoma kinase gene
  • ROS ROS proto-oncogene 1
  • Targeted therapies for EGFR mutations include, but are not limited to, cetuximab, panitumumab, erlotinib, gefitinib, and afatinib.
  • Targeted therapies for ALK mutations include, but are not limited to, crizotinib, entrectinib, lorlatinib, repotrectinib, brigatinib, alkotinib, alectinib, ensartinib, and ceritinib.
  • Targeted therapies for ROS1 mutations include, but are not limited to, crizotinib, entrecetinib, ensartinib, alkotinib, brigatinib, taletrectinib, cabozantinib, repotrectinib, lorlatinib, and ceritinib.
  • the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (see, e.g., Zubrod et al., 1960).
  • Status 0 indicates fully active and able to carry on all pre-disease performance without restriction.
  • Status 1 indicates restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
  • Status 2 indicates ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours.
  • Status 3 indicates capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
  • Status 4 indicates completely disabled, cannot carry on any selfcare and totally confined to bed or chair.
  • Status 5 indicates death.
  • the methods comprise administering a reduced total daily dose of sotorasib when the patient experiences an adverse event to the initial total daily dose.
  • the initial daily dose is 960 mg sotorasib and the reduced total daily dose is 480 mg sotorasib.
  • the initial daily dose is 480 mg sotorasib and the reduced total daily dose is 240 mg sotorasib.
  • the methods further comprise administering a second reduced total daily dose of sotorasib when the patient experiences an adverse event to the reduced total daily dose.
  • AE reverse event
  • the adverse event is hepatotoxicity (e.g., elevation of liver enzymes), interstitial lung disease (ILD)/pneumonitis, diarrhea, and/or nausea/vomiting.
  • hepatotoxicity e.g., elevation of liver enzymes
  • ILD interstitial lung disease
  • Pneumonitis e.g., diarrhea, and/or nausea/vomiting.
  • the adverse event is hepatotoxicity.
  • hepatotoxicity refers to a patient having abnormal laboratory values of liver biomarkers (e.g., alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine aminotransferase (ALT), and/or total bilirubin (TBL)), when the patient had baseline levels of the liver biomarker(s) prior to sotorasib administration that were not abnormal laboratory values or were lower than those measured after administration of sotorasib.
  • ALP alkaline phosphatase
  • AST aspartate amino transferase
  • ALT alanine aminotransferase
  • TBL total bilirubin
  • ALT Alanine transaminase
  • SGPT serum glutamic pyruvate transaminase
  • ALAT alanine aminotransferase
  • AST Aspartate transaminase
  • SGOT serum glutamic oxaloacetic transaminase
  • ASAT aspartate aminotransferase
  • AST can increase in response to liver damage. Elevated AST also can result from damage to other sources, including red blood cells, cardiac muscle, skeletal muscle, kidney tissue, and brain tissue. The ratio of AST to ALT can be used as a biomarker of liver damage.
  • Bilirubin is a catabolite of heme that is cleared from the body by the liver. Conjugation of bilirubin to glucuronic acid by hepatocytes produces direct bilirubin, a water-soluble product that is readily cleared from the body. Indirect bilirubin is unconjugated, and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin can be indicative of liver impairment.
  • Alkaline phosphatase hydrolyzes phosphate groups from various molecules and is present in the cells lining the biliary ducts of the liver. ALP levels in plasma can rise in response to liver damage and are higher in growing children and elderly patients with Paget's disease. However, elevated ALP levels usually reflect biliary tree disease.
  • the patient is not suffering from a disorder that results in elevated liver biomarkers.
  • Disorders associated with elevated liver biomarkers include, but are not limited to, hepatobiliary tract disease; viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; heritable disorders causing impaired glucuronidation (e.g., Gilbert’s syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); alpha-one
  • the baseline liver function of the patient can be assessed by various means known in the art, such as blood chemistry tests measuring biomarkers of liver function.
  • the methods described herein comprise monitoring liver biomarkers in the patient and withholding sotorasib administration in patients having > Grade 2 abnormal liver function, as assessed by levels of AST and/or ALT.
  • sotorasib administration is paused until the AST and/or ALT levels in the patient improve(s) to Grade 1 or better (baseline).
  • Adverse effect Grades for abnormal liver function are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 1 . See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017, by the National Cancer Institute, incorporated herein by reference in its entirety.
  • CTC Common Toxicity Criteria
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • ULN upper limit of normal
  • WNL within normal limits
  • Grade 0 levels are characterized by biomarker levels within normal limits (WNL).
  • Normal refers to Grade 0 adverse effects.
  • Abnormal liver function, as used herein, refers to Grade 1 and above adverse effects.
  • Grade 1 liver function abnormalities include elevations in ALT or AST greater than the ULN and less than or equal to 3-times the ULN if baseline was normal; 1.5 - 3. O x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of bilirubin levels greater than the ULN and less than or equal to 1.5-times the ULN if baseline was normal; > 1.0 - 1.5 x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of ALP greater than the ULN and less than or equal to 2.5-times the ULN if baseline was normal; > 2.0 - 2.5 x baseline if baseline was abnormal.
  • Grade 2 liver function abnormalities include elevations in ALT or AST greater than 3-times and less than or equal to 5-times the upper limit of normal (ULN) if baseline was normal; >3.0 - 5.0 x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than 1 .5- times and less than or equal to 3-times the ULN if baseline was normal; > 1.5 - 3. O x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of ALP greater than 2.5-times and less than or equal to 5-times the ULN if baseline was normal; > 2.5 - 5.0 x baseline if baseline was abnormal.
  • Grade 3 liver function abnormalities include elevations in ALT, AST, or ALP greater than 5-times and less than or equal to 20-times the ULN if baseline was normal; >5.0 - 20.0 x baseline if baseline was abnormal.
  • Grade 3 liver function abnormalities also include elevations of bilirubin levels greater than 3-times and less than or equal to 10-times the ULN if baseline was normal; > 3.0 - 10 x baseline if baseline was abnormal.
  • Grade 4 liver function abnormalities include elevations in ALT, AST, or ALP greater than 20-times the ULN if baseline was normal; > 20 x baseline if baseline was abnormal. Grade 4 liver function abnormalities also include elevations of bilirubin levels greater than 10 times the ULN if baseline was normal; > 10.0 x baseline if baseline was abnormal.
  • the ULN for various indicators of liver function depends on the assay used, the patient population, and each laboratory's normal range of values for the specified biomarker, but can readily be determined by the skilled practitioner. Exemplary values for normal ranges for a healthy adult population are set forth in Table 2 below.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the AST and/or ALT level(s) in the patient is/are elevated, e.g., to a Grade 2 or Grade 3 level, where the baseline AST and/or ALT levels of the patient were below Grade 2 or Grade 3 levels.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg), when the AST and/or ALT level(s) in the patient is/are elevated is to a Grade 1 level, wherein the baseline AST and/or ALT levels of the patient were below Grade 1 levels.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when (1) AST and bilirubin levels in the patient are elevated, or (2) when AST or ALP levels in the patient are elevated, or (3) when ALT and bilirubin levels in the patient are elevated, or (4) when ALT and ALP levels in the patient are elevated, or (5) when bilirubin and ALP levels in the patient are elevated, e.g., to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline AST, bilirubin, ALP, and/or ALT levels of the patient were below Grade 1 , Grade 2, Grade 3 or Grade 4 levels, respectively.
  • sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when (1) AST and bilirubin levels in the patient are elevated, or (2) when AST or ALP levels in the patient are elevated, or (3) when ALT and
  • three biomarkers of liver function may be elevated in the patient (e.g., ALT and AST and bilirubin, or ALT and AST and ALP) to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline biomarker levels of the patient were below Grade 1, Grade 2, Grade 3 or Grade 4 levels, respectively.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 3 times compared to the upper limit of normal (ULN).
  • the abnormal level of ALT and/or AST is greater than about 3- to about 5-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality".
  • the Grade 2 abnormality is an abnormal level of ALT and/or AST greater than about 3-fold to about 5-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 2.5- to about 5-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality".
  • the Grade 2 abnormality is an abnormal level of ALP greater than about 2.5-fold to about 5-fold increase compared to baseline.
  • the abnormal level of bilirubin is greater than about 1 .5- to about 3-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality”.
  • the Grade 2 abnormality is an abnormal level of bilirubin greater than about 1 .5-fold to about 3-fold increase compared to baseline.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 5 times compared to the upper limit of normal (ULN).
  • the total daily dose is reduced when the level of ALT, AST, or ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality".
  • the Grade 3 abnormality is an abnormal level of ALT and/or AST greater than about 5-fold to about 20-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality".
  • the Grade 3 abnormality is an abnormal level of ALP greater than about 5-fold to about 20- fold increase compared to baseline.
  • the total daily dose is reduced when the level of bilirubin is greater than about 3- to about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality".
  • the Grade 3 abnormality is an abnormal level of bilirubin greater than about 3-fold to about 10-fold increase compared to baseline.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 20 times compared to the upper limit of normal (ULN) (i.e., a “Grade 4 abnormality”).
  • the Grade 4 abnormality is an abnormal level of ALT and/or AST greater than about 20-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality".
  • the Grade 4 abnormality is an abnormal level of ALP greater than about 20- fold increase compared to baseline.
  • the total daily dose is reduced when the level of bilirubin is greater than about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality".
  • the Grade 4 abnormality is an abnormal level of bilirubin greater than about 10-fold increase compared to baseline.
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when liver biomarker(s) in the patient has improved to a Grade 1 or better (e.g., baseline).
  • sotorasib e.g., from 240 mg to 480mg, or from 480 mg to 960 mg
  • the adverse event is nausea or vomiting.
  • the nausea/vomiting is present despite appropriate supportive care (e.g., anti-emetic therapy).
  • “Nausea” as used herein refers to a disorder characterized by a queasy sensation and/or the urge to vomit.
  • the methods described herein comprise withholding sotorasib administration in a patient having 3 Grade 3 nausea until the patient has improved to £ Grade 1 or baseline.
  • the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
  • the methods described herein comprise withholding sotorasib administration in a patient having 3 Grade 3 vomiting until the vomiting improves to £ Grade 1 or baseline.
  • the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when nausea in the patient has improved to a Grade 1 or better (e.g., baseline).
  • sotorasib e.g., from 240 mg to 480mg, or from 480 mg to 960 mg
  • the adverse event is diarrhea.
  • the diarrhea is present despite appropriate supportive care (e.g., anti-diarrheal therapy).
  • An anti-diarrheal therapy can be administration of an anti-diarrheal agent, such as loperamide or atropine/diphenoxylate.
  • Adverse effect Grades for diarrhea are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 4. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017, by the National Cancer Institute, incorporated herein by reference in its entirety.
  • CTC Common Toxicity Criteria
  • the methods described herein comprise withholding sotorasib administration in a patient having 3 Grade 3 diarrhea until the patient has improved to £ Grade 1 or baseline. In some embodiments, once the patient has improved to £ Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient. In some embodiments, the methods described herein comprise administering an anti-diarrheal agent to the patient. In some embodiments, the anti-diarrheal agent is loperamide or atropine/diphenoxylate.
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when diarrhea in the patient has improved to a Grade 1 or better (e.g., baseline).
  • sotorasib e.g., from 240 mg to 480mg, or from 480 mg to 960 mg
  • the adverse event is interstitial lung disease (ILD) or pneumonitis.
  • ILD interstitial lung disease
  • pneumonitis In cases where ILD or pneumonitis is suspected at any grade level, sotorasib is withheld. In cases where ILD or pneumonitis is confirmed, and no other causes of the ILD or pneumonitis is identified, sotorasib is permanently discontinued.
  • Response rates or results for patients administered the therapy i.e., sotorasib and trametinib (and optionally an anti-EGFR antibody) in the methods disclosed herein can be measured in a number of ways, after the patient has been taking the therapy for a suitable length of time.
  • a patient is administered the therapy for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, e.g., for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months.
  • the patient is administered the therapy for at least 1 month.
  • the patient is administered the therapy for at least 3 months.
  • the patient is administered the therapy for at least 6 months.
  • the patient can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009).
  • SD stable disease
  • the stable disease is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD).
  • Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases.
  • the progression of a patient’s disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof.
  • CT computerized tomography
  • PET positron emission tomography
  • MRI magnetic resonance imaging
  • Progression free survival can be assessed as described in the RECIST 1.1 protocol.
  • the patient exhibits a PFS of at least 1 month.
  • the patient exhibits a PFS of at least 3 months.
  • the patient exhibits a PFS of at least 6 months.
  • the methods described herein comprise treating a cancer with a KRAS G12C mutation in a patient, wherein the methods comprise administering to the patient sotorasib and trametinib (and optionally an anti-EGFR antibody) in amounts effective to treat the cancer.
  • sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C (Hong et al., 2020). Hong et al.
  • sotorasib at a total daily dose of 240 mg is disclosed for use in treating cancer, wherein one or more cells express KRAS G12C mutant protein.
  • Sotorasib was evaluated in a Phase 1 dose escalation and expansion trial with 129 patients having histologically confirmed, locally advanced or metastatic cancer with the KRAS p.G12C mutation identified by local molecular testing on tumor tissues, including 59 patients with non-small cell lung cancer, 42 patients with colorectal cancer, and 28 patients with other tumor types (Hong et al., 2020, at page 1208-1209). Hong et al. report a disease control rate (95% Cl) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer and 75.0% for other tumor types (Hong et al., 2020, at page 1213, Table 3).
  • the cancer types showing either stable disease (SD) or partial response (PR) as reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma (Hong et al., 2020, at page 1212 ( Figure A), and Supplementary Appendix (page 59 ( Figure S5) and page 63 ( Figure S6)).
  • SD stable disease
  • PR partial response
  • KRAS G12C mutations occur with the alteration frequencies shown in the table below (Cerami et al., 2012; Gao et al., 2013). For example, the table shows that 11.6% of patients with non-small cell lung cancer have a cancer, wherein one or more cells express KRAS G12C mutant protein. Accordingly, sotorasib, which specifically and irreversibly bind to KRAS G12C is useful for treatment of patients having a cancer, including, but not limited to the cancers listed in Table 5 below.
  • the cancer is a solid tumor.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer.
  • the cancer is non-small cell lung cancer. In some embodiments, the cancer is metastatic or locally advanced non-small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.
  • the presence or absence of G12C, STK11, KEAP1, EGFR, ALK and/or ROS1 mutations in a cancer as described herein can be determined using methods known in the art. Determining whether a tumor or cancer comprises a mutation can be undertaken, for example, by assessing the nucleotide sequence encoding the protein, by assessing the amino acid sequence of the protein, or by assessing the characteristics of a putative mutant protein or any other suitable method known in the art.
  • the nucleotide and amino acid sequences sequence of wild-type human KRAS (nucleotide sequence set forth in Genbank Accession No. BC010502; amino acid sequence set forth in Genbank Accession No.
  • AGC09594 STK11 (Gene ID: 6794; available at www.ncbi.nlm.nih.gov/gene/6794; accessed January 2020), KEAP1 (Gene ID: 9817; available at www.ncbi.nlm.nih.gov/gene/9817; accessed January 2020), EGFR (Gene ID: 1956; available at www.ncbi.nlm.nih.gov/gene/1956; accessed March 2021), ALK (Gene ID: 238; available at www.ncbi.nlm.nih.gov/gene/238; accessed March 2021), and ROS1 (Gene ID: 6098; available at www.ncbi.nlm.nih.
  • Methods for detecting a mutation include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct and/or next generation-based sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • MSA mutant allele-specific PCR amplification
  • samples are evaluated for mutations, such as the KRAS G12C mutation, by real-time PCR.
  • fluorescent probes specific for a certain mutation such as the KRAS G12C mutation
  • the probe binds and fluorescence is detected.
  • the mutation is identified using a direct sequencing method of specific regions in the gene. This technique identifies all possible mutations in the region sequenced.
  • gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and/or arrays can be used to detect the presence or absence of insertion mutations.
  • the methods include, but are not limited to, detection of a mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.
  • a binding agent e.g., an antibody
  • multiplex PCR-based sequencing is used for mutation detection and can include a number of amplicons that provides improved sensitivity of detection of one or more genetic biomarkers.
  • multiplex PCR-based sequencing can include about 60 amplicons (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 amplicons).
  • multiplex PCR-based sequencing can include 61 amplicons.
  • Amplicons produced using multiplex PCR-based sequencing can include nucleic acids having a length from about 15 bp to about 1000 bp (e.g., from about 25 bp to about 1000 bp, from about 35 bp to about 1000 bp, from about 50 bp to about 1000 bp, from about 100 bp to about 1000 bp, from about 250 bp to about 1000 bp, from about 500 bp to about 1000 bp, from about 750 bp to about 1000 bp, from about 15 bp to about 750 bp, from about 15 bp to about 500 bp, from about 15 bp to about 300 bp, from about 15 bp to about 200 bp, from about 15 bp to about 100 bp, from about 15 bp to about 80 bp, from about 15 bp to about 75 bp, from about 15 bp to about 50 bp, from about 15 bp to about 40 bp, from about 15
  • the presence of one or more mutations present in a sample obtained from a patient is detected using sequencing technology (e.g., a next-generation sequencing technology).
  • sequencing technology e.g., a next-generation sequencing technology.
  • methods for detection and characterization of circulating tumor DNA in cell-free DNA can be described elsewhere (see, e.g., Haber and Velculescu, 2014).
  • Non-limiting examples of such techniques include SafeSeqs (see, e.g., Kinde et al., 2011), OnTarget (see, e.g., Forshew et al., 2012), and TamSeq (see, e.g., Thompson et al., 2012).
  • the presence of one or more mutations present in a sample obtained from a patient is detected using droplet digital PCR (ddPCR), a method that is known to be highly sensitive for mutation detection.
  • ddPCR droplet digital PCR
  • the presence of one or more mutations present in a sample obtained from a patient is detected using other sequencing technologies, including but not limited to, chain-termination techniques, shotgun techniques, sequencing-by-synthesis methods, methods that utilize microfluidics, other capture technologies, or any of the other sequencing techniques known in the art that are useful for detection of small amounts of DNA in a sample (e.g., ctDNA in a cell-free DNA sample).
  • the presence of one or more mutations present in a sample obtained from a patient is detected using array-based methods.
  • the step of detecting a genetic alteration (e.g., one or more genetic alterations) in cell-free DNA is performed using a DNA microarray.
  • a DNA microarray can detect one more of a plurality of cancer cell mutations.
  • cell-free DNA is amplified prior to detecting the genetic alteration.
  • array-based methods that can be used in any of the methods described herein, include: a complementary DNA (cDNA) microarray (see, e.g., Kumar et al. 2012; Laere et al.
  • oligonucleotide microarray see, e.g., Kim et al. 2006; Lodes et al. 2009
  • BAC bacterial artificial chromosome
  • SNP single-nucleotide polymorphism
  • the cDNA microarray is an Affymetrix microarray (see, e.g., Irizarry 2003; Dalma-Weiszhausz et al. 2006), a NimbleGen microarray (see, e.g., Wei et al. 2008; Albert et al.
  • the oligonucleotide microarray is a DNA tiling array (see, e.g., Mockler and Ecker, 2005; Bertone et al. 2006).
  • Other suitable array-based methods are known in the art.
  • Methods for determining whether a tumor or cancer comprises a mutation can use a variety of samples.
  • the sample is taken from a patient having a tumor or cancer.
  • the sample is a fresh tumor/cancer sample.
  • the sample is a frozen tumor/cancer sample.
  • the sample is a formalin-fixed paraffin-embedded (FFPE) sample.
  • the sample is a circulating cell-free DNA and/or circulating tumor cell (CTC) sample.
  • the sample is processed to a cell lysate.
  • the sample is processed to DNA or RNA.
  • the sample is acquired by resection, core needle biopsy (CNB), fine needle aspiration (FNA), collection of urine, or collection of hair follicles.
  • CNB core needle biopsy
  • FNA fine needle aspiration
  • collection of urine or collection of hair follicles.
  • a liquid biopsy test using whole blood or cerebral spinal fluid may be used to assess mutation status.
  • a test approved by a regulatory authority such as the US Food and Drug Administration (FDA) is used to determine whether the patient has a mutation, e.g., a KRAS G12C mutated cancer, or whether the tumor or tissue sample obtained from such patient contains cells with a mutation.
  • a regulatory authority such as the US Food and Drug Administration (FDA)
  • FDA US Food and Drug Administration
  • the test for a KRAS mutation used is therascreen® KRAS RGQ PCR Kit (Qiagen).
  • the therascreen® KRAS RGQ PCR Kit is a real-time qualitative PCR assay for the detection of 7 somatic mutations in codons 12 and 13 of the human KRAS oncogene (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) using the Rotor-Gene Q MDx 5plex HRM instrument.
  • the kit is intended for use with DNA extracted from FFPE samples of NSCLC samples acquired by resection, CNB, or FNA.
  • Mutation testing for STK11, KEAP1, EGFR, ALK and/or ROS1 can be conducted with commercially available tests, such as the Resolution Bioscience Resolution ctDx LungTM assay that includes 24 genes (including those actionable in NSCLC). Tissue samples may be tested using Tempus xT 648 panel.
  • the cancer has been identified as having a KRAS G12C mutation. In some embodiments, the cancer has been identified as having a mutation of STK11, e.g., a loss-of-function mutation.
  • the cancer has been identified as having a mutation of KEAP1, e.g., a loss-of-function mutation. In some embodiments, the cancer has been identified as having wild-type STK11. In some embodiments, the cancer has been identified as having wild-type KEAP1.
  • the cancer has been identified as having a loss-of-function mutation of STK11 and wild-type KEAP1. In some embodiments, the cancer has been identified as having a loss-of-function mutation of STK11 and a loss-of-function mutation of KEAP1. In some embodiments, the cancer has been identified as having wild-type of STK11 and wild-type KEAP1. In some embodiments, the cancer has been identified as having wild-type of STK11 and a loss-of-function mutation of KEAP1.
  • loss-of-function mutation refers to a mutation (e.g., a substitution, deletion, truncation, or frameshift mutation) that results in expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological activity or enzymatic activity), results in expression of only a fragment of the protein that no longer exhibits wild-type activity, or results in no expression of the wild-type protein.
  • a mutation e.g., a substitution, deletion, truncation, or frameshift mutation
  • a loss-of-function mutation affecting the STK11 gene in a cell may result in the loss of expression of the STK11 protein, expression of only a fragment of the STK11 protein, or expression of the STK11 protein that exhibits diminished or no enzymatic activity (e.g., no serine/threonine kinase enzymatic activity) in the cancerous cell.
  • enzymatic activity e.g., no serine/threonine kinase enzymatic activity
  • a loss-of-function mutation affecting the KEAP1 gene in a cell may result in the loss of expression of the KEAP1 protein, expression of only a fragment of the KEAP1 protein, or expression of a KEAP1 protein that exhibits diminished or no activity (e.g., inability to interact with or activate Nuclear factor erythroid 2-related factor 2 (NRF2)) in the cell.
  • NEF2 Nuclear factor erythroid 2-related factor 2
  • PD-L1 expression can be determined by methods known in the art.
  • PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with pembrolizumab.
  • IHC in vitro diagnostic immunohistochemistry
  • This is qualitative assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 PD-L1 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in FFPE samples, such as human non-small cell lung cancer tissue.
  • Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining at any intensity.
  • TPS tumor proportion score
  • PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, the FDA- approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Myers Squibb as a companion test for treatment with nivolumab.
  • IHC in vitro diagnostic immunohistochemistry
  • This qualitative assay uses the Monoclonal rabbit anti-PD-L1, Clone 28-8 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissue.
  • FFPE paraffin-embedded
  • Ventana SP263 assay developed by Ventana in collaboration with AstraZeneca
  • monoclonal rabbit anti- PD-L1, Clone SP263 and the Ventana SP142 Assay (developed by Ventana in collaboration with Genentech/Roche) that uses rabbit monoclonal anti-PD-L1 clone SP142.
  • a test approved by a regulatory authority such as the US Food and Drug Administration (FDA) is used to determine the PD-L1 TPS of a cancer as disclosed herein.
  • the PD-L1 TPS is determined using a immunohistochemistry (IHC) test.
  • the IHC test is the PD-L1 IHC 22C3 pharmDx test.
  • the IHC test conducted with samples acquired by, for example, resection, CNB, or FNA.
  • the patient has a PD-L1 TPS of less than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
  • the patient has a PD-L1 TPS of less than 50%, or less than 1%.
  • the patient has a PD-L1 TPS of more than or equal to 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
  • the patient has a PD-L1 TPS of less than or equal to 100%, 95%, 90%, 85%, 80%,
  • the patient has a PD-L1 TPS of less than or equal to 50%, or less than or equal to 1%. In various embodiments, the patient has a PD-L1 TPS of more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,
  • the patient has a PD-L1 TPS score a range bound by any of the values cited in the foregoing embodiments.
  • the patient has a PD-L1 TPS score in the range of less than 50% and more than or equal to 1 %, less than or equal to 50% and more than 1 %, less than or equal to 50% and more than or equal to 1%, or less than 50% and more than 1%.
  • the patient has a PD-L1 TPS score in the range of less than 50% and more than or equal to 1%. In some embodiments, the patient has a PD-L1 TPS score in the range of more than or equal to 0% and less than 1%. In some embodiments, the patient has a PD-L1 TPS score in the range of more than 50% and less than or equal to 100%. In some embodiments, the patient has a PD-L1 TPS score of less than 1%. In some embodiments, the patient as a PD-L1 TPS score of 1-49%. In some embodiments, the patient has a PD-L1 TPS score of 50% or greater (i.e., 50%-100%). Embodiments
  • a method of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and trametinib once daily, wherein the sotorasib and trametinib are administered to the patient in amounts effective to treat the cancer.
  • the anti-EGFR antibody comprises a heavy chain variable region comprising HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.
  • the anti-EGFR antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 5 and a light chain comprising the sequence of SEQ ID NO: 10. 16. The method of embodiment 12, wherein the anti-EGFR antibody is panitumumab.
  • the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • platinum-based chemotherapy comprises fluoropyrimidine, oxaliplatin, or irinotecan.
  • CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, or troglitazone.
  • CYP3A4 substrate is abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizot
  • Example 1 Sotorasib in combination with trametinib and optionally panitumumab
  • Sotorasib at 960 mg QD was shown to be safe and effective under study conditions under Study 20170543 (CodeBreaklOO).
  • the addition of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, to sotorasib, a targeted therapy against mutant KRAS p.G12C may lead to significant inhibition of rat sarcoma viral oncogene homolog/RAF proto oncogene serine/threonine protein kinase/MEK/extracellular signal regulated kinase (RAS/RAF/MEK/ERK) signaling pathway and enhance the anti-tumor activity.
  • MK mitogen-activated protein kinase
  • sotorasib Since resistance to sotorasib may be mediated by upregulation of signaling through epidermal growth factor receptor (EGFR) pathway, adding an EGFR inhibitor to the combination of sotorasib and trametinib may block bypass activation of the mitogen activated kinase (MAPK) signaling and lead to improved anti-tumor activity.
  • MAPK mitogen activated kinase
  • This study will therefore explore sotorasib in combination with trametinib (MEK inhibitor) and sotorasib in combination with trametinib and panitumumab (EGFR targeted monoclonal antibody).
  • the term “subject” is used herein interchangeably with “patient.”
  • a multicenter, open label study is set up to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of sotorasib in combination with trametinib in subjects with KRAS G12C mutant advanced solid tumors or in combination with trametinib and panitumumab in subjects with KRAS G12C mutant advanced solid tumors. Overall, approximately 140 subjects will be enrolled in the study. Sotorasib is administered orally once daily (QD), and trametinib is administered orally QD. Panitumumab is administered as a 60 minute (£ 1000 mg) or 90 minute (> 1000 mg) intravenous (IV) infusion on day 1 every 2 weeks (Q2W).
  • Sotorasib in combination with trametinib is evaluated in Part 1 (dose exploration) and Part 2 (dose expansion).
  • Sotorasib in combination with trametinib and panitumumab is evaluated in Part 3 (dose exploration) and Part 4 (dose expansion).
  • Sotorasib is administered orally QD
  • trametinib is administered orally QD.
  • the sotorasib dose is 960 mg/day. Sotorasib is administered orally QD continuously with or without food for treatment cycles which are defined as 21 days (Part 1 and Part 2) or 28 days (Part 3). Subjects take all of the sotorasib dose as oral tablets at approximately the same time every day. The sotorasib dose should not be taken more than 2 hours earlier than the target time based on previous day’s dose. The sotorasib dose should not be taken more than 6 hours after the dosing time. Take the next dose as prescribed. If vomiting occurs after taking sotorasib, an additional dose should not be taken. The next dose should be taken as prescribed.
  • the trametinib dose is 0.5 to 2 mg/day.
  • Trametinib is administered orally QD continuously with or without food for a treatment cycle of 21 days or 28 days (when administered in combination with panitumumab).
  • panitumumab dose is 3.6 to 6 mg/kg Q2W.
  • Panitumumab is administered as a 60 minute (£
  • Sotorasib is administered orally QD, and trametinib is administered orally QD.
  • Panitumumab is administered as 60 minute (£ 1000 mg) or 90 minute (> 1000 mg) IV infusion Q2W.
  • Part 1 of the study assesses the safety of the selected starting dose of sotorasib in combination with trametinib.
  • the starting dose for sotorasib and trametinib is based on the review of the safety, PK and pharmacodynamic data from the first in human study exploring sotorasib as a monotherapy and the available safety data for trametinib.
  • Dose exploration begins with 2-4 subjects treated at Dose Level 1.
  • the study dose limiting toxicity (DLT) period is 21 days. Once all subjects enrolled at a certain dose level are DLT evaluable, a Dose Level Review Team (DLRT) meeting is convened. Depending on observed safety data, the following occurs: (1) dose escalation to Dose Level 2 or (2) additional enrollment to Dose Level 1 or (3) dose de-escalation to Dose Level -1 .
  • Rules for dose-escalation/de-escalation are derived using a modified Toxicity Probability Interval-2 (mTPI-2) model (Guo et al, 2017) with a target toxicity probability of 0.30.
  • mTPI-2 modified Toxicity Probability Interval-2
  • Re-escalation to Dose Level 1 or Dose Level 2 may be allowed, as appropriate, only in the following instances: 1) 1 of 2 or 1 of 3 evaluable subjects experience a DLT at the applicable dose level 2) 2 of 5 or 2 of 6 evaluable subjects experience a DLT 3) 3 of 8 or 3 of 9 subjects experience a DLT or 4) 4 of 10 subjects experience a DLT. c As appropriate to better understand safety profile for a dose level, the number of evaluable subjects may be expanded up to 10.
  • further degree of dose modification e.g., intermediate doses
  • schedule of administration e.g., alternate dosing
  • MTD maximum tolerated dose
  • isotonic regression Ji et al, 2010
  • the MTD is the dose level with the estimated DLT rate closest to 0.30.
  • -Dose Level 2 is determined to be safe and tolerable (minimum of 6 evaluable subjects overall).
  • Dose Level 1 or Dose Level -1 is determined to be safe and tolerable (minimum of 6 evaluable subjects) and the next higher dose level is determined to be un-safe and intolerable.
  • dose escalation may be halted or modified by the Sponsor as deemed appropriate.
  • Part 2 Upon completing the dose exploration part of the study and depending on data obtained, enrollment will commence in the dose expansion phase (Part 2) to confirm the safety and tolerability of the selected dose and to further evaluate anti-tumor activity.
  • Part 2 consists of 3 groups:
  • -Group 2a consists of subjects with advanced NSCLC with KRAS G12C mutation
  • Group 2b consists of subjects with advanced CRC with KRAS G12C mutation
  • -Group 2c consists of subjects with advanced solid tumors (except NSCLC and CRC) with KRAS G12C mutation
  • R2D phase 2 dose
  • Part 3 of the study assesses the safety of the selected starting dose of sotorasib in combination with trametinib and panitumumab.
  • Dose exploration begins with 3 to 6 subjects treated at Dose Level 1 .
  • the DLT period is 28 days.
  • a DLRT meeting will be convened. Depending on observed safety data, the following may occur: 1) dose escalation to both Dose Level 2A and/or 2B, 2) additional enrollment to Dose Level 1 or 3) dose de-escalation to both Dose Level -1A and/or -1B.
  • Dose Level 2A and/or 2B are initiated, depending on observed safety data, the following may occur: 1) dose escalation to Dose Level 3 if Dose Level 2B is deemed safe and tolerable, 2) additional enrollment to both Dose Level 2A and/or 2B, or 3) de-escalation to Dose Level 1 if Dose Level 2A is deemed not tolerable.
  • Dose Level -1A and/or -1 B is initiated, depending on observed safety data, the following occurs: 1) additional enrollment to Dose Level -1 A and/or -1 B, 2) dose de-escalation to Dose Level -2 if both Dose Level - 1A and -1 B are not tolerable, or 3) re-escalation to Dose Level 1 .
  • DLT - dose limiting toxicity a A subject is evaluable if subject experiences a dose limiting toxicity (DLT) or completes 28 days on treatment and receives D 80% of planned dose of sotorasib, trametinib and panitumumab. A subject without a DLT will not be DLT evaluable if the date of decision to end both investigational products is before the completion of the DLT window.
  • DLT dose limiting toxicity
  • a subject without a DLT will not be DLT evaluable if the date of decision to end both investigational products is before the completion of the DLT window.
  • De-escalate guideline applies only when enrollment is allowed to a lower dose level. Re-escalation to a higher dose level may be allowed, as appropriate, only in the following instances: 1) 2 of 5 or 2 of 6 evaluable subjects experience a DLT or 2) 3 of 8 or 3 of 9 subjects experience a DLT.
  • the current dose level can be expanded or if at least 6 subjects are DLT evaluable at that dose level, it can be declared the maximum tolerated dose (MTD) if deemed safe.
  • MTD maximum tolerated dose
  • further degree of dose modification e.g., intermediate doses
  • schedule of administration e.g., alternate dosing
  • MTD maximum tolerated dose
  • Part 3 ends once any of the following events occur:
  • -Dose Level 3 is determined to be safe and tolerable (minimum of 6 evaluable subjects overall).
  • Dose Level (including any intermediate dose level) Is determined to be safe and tolerable (minimum of 6 evaluable subjects) and the next higher Dose Level (if any) is deemed unsafe and intolerable.
  • dose escalation may be halted or modified by the Sponsor as deemed appropriate.
  • CRC including fluoropyrimidine, oxaliplatin, and irinotecan-based regimens.
  • fluoropyrimidine for those CRC subjects with tumors that are MSI-H, at least 1 of the prior systemic regimens must be treatment with either nivolumab or pembrolizumab if they were clinically able to receive inhibitors and 1 of these agents is approved for that indication in the region or country, or if subject refused standard therapy.
  • Subjects must be willing to undergo tumor biopsy, if medically feasible, before start of treatment and between week 2 to week 5 after starting treatment. If a tumor biopsy prior to treatment is not medically feasible, subjects must be willing to provide archived tissue samples (formalin fixed embedded [FFPR] sample) collected within the past 5 years). Subject who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator if a tumor biopsy is not feasible.
  • FFPR formalin fixed embedded
  • ANC neutrophil count
  • Adequate renal laboratory assessments include measured creatinine clearance or estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation 3 60 mL/min/1 .73 m 2 .
  • Adequate hepatic laboratory assessments are as follows:
  • PT Prothrombin time
  • PTT partial thromboplastin time
  • INR International normalized ratio
  • Cardiac ejection fraction 350%, with no evidence of pericardial effusion as determined by an echocardiogram (ECFIO) or multigated acquisition scan (MUGA).
  • ECFIO echocardiogram
  • MUGA multigated acquisition scan
  • Active brain metastases or leptomeningeal disease from non-brain tumors Subjects who have had brain metastases resected or have received whole brain radiation therapy ending at least 4 weeks (or stereotactic radiosurgery ending at least 2 weeks) prior to study day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms grade £2; b) on stable doses of dexamethasone, if applicable; and c) follow-up MRI performed within 28 days shows no new or enlarging lesions appearing.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events v5.0
  • Active brain metastases can be assessed by the presence of intracranial lesions. It is to be understood that while “metastases” is plural, patients exhibiting only one intracranial lesion under the criteria noted below is a patient who has “active brain metastases.”
  • Gastrointestinal (Gl) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for IV alimentation, uncontrolled inflammatory Gl disease (e.g., Crohn’s disease, ulcerative colitis).
  • HepBsAg Positive Hepatitis B Surface Antigen
  • Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. Detectable Hepatitis C virus RNA suggests chronic hepatitis C.
  • HIV human immunodeficiency virus
  • RVO retinal vein occlusion
  • retinal pigment epithelial detachment or unresolved keratitis.
  • Anti-tumor therapy* (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with breast cancer], or investigational agent) within 28 days of start of study day 1 ; concurrent use of hormone deprivation therapy for hormone refractory prostate cancer or breast cancer is permitted.
  • cytochrome P450 (CYP) 3A4 sensitive substrates or P-glycoprotein (P-gp) substrates both with a narrow therapeutic window or index
  • CYP3A4 sensitive substrates with a narrow therapeutic index include alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, primozide, quinidine, tacrolimus, and sirolimus.
  • P-gp substrates with a narrow therapeutic index include digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, or vincristine.
  • CYP3A4 Use of strong inducers of CYP3A4 (including herbal supplements such as St. John’s wort) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 .
  • Strong inducers of CYP3A4 include rifampin, phenytoin, mitotane, carbamazepine, avasimibe, enzalutamide, rifapentine, St John's Wort extract, apalutamide, lumacaftor, and ivosidenib.
  • Subject has known sensitivity to any of the products or components to be administered during dosing.
  • Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 7 days after the last dose of sotorasib.
  • Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 4 months after the last dose of trametinib.
  • the DLT window (i.e., DLT-evaluable period) will be the first 21 days of sotorasib and trametinib treatment (starting cycle 1 , day 1) for Part 1 or the first 28 days of sotorasib, trametinib, and panitumumab treatment (Part 3).
  • the grading of AEs will be based on the guidelines provide din the CTCAE version 5.0.
  • a subject is DLT evaluable if the subject has completed the DLT window as described above and received 380% of the planned dose of sotorasib and trametinib (and panitumumab, if applicable) or experienced a DLT any time during the DLT window.
  • a subject without a DLT will not be DLT evaluable if the date of decision to end both investigational products is before the completion of the DLT window.
  • DLT is defined as any adverse event meeting the criteria listed below occurring during the first treatment cycle and attributable to sotorasib and/or trametinib and/or panitumumab, if applicable.
  • Hy’s Law case i.e., severe drug-induced liver injury [DILI]
  • DLT severe drug-induced liver injury
  • a Hy’s Law case is defined as: AST or ALT values of 3 3 x ULN AND with serum total bilirubin level (TBL) of > 2 x ULN without signs of cholestasis and with no other clear alternative reason to explain the observed liver related laboratory abnormalities.
  • Dose reduction levels of sotorasib for toxicity management of individual subjects is provided in the following table. Up to two reductions are allowed. Dose reductions below 240 mg are not allowed.
  • Sotorasib will be discontinued, or dosage reduced, in the event of a toxicity that, in the opinion of the investigator, warrants the discontinuation, or dose reduction as indicated in the table below (Sotorasib dose modification guidelines for hematologic and non-hematologic toxicities). Subjects who experience an adverse event requiring dose reductions below 240 mg should be permanently discontinued from sotorasib treatment.
  • panitumumab should be held as well. Trametinib treatment can be continued if sotorasib is held.
  • INR international normalized ratio
  • LFT liver function test
  • TBL total bilirubin
  • ULN upper limit of normal
  • ULOQ upper limits of quantification
  • Hepatotoxicity Response Subjects with abnormal hepatic laboratory values (i.e., alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBL)) and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as described below) may meet the criteria for withholding or permanent discontinuation of sotorasib or other protocol-required therapies, as specified in the Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009.
  • ALP alkaline phosphatase
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • TBL total bilirubin
  • ILR international normalized ratio
  • signs/symptoms of hepatitis as described below
  • AST/ALT and/or TBL values include, but are not limited to: Hepatobiliary tract disease; Viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); Right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; Heritable disorders causing impaired glucuronidation (e.g., Gilbert’s syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indina
  • Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and/or the laboratory abnormalities resolve to normal or baseline, as described in the below.
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • INR international normalized ratio
  • TBL total bilirubin
  • ULN upper limit of normal
  • panitumumab For subjects who experience toxicities while on study, 1 or more doses of panitumumab are withheld, reduced, or delayed (administered at > 14 day intervals). Exemplary panitumumab dose reductions are listed in the table below. [00220] Criteria for Withholding and Discontinuing Dose Modification [00221] Dermatological Toxicity
  • panitumumab dose modification guidelines due to dermatological toxicities are provided in the table below.
  • panitumumab In the event of severe or life-threatening inflammatory or infectious complications, consider withholding or discontinuing panitumumab as clinically appropriate.
  • Proactive skin treatment including skin moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) may be useful in the management of skin toxicities.
  • Subjects may be advised to apply moisturizer and sunscreen to face, hands, feet, neck, back and chest every morning during treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every night.
  • Treatment of skin reactions should be based on severity and may include a moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics, as prescribed by a physician.
  • sunscreen SPF > 15 UVA and UVB
  • topical steroid cream not stronger than 1% hydrocortisone
  • panitumumab In the event of acute onset or worsening of pulmonary symptoms, consider withholding panitumumab. If interstitial lung disease is confirmed, discontinue panitumumab.
  • Ocular Toxicity Monitor for keratitis or ulcerative keratitis. In the event of acute or worsening keratitis, withhold or discontinue panitumumab.
  • panitumumab for any grade 3 or 4 panitumumab-related toxicity with the following exceptions:
  • Panitumumab will only be withheld for symptomatic grade 3 or 4 hypomagnesemia and/or hypocalcemia that persists despite aggressive magnesium and/or calcium replacement
  • Panitumumab will only be withheld for grade 3 or 4 nausea, diarrhea, or vomiting that persists despite maximum supportive care.
  • retinal findings e.g., retinal pigment epithelial detachment (RPED) or retinovascular abnormalities (i.e., branch or central retinal vein occlusions (RVO).
  • RPED retinal pigment epithelial detachment
  • RVO central retinal vein occlusions
  • ADL activities of daily living
  • CTCAE Common Terminology Criteria for Adverse Events
  • RPED retinal pigment epithelial detachment.
  • sotorasib Avoid co-administration of sotorasib with proton pump inhibitors and H2 receptor antagonists. If an acid-reducing agent cannot be avoided, administered sotorasib 4 hours before of 10 hours after a local antacids.
  • BCRP substrates should be used with caution when co administered with sotorasib, which may increase the circulating concentrations of BCRP substrates.
  • the screening scans must be performed within 28 days prior to enrollment and will be used as baseline. Imaging performed as part of standard of care that falls within the 28 day screening window given for scans may be used for the baseline scan as long as it meets the scan requirements for screening. All subsequent scans will be performed in the same manner as at screening, with the same contrast, preferably on the same scanner. Radiological assessment must include CT of the chest, and contrast-enhanced CT or MRI of the abdomen and pelvis, as well as assessment of all other known sites of disease as detailed within the Site Imaging Manual.
  • Radiographic response requires confirmation by a repeat, consecutive scan at least 4 weeks after the first documentation of response and may be delayed until the next scheduled scan to avoid unnecessary procedures.
  • All subjects must have MRI of the brain performed within 28 days prior to first dose of sotorasib. Subsequently, brain scans may be performed at any time if clinically indicated, in the judgement of the managing physician. All brain scans on protocol are required to be MRI unless MRI is contraindicated, and then CT with contrast is acceptable.
  • Radiological imaging assessment at the end of the study or during the end of treatment (EOT) visit should be performed only for subjects that discontinue treatment for a reason other than disease progression per RECIST v1.1 guidelines.
  • Measurable Tumor Lesions - Non-nodal lesions with clear borders that can be accurately measured in at least 1 dimension with longest diameter 3 10 mm in CT/MRI scan with slice thickness no greater than 5 mm. When slice thickness is greater than 5 mm, the minimum size of measurable lesion should be twice the slice thickness.
  • lymph node must be 3 15 mm in short axis when assessed by CT/MRI (scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis is measured and followed. Nodal size is normally reported as two dimensions in the axial plane. The smaller of these measures is the short axis (perpendicular to the longest axis).
  • Non-measurable Lesions All other lesions, including small lesions (longest diameter ⁇ 10 mm or pathological lymph nodes with 3 10 mm but to ⁇ 15 mm short axis with CT scan slice thickness no greater than 5 mm) are considered non-measurable and characterized as non-target lesions.
  • non-measurable lesions include:
  • Measurement of Lesions The longest diameter of selected lesions should be measured in the plane in which the images were acquired (axial plane). All measurements should be taken and recorded in metric notation. All baseline evaluations should be performed as closely as possible to the beginning of treatment and not more than 4 weeks before study Day 1 .
  • Methods of Assessment The same method of assessment and the same technique should be used to characterize each identified and reported lesion throughout the trial.
  • CT / MRI - Contrast-enhanced CT or MRI should be used to assess all lesions. Optimal visualization and measurement of metastasis in solid tumors requires consistent administration (dose and rate) of IV contrast as well as timing of scanning. CT and MRI should be performed with £ 5 mm thick contiguous slices.
  • Target Lesions All measurable lesions up to a maximum of two (2) lesions per organ and five (5) lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline.
  • Target lesions should be selected on the basis of their size (lesions with the longest diameter) and suitability for accurate repeated measurements.
  • Pathologic lymph nodes (with short axis 3 15 mm) may be identified as target lesions. All other pathological nodes (those with short axis 3 10 mm but ⁇ 15 mm) should be considered non-target lesions.
  • a sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions are calculated and reported as the baseline sum of diameters.
  • the baseline sum of diameters are used as reference by which to characterize objective tumor response.
  • Non-T arget Lesions All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, and these lesions should be followed as “present”, “absent”, or “unequivocal progression” throughout the study. In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case report form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).
  • the best overall response is the best response recorded from the start of the study treatment until the end of treatment or disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
  • the subject's best response assignment depends on the findings of both target and non target disease and also take into consideration the appearance of new lesions.
  • Non-CR/non-PD is preferred over “SD” for non-target disease since SD is increasingly used as endpoint for assessment of efficacy in some trials so as to assign this category when no lesions can be measured is not advised.
  • Nodal lesions - Lymph nodes identified as target lesions should always have the actual short axis measurement recorded, even if the nodes regress to below 10 mm on study. In order to qualify for CR, each node must achieve a short axis ⁇ 10 mm, NOT total disappearance. Nodal target lesion short axis measurements are added together with target lesion’ longest diameter measurements to create the sum of target lesion diameters for a particular assessment (time point).
  • Target lesions that become “too small to measure” While on study, all lesions (nodal and non-nodal) recorded at baseline should have their measurements recorded at each subsequent evaluation. If a lesion becomes less than 5 mm, the accuracy of the measurement becomes reduced. Therefore, lesions less than 5 mm are considered as being “too small to measure” and are not measured. With this designation, they are assigned a default measurement of 5mm. No lesion measurement less than 5mm should be recorded, unless a lesion totally disappears and “0” can be recorded for the measurement.
  • New lesions The term “new lesion” always refers to the presence of a new finding that is definitely tumor. New findings that only may be tumor, but may be benign (infection, inflammation, etc.) are not selected as new lesions, until that time when the review is certain they represent tumor.
  • a lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression, regardless of any response that may be seen in target or non-target lesions present from baseline.
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • PET/CT PET/computed tomography
  • fine needle aspirate/biopsy to confirm the CR status.
  • Duration of overall response The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date the recurrent or progressive disease is objectively documented or death, whichever is earlier.
  • Duration of Stable Disease - SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started, or death, whichever is earlier.
  • Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea.
  • Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation or dyspnea.
  • Class IV Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest. If any physical activity is undertaken, discomfort is increased.
  • Preliminary results [00294] Patients with pretreated, KRAS G ⁇ C-mutated NSCLC, CRC or other types of solid tumors were enrolled. In part 1 , sotorasib was given as a fixed oral daily dose of 960 mg. The planned oral daily doses of trametinib were 1 mg (dose level 1), 2 mg (dose level 2), and 0.5 mg (dose level -1). Primary endpoint was safety, including dose-limiting toxicities and adverse events; secondary endpoint was efficacy, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), etc.
  • ORR objective response rate
  • DCR disease control rate
  • DOR duration of response
  • NSCLC NSCLC patients receiving treatment with sotorasib (960 mg) and trametinib (1 mg or 2 mg), 3 patients exhibited a best overall response of partial response (PR), 12 patients exhibited a stable disease (SD) and 2 had a progressive disease (PD).
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • NSCLC of 3 patients that had received prior treatment with a KRAS G12C inhibitor, 2 patients exhibited clinically meaningful tumor shrinkage compared to baseline.
  • sotorasib was given as a fixed oral daily dose of 960 mg.
  • the planned oral daily doses of trametinib were 1 mg or 2 mg.
  • Primary endpoint was safety, including dose-limiting toxicities and adverse events; secondary endpoint was efficacy, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS) per RECIST 1.1.
  • 18 CRC patients (7 of which were previously treated with a KRAS G12C inhibitor) 3 patients received treatment with sotorasib 960 mg and trametinib 1 mg, and 15 patients received sotorasib 960 mg and trametinib 2 mg.
  • 18 NSCLC patients (3 of which were previously treated with a KRAS G12C inhibitor) all received sotorasib 960 mg and trametinib 2 mg.
  • the 5 patients with other solid tumors (2 of which were previously treated with a KRAS G12C inhibitor)
  • 3 received sotorasib 960 mg and trametinib 2 mg The baseline characteristics were as follows:
  • TRAEs 14 patients exhibiting a grade 3 3 TRAE and 2.4% (1 patient) exhibiting a grade 3 4 TRAE.
  • the most common TRAEs included diarrhea (all grades 43.9%, 18 patients, and 33 grade 4.9%, 2 patients); rash (34.1%, 14 patients, all grade £2); dermatitis acneiform (all grades 31.7%, 13 patients, and 33 grade 2.4%, 1 patient); nausea (29.3%, 12 patients, all grade £2); vomiting (22.0%, 9 patients, all grade £2); peripheral edema (19.5%,
  • grade 3 TRAEs reported included dyspnea, erythema muliforme, fatigue, hypertension, hypokalemia, neutropenia, and maculo-papular rash. No new or unexpected toxicities were identified.
  • PK data were available for subjects with advanced solid tumors with the specific KRAS G12C mutation, with doses ranging from 180 to 960 mg PO QD.
  • Dose-related increases in exposure on day 1 from 180 to 960 mg PO QD were observed. Increases in exposure were less than dose- proportional on day 1.
  • the change in exposure from 180 to 960 mg PO QD was less than dose-proportional on day 8. Rapid absorption was observed with tmax between 1 to 2 hours after PO administration.
  • Figure 1 shows the mean plasma concentration time profile after oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1.
  • Figure 2 shows the concentrations after once daily dosing for 8 days (Day 8).
  • the table below provides the pharmacokinetic parameters, where AUCo-24h is the area under the concentration-time curve from time 0 to 24 hr postdose; C ma x is the maximum observed drug concentration during a dosing interval; ti/2, z is the terminal elimination half-life; t ma x is the time to reach C ma x.
  • Data reported are presented as geometric mean (arithmetic CV%) except ax and , which are reported as a median (range) and arithmetic mean (SD), respectively. Values are reported to three significant figures, except CV% and t ma x, which are reported to 0 decimal places and 2 significant figures, respectively.
  • Example 3 - Acquired resistance to sotorasib can be reversed with combination therapy with a MEK inhibitor
  • a patient with stage IV NSCLC was initially treated with carboplatin/pemetrexed/pembrolizumab followed by maintenance pemetrexed/pembrolizumab. This regimen lead to a partial radiologic response lasting for nearly one year.
  • the patient was treated with sotorasib 960mg and had a confirmed partial response lasting 5.6 months.
  • sotorasib monotherapy (ending on day 168) the patient was briefly treated with several lines of standard therapy, including ipilimumab/nivolumab, gemcitabine/vinorelbine and docetaxel/ramumirumab, without experiencing significant clinical or radiologic benefit.
  • the patient started sotorasib (960 mg) in combination with trametinib (2 mg) and had a partial response to therapy (unconfirmed timepoint response). The treatment has been well- tolerated without any adverse events leading to dose modifications.
  • Example 5 Contraindication with co-administration of sotorasib with acid-reducing agents under fed conditions
  • Geometric least-square mean ratios of sotorasib AUCinf and C max were 0.622 and 0.654, respectively when comparing sotorasib coadministered with famotidine and sotorasib alone under fed conditions.
  • Geometric least-square mean ratios of sotorasib AUCM and C max were 0.430 and 0.349, respectively, when comparing sotorasib coadministered with omeprazole and sotorasib alone.
  • Doses of 960 mg sotorasib were safe and well tolerated with coadm concluded with a single dose of 40 mg famotidine and following multiple daily dosing of 40 mg omeprazole under fed conditions to healthy subjects.
  • This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 960 mg sotorasib on Days 1, 3 and 18, and 600 mg rifampin on Day 3 and Days 5 to 19. Blood samples for sotorasib PK were collected predose and up to 48 hours post-sotorasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
  • Geometric mean sotorasib AUCM area under the curve from time zero to infinity
  • C max maximal plasma concentration following coadministration of single dose of rifampin with sotorasib (19600 h*ng/mL and 5340 ng/mL, respectively)
  • Geometric mean sotorasib AUCM and C max following coadministration of multiple doses of rifampin with sotorasib (12400 h*ng/mL and 4110 ng/mL, respectively) were lower compared to those of sotorasib alone (25600 h*ng/mL and 6350 ng/mL, respectively).
  • Sotorasib was safe and well tolerated when coadministered with 600 mg rifampin or administered alone to healthy subjects.
  • Single dose of rifampin did not have a clinically meaningful effect on sotorasib PK indicating sotorasib is not a substrate of OATP1 B1.
  • Multiple doses of rifampin decreased sotorasib AUCin f by 51% and C max by 35%, indicating sotorasib is a CYP3A4 substrate, consistent with in vitro data.
  • This Phase 1 open-label, fixed-sequence study enrolled 5 subjects with previously untreated NSCLC who received a single, oral dose of 2 mg midazolam alone of day -1, 960 mg sotorasib orally on days 1 through 14, and a single oral dose of 2 mg midazolam at approximately the same time as an oral dose of 960 mg sotorasib on day 15.
  • Blood samples for sotorasib PK were collected predose and up to 48 hours post-sotorasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
  • This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 0.5 mg digoxin on Day 1 and 960 mg sotorasib followed by 0.5 mg digoxin on Day 7. Blood samples for digoxin PK were collected predose and up to 144 hours post-digoxin dose. Samples were measured using validated high-performance liquid chromatography tandem mass spectrometry methods. PK parameters were estimated using non-compartmental methods. Safety and tolerability were monitored throughout the study. [00326] Digoxin median time to maximal plasma concentration (t ma x) and mean terminal half-life (tic) were similar following coadministration of digoxin with sotorasib compared to those of digoxin alone.
  • Geometric mean digoxin AUCinf (area under the curve from time zero to infinity) following coadministration of digoxin with sotorasib (40.3 h*ng/mL) was similar to that of digoxin alone (33.2 h*ng/mL).
  • Geometric mean digoxin C ma x (maximal plasma concentration) following coadministration of digoxin with sotorasib (3.64 ng/mL) was higher compared to that of digoxin alone (1 .90 ng/mL).
  • Single doses of 0.5 mg digoxin were safe and well tolerated when administered alone or coadministered with 960 mg sotorasib.
  • VECTIBIX® US Prescribing Information Amgen Inc., Thousand Oaks, California, 91320, revision/2017

Abstract

Provided herein are methods of treating cancer comprising a KRAS G12C mutation in a patient comprising orally administering to the patient sotorasib and trametinib once daily, wherein the sotorasib and trametinib are administered to the patient in amounts effective to treat the cancer in the patient. Further provided herein are methods further comprising administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient.

Description

METHODS OF TREATING CANCER WITH A COMBINATION OF SOTORASIB AND TRAMETINIB
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/197,685, filed June 7, 2021, and U.S. Provisional Patent Application No. 63/249,334, filed September 28, 2021, each of which is incorporated herein by reference in its entirety.
INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY
[0002] The name of the text file containing the Sequence Listing is “A-2729-US-PSP_55327P_Seqlisting.txt", which was created on June 4, 2021 , and is 9,492 bytes in size. The subject matter of the Sequence Listing is incorporated herein in its entirety by reference.
BACKGROUND
[0003] The rat sarcoma (RAS) proto-oncogene has been identified as an oncogenic driver of tumorigenesis in cancers, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The RAS family consists of 3 closely related genes that express guanosine triphosphate (GTP)-ases responsible for regulating cellular proliferation and survival. The RAS proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS) can be mutationally activated at codons 12, 13, or 61, leading to human cancers. Different tumor types are associated with mutations in certain isoforms of RAS, with KRAS being the most frequently mutated isoform in most cancers. While the role of KRAS mutations in human cancers has been known for decades, no anti-cancer therapies specifically targeting KRAS mutations have been successfully developed, until recently, largely because the protein had been considered intractable for inhibition by small molecules.
SUMMARY
[0004] Described herein are methods of treating cancer comprising a KRAS G12C mutation in a patient comprising orally administering to the patient sotorasib and trametinib once daily, wherein the sotorasib and trametinib are administered to the patient in amounts effective to treat the cancer in the patient. In some embodiments, the methods further comprise administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient. In some embodiments, the anti-EGFR antibody comprises a heavy chain variable region comprising heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8. In some embodiments, the heavy chain variable region comprises the sequence of SEQ ID NO: 4 and the light chain variable region comprises the sequence of SEQ ID NO: 9. In some embodiments, the anti-EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10. In some embodiments, the anti-EGFR antibody is panitumumab. [0005] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, and in some cases, is metastatic or locally advanced. In various embodiments, the cancer is colorectal cancer. In various embodiments, the cancer is pancreatic cancer. In various embodiments, the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
BRIEF DESCRIPTION OF THE FIGURES
[0006] Figure 1 shows the mean plasma concentration time profile after once daily oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1 , where N indicates number of observations across data points.
[0007] Figure 2 shows the mean plasma concentration time profile after once daily oral administration of 180, 360, 720, or 960 mg sotorasib on Day 8, where N indicates number of observations across data points.
DETAILED DESCRIPTION
[0008] Provided herein are methods of treating cancer comprising a KRAS G12C mutation in a patient comprising administering sotorasib and trametinib (a MEK inhibitor) to the patient in an amount effective to treat the cancer. In some embodiments, the methods further comprise administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient.
[0009] The methods of treatment disclosed herein regarding administration of two or more therapeutics (e.g., sotorasib, trametinib) to a patient include concomitant administration of the therapeutics (e.g., within 1 hour, within 45 minutes, within 30 minutes, within 15 minutes, or within 10 minutes of each other), and sequential administration (e.g., administration separated by at least 1 hour, or at least two hours, or at least four hours, or at least six hours, or at least eight hours, or at least twelve hours, or at least 24 hours, or at least 2 days, or at least 3 days). Unless otherwise described herein, combination therapy of two or more therapeutics as discussed herein include both concomitant and sequential administration.
[0010] Sotorasib
[0011] Sotorasib is a small molecule that irreversibly inhibits the KRASG12C mutant protein. Sotorasib is also referred to as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1/W)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4- [(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-cf]pyrimidin-2(1/-/)-one and has the following structure:
Figure imgf000004_0001
[0012] Sotorasib binds to the P2 pocket of KRAS adjacent to the mutant cysteine at position 12 and the nucleotide-binding pocket. The inhibitor contains a thiol reactive portion which covalently modifies the cysteine residue and locks KRASG12C in an inactive, guanosine diphosphate (GDP) bound conformation. This blocks the interaction of KRAS with effectors such as rapidly accelerated fibrosarcoma (RAF), thereby preventing downstream signaling, including the phosphorylation of extracellular signal regulated kinase (ERK) (Cully and Downward, 2008; Ostrem et al., 2013; Simanshu et al., 2017). Inactivation of KRAS by RNA interference (RNAi) or small molecule inhibition has previously demonstrated an inhibition of cell growth and induction of apoptosis in tumor cell lines and xenografts harboring KRAS mutations (including the KRAS G12C mutation) (Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016). Studies with sotorasib have confirmed these in vitro findings and have likewise demonstrated inhibition of growth and regression of cells and tumors harboring KRAS G12C mutations (Canon et al., 2019). See also, LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 5/2021), which is herein incorporated by reference in its entirety.
[0013] Trametinib
[0014] Trametinib is a pyrido-pyrimidine derivative that is a potent and highly selective allosteric non competitive inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and kinase 2 (MEK2) activation and kinase activity (Gilmartin et al, 2011). Trametinib, marketed as MEKINIST®, has a structure of
Figure imgf000005_0001
[0015] Trametinib has potent anti-proliferative activity against multiple cancer cell lines, but has minimal effect on normal, non-proliferating cells. Trametinib is indicated, for example, as a monotherapy or in combination with dabrafenib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutation as detected by a Food and Drug Administration (FDA) approved test. Trametinib in combination with dabrafenib is also indicated in patients with metastatic non-small cell lung cancer with BRAF V600E mutation as detected by an FDA-approved test (Falchook et al, 2012, Flaherty et al, 2012). See also,
MEKINIST® US Prescribing Information, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, (revision 5/2021), which is herein incorporated by reference in its entirety.
[0016] Anti-EGFR antibody
[0017] In some embodiments, the methods further comprise administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient. In some embodiments, the anti-EGFR antibody comprises a heavy chain variable region comprising heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8. In some embodiments, the heavy chain variable region comprises the sequence of SEQ ID NO: 4 and the light chain variable region comprises the sequence of SEQ ID NO: 9. In some embodiments, the anti-EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10. In some embodiments, the anti-EGFR antibody is panitumumab.
[0018] Panitumumab is a fully human immunoglobulin (lg)G2 monoclonal antibody to the epidermal growth factor receptor (EGFR). Panitumumab binds to the extracellular domain of EGFR, thus preventing its activation and intracellular signaling.
[0019] Panitumumab (VECTIBIX®) has been approved for the treatment of patients with wild-type RAS (in both KRAS and NRAS as determined by an FDA approved test for this use) metastatic colorectal cancer (mCRC) as first line therapy in combination with FOLFOX (leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin) and as monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin and irinotecan-containing chemotherapy. The recommended dose is 6 mg/kg, administered as an IV infusion over 60 minutes (£ 1000 mg) or 90 minutes (> 1000 mg), Q2W. See also, VECTIBIX® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 6/2017)), which is herein incorporated by reference in its entirety.
[0020] Dosing Regimens
[0021] In some embodiments, the methods comprise administering sotorasib in an amount ranging from 240 mg to 960 mg. In some embodiments, the methods comprise administering 960 mg sotorasib to the patient once daily. In some embodiments, the methods comprise administering 240 mg to the patient once daily. In some embodiments, the methods comprise administering 480 mg to the patient twice daily. In some embodiments, the methods comprise administering 240 mg to the patient twice daily.
[0022] In some embodiments, the methods comprise administering trametinib in an amount ranging from 0.5 mg - 2 mg (e.g., 0.5 mg, 0.6 mg, 0,7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.5 mg, 1.6 mg, 1.7 mg,
1 .8 mg, 1 .9 mg, or 2 mg) In some embodiments, the methods comprise administering 1 mg trametinib to the patient. In some embodiments, the methods comprise 2 mg trametinib to the patient. In some embodiments, 0.5 mg trametinib to the patient.
[0023] In some embodiments, the methods comprise orally administering 960 mg sotorasib and trametinib in an amount ranging from 0.5 mg - 2 mg (e.g., 0.5 mg, 0.6 mg, 0,7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1 .5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1 .9 mg, or 2 mg) once daily to the patient. In some embodiments, the methods comprise orally administering 960 mg sotorasib and 0.5 mg trametinib once daily to the patient. In some embodiments, the methods comprise orally administering 960 mg sotorasib and 1 mg trametinib once daily to the patient. In some embodiments, the methods comprise orally administering 960 mg sotorasib and 2 mg trametinib once daily to the patient. [0024] In some embodiments, the treatment cycle is at least 21 days. In some embodiments, the treatment cycle is 28 days or less. In some embodiments, the treatment cycle is between 21 and 28 days in length. In some embodiments, the treatment cycle is 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days or 28 days in length. In some embodiments, the treatment cycle is 28 days. In some embodiments, the patient is treated for one or more treatment cycles. In various embodiments, a patient can undergo two or more treatment cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more treatment cycles, or more specifically 1 to 20, 2 to 15, or 2 to 10 treatment cycles, depending upon the response of the patient to the treatment and the consideration of the attending clinician.
[0025] In some embodiments, the methods described herein further comprise administering panitumumab to the patient once every two weeks. In some embodiments, the methods further comprise administering panitumumab in an amount ranging from 3.6 mg/kg to 6 mg/kg (e.g., 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/kg, 4.0 mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg, 4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg,
5 mg/kg, 5.1 mg.kg, 5.2 mg/kg, 5.3 mg/kg, 5.4 mg/kg, 5.5 mg/kg, 5.6 mg/kg, 5.7 mg/kg, 5.8 mg/kg, 5.9 mg/kg, or
6 mg/kg) via IV administration once every two weeks. In some embodiments, In some embodiments, the methods further comprise administering 6 mg/kg panitumumab. In some embodiments, the methods further comprise administering 4.8 mg/kg panitumumab. In some embodiments, the methods further comprise administering 3.6 mg/kg panitumumab.
[0026] In some embodiments, the methods described herein comprise administering (a) 960 mg sotorasib orally and trametinib in an amount ranging from 0.5 mg - 2 mg (e.g., 0.5 mg, 0.6 mg, 0,7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2 mg) once daily to the patient; and (b) panitumumab in an amount ranging from 3.6 mg/kg to 6 mg/kg (e.g., 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/kg, 4.0 mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg, 4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg,
5 mg/kg, 5.1 mg.kg, 5.2 mg/kg, 5.3 mg/kg, 5.4 mg/kg, 5.5 mg/kg, 5.6 mg/kg, 5.7 mg/kg, 5.8 mg/kg, 5.9 mg/kg, or
6 mg/kg) via IV administration once every two weeks.
[0027] In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and (b) 4.8 mg/kg panitumumab via IV administration every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and (b) 6 mg/kg panitumumab via IV administration every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1.5 mg trametinib orally once daily; and (b) 6 mg/kg panitumumab via IV administration every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 2 mg trametinib orally once daily; and (b) 6 mg/kg IV panitumumab via IV administration every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and (b) 4.8 mg/kg panitumumab via IV administration every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and (b) 3.6 mg/kg panitumumab via IV administration once every two weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and (b) 3.6 mg/kg panitumumab via IV administration once every two weeks.
[0028] In various embodiments, sotorasib is administered with food. In various embodiments, sotorasib is administered without food. In various embodiments trametinib is administered at least 1 hour (e.g., 1 hour, 2 hours, 3 hours, and 4 hours) before a meal. In various embodiments, trametinib is administered at least 2 hours (e.g., 2 hours, 3 hours, 4 hours, and 5 hours) after a meal.
[0029] In various embodiments, the patient is in further need of treatment with an acid-reducing agent. Acid- reducing agents include, but are not limited to, a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), and a locally acting antacid. In some embodiments, the patient is further in need of treatment with a PPI or a H2RA. Exemplary PPIs include, but are not limited to, omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. Exemplary H2RAs include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine, roxatidine and lafutidine. Exemplary locally acting antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide. In some embodiments, the patient, who is in further need of treatment with an acid reducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib. In some embodiments, the patient, who is in further need of treatment with an acid-reducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib, but is administered a locally acting antacid in combination with sotorasib. In some embodiments, sotorasib is administered about 4 hours before or about 10 hours after a locally acting antacid.
[0030] In various embodiments, the patient is in further need of treatment with a CYP3A4 inducer. In some embodiments, the patient is not administered a CYP3A4 inducer in combination with sotorasib. Exemplary CYP3A4 inducers include, but are not limited to, barbiturates, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, and troglitazone. See, e.g., Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), www.drug-interactions.medicine.iu.edu, accessed May 2021 . In some embodiments, the patient is not administered a strong CYP3A4 inducer in combination with sotorasib.
Exemplary strong CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates- inhibitors-and-inducers, accessed May 2021. In some embodiments, strong CYP3A4 inducers include, but are not limited to, rifampin, phenytoin, mitotane, carbamazepine, avasimibe, enzalutamide, rifapentine, St John's Wort extract, apalutamide, lumacaftor, and ivosidenib.
[0031] In various embodiments, the patient is in further need of treatment with a CYP3A4 substrate. In some embodiments, the patient is not administered a CYP3A4 substrate in combination with sotorasib. Exemplary CYP3A4 substrates include, but are not limited to, abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib, cyclosporine, dabrafenib, daclatasvir, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, dolutegravir, domperidone, doxepin, elagolix, elbasvir/grazoprevir, eliglustat, enzalutamide, eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, imatinib (GLEEVEC©), haloperidol, hydrocortisone, ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isavuconazonium, ivabradine, ivacaftor, lansoprazole, lenvatinib, lercanidipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, midazolam, naldemedine, naloxegol, nateglinide, nelfinavir, neratinib, netupitant/palonosetron, nevirapine, nifedipine, nisoldipine, nitrendipine, olaparib, omeprazole, ondansetron, osimertinib, ospemifene, palbociclib, panobinostat, pantoprazole, perampanel, pimavanserin, pimozide, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, ribociclib, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast, rolapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus, sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus(fk506), tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, vilazodone, vincristine, vorapaxar, voriconazole, zaleplon, and ziprasidone. See, e.g., Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), https://drug- interactions.medicine.iu.edu, accessed May 2021 . In some embodiments, CYP3A4 substrates with a narrow therapeutic index, include but are not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, primozide, quinidine, tacrolimus, and sirolimus.
[0032] In various embodiments, the patient is in further need of treatment with a P-glycoprotein (P-gp) substrate. In some embodiments, the patient is not administered a P-gp substrate in combination with sotorasib. Exemplary P-gp substrates include, but are not limited to, dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine. See, e.g., www.fda.gov/drugs/drug-interactions- labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed May 2021 .
In some embodiments, the patient is not administered a P-gp substrate in combination with sotorasib, wherein the P-gp substrate is a P-gp substrate with a narrow therapeutic index. Exemplary P-gp substrates with a narrow therapeutic index include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, and vincristine. In some embodiments, p-gp substrates with a narrow therapeutic index include, but are not limited to, digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, and vincristine.
[0033] In various embodiments, the patient has a cancer that was determined to have one or more cells expressing the KRASG12C mutant protein prior to administration of sotorasib as disclosed herein. Determination of KRASG12C mutant protein can be assessed as described elsewhere in this disclosure. [0034] In some embodiments, the patient administered sotorasib in the methods described herein have been previously treated with a different anti-cancer therapy, e.g., at least one - such as one, or two, or three - other systemic cancer therapy. In some embodiments, the patient had previously been treated with one other systemic cancer therapy, such that the sotorasib therapy is a second line therapy. In some embodiments, the patient had previously been treated with two other systemic cancer therapies, such that the sotorasib therapy as provided herein is a third line therapy.
[0035] In some embodiments, the prior systemic cancer therapy is a therapy with a KRASG12C inhibitor. In certain embodiments, the patient exhibits reduced sensitivity to a therapy with a KRASG12C inhibitor. In some embodiments, the patient is resistant to a therapy with a KRASG12C inhibitor. In some embodiments, KRASG12C inhibitor is sotorasib, adagrasib, GDC-6036, D-1553, JDQ443, LY3484356, BI1823911, JAB-21822, RMC-6291, or APG-1842. In certain embodiments the KRASG12C inhibitor is sotorasib. In certain embodiments, the KRASG12C inhibitor is adagrasib. In some embodiments, the therapy is monotherapy. In one embodiment, the therapy with a KRASG12C inhibitor is sotorasib monotherapy. In another embodiment, the therapy with a KRASG12C inhibitor is monotherapy with adagrasib.
[0036] As used herein “sensitivity” refers to the way a cancer reacts to a drug, e.g., sotorasib. In exemplary aspects, “sensitivity” means “responsive to treatment” and the concepts of “sensitivity” and “responsiveness” are positively associated in that a cancer or tumor that is responsive to a drug treatment is said to be sensitive to that drug. “Sensitivity” in exemplary instances is defined according to Pelikan, Edward, Glossary of Terms and Symbols used in Pharmacology (Pharmacology and Experimental Therapeutics Department Glossary at Boston University School of Medicine), as the ability of a population, an individual or a tissue, relative to the abilities of others, to respond in a qualitatively normal fashion to a particular drug dose. The smaller the dose required producing an effect, the more sensitive is the responding system. “Sensitivity” may be measured or described quantitatively in terms of the point of intersection of a dose-effect curve with the axis of abscissal values or a line parallel to it; such a point corresponds to the dose just required to produce a given degree of effect. In analogy to this, the “sensitivity” of a measuring system is defined as the lowest input (smallest dose) required producing a given degree of output (effect). In exemplary aspects, “sensitivity” is opposite to “resistance” and the concept of “resistance” is negatively associated with “sensitivity”. For example, a cancer that is resistant to a drug treatment is either not sensitive nor responsive to that drug or was initially sensitive to the drug and is no longer sensitive upon acquiring resistance; that drug is not or no longer an effective treatment for that tumor or cancer cell.
[0037] Prior systemic cancer therapies include, but are not limited to, chemotherapies and immunotherapies. Specific contemplated prior systemic cancer therapies include, but are not limited to, anti-PD1 therapy, anti-PDL1 therapy, and platinum based chemotherapy. Some examples of anti-PD1 therapy and anti-PDL1 therapies include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, tisielizumab, toripalimab, aspartalizumab, dostarlimab, retifanlimab, simtilimab, pidilizumab atezolizumab, avelumab, durvalumab, and zeluvalimab (AMG 404). In some embodiments, the anti-PD1 therapy includes, but is not limited to, balstilimab, budigalimab, cadonilimab, camrelizumab, cetrelimab, cemiplimab, dostarlimab, ezabenlimab, finotonlimab, nivolumab, penpulimab, pembrolizumab, pucotenlimab, retifanlimab, rulonilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, toripalimab, zeluvalimab (AMG 404), and zimberelimab. In some embodiments, the anti-PD1 therapy include, but is not limited to, cemiplimab, dostarlimab, pembrolizumab, or nivolumab. In some embodiments, the anti-PD1 therapy is pembrolizumab (KEYTRUDA®). In some embodiments, the anti-PD-L1 therapy includes, but is not limited to, adebrelimab, atezolizumab, avelumab, cosibelimab, durvalumab, envafolimab, erfonrilimab, garivulimab, lodapolimab, opucolimab, sugemalimab, socazolimab, and tagitanlimab. In some embodiments, the anti-PD-L1 therapy includes, but is not limited to, atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), and avelumab (BAVENCIO®). Some examples of platinum based chemotherapies include, but are not limited to, carboplatin, oxaliplatin, cisplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin, ProLindac, and aroplatin.
[0038] In some embodiments, the patient has previously been administered a systemic cancer therapy that is a targeted therapy if the cancer was identified to have an actionable oncogenic driver mutation in the epidermal growth factor receptor gene ( EGFR ), anaplastic lymphoma kinase gene (ALK), and/or ROS proto-oncogene 1 (ROS1). Targeted therapies for EGFR mutations include, but are not limited to, cetuximab, panitumumab, erlotinib, gefitinib, and afatinib. Targeted therapies for ALK mutations include, but are not limited to, crizotinib, entrectinib, lorlatinib, repotrectinib, brigatinib, alkotinib, alectinib, ensartinib, and ceritinib. Targeted therapies for ROS1 mutations include, but are not limited to, crizotinib, entrecetinib, ensartinib, alkotinib, brigatinib, taletrectinib, cabozantinib, repotrectinib, lorlatinib, and ceritinib.
[0039] In various embodiments, the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (see, e.g., Zubrod et al., 1960). Status 0 indicates fully active and able to carry on all pre-disease performance without restriction. Status 1 indicates restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. Status 2 indicates ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours. Status 3 indicates capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. Status 4 indicates completely disabled, cannot carry on any selfcare and totally confined to bed or chair. Status 5 indicates death.
[0040] Adverse Events
[0041] In some embodiments, the methods comprise administering a reduced total daily dose of sotorasib when the patient experiences an adverse event to the initial total daily dose. For example, in some embodiments, the initial daily dose is 960 mg sotorasib and the reduced total daily dose is 480 mg sotorasib. In some embodiments, the initial daily dose is 480 mg sotorasib and the reduced total daily dose is 240 mg sotorasib. In some embodiments, the methods further comprise administering a second reduced total daily dose of sotorasib when the patient experiences an adverse event to the reduced total daily dose. [0042] The term “adverse event” or “(AE)” as used herein refers to any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may be considered related to the medical treatment or procedure.
[0043] In some embodiments, the adverse event is hepatotoxicity (e.g., elevation of liver enzymes), interstitial lung disease (ILD)/pneumonitis, diarrhea, and/or nausea/vomiting.
[0044] Hepatotoxicity
[0045] In some embodiments, the adverse event is hepatotoxicity. The term “hepatotoxicity” as used herein refers to a patient having abnormal laboratory values of liver biomarkers (e.g., alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine aminotransferase (ALT), and/or total bilirubin (TBL)), when the patient had baseline levels of the liver biomarker(s) prior to sotorasib administration that were not abnormal laboratory values or were lower than those measured after administration of sotorasib.
[0046] Alanine transaminase (ALT), also called serum glutamic pyruvate transaminase (SGPT) or alanine aminotransferase (ALAT), catalyzes the transfer of an amino group from alanine to a-ketoglutarate to produce pyruvate and glutamate. When the liver is damaged, levels of ALT in the blood can rise due to the leaking of ALT into the blood from damaged or necrosed hepatocytes.
[0047] Aspartate transaminase (AST) also called serum glutamic oxaloacetic transaminase (SGOT or GOT) or aspartate aminotransferase (ASAT), catalyzes the transfer of an amino group from aspartate to a-ketoglutarate to produce oxaloacetate and glutamate. AST can increase in response to liver damage. Elevated AST also can result from damage to other sources, including red blood cells, cardiac muscle, skeletal muscle, kidney tissue, and brain tissue. The ratio of AST to ALT can be used as a biomarker of liver damage.
[0048] Bilirubin is a catabolite of heme that is cleared from the body by the liver. Conjugation of bilirubin to glucuronic acid by hepatocytes produces direct bilirubin, a water-soluble product that is readily cleared from the body. Indirect bilirubin is unconjugated, and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin can be indicative of liver impairment.
[0049] Alkaline phosphatase (ALP) hydrolyzes phosphate groups from various molecules and is present in the cells lining the biliary ducts of the liver. ALP levels in plasma can rise in response to liver damage and are higher in growing children and elderly patients with Paget's disease. However, elevated ALP levels usually reflect biliary tree disease.
[0050] In some embodiments, the patient is not suffering from a disorder that results in elevated liver biomarkers. Disorders associated with elevated liver biomarkers (such as AST/ALT and/or TBL values) include, but are not limited to, hepatobiliary tract disease; viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; heritable disorders causing impaired glucuronidation (e.g., Gilbert’s syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); alpha-one antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson’s disease and hemochromatosis; nonalcoholic fatty liver disease including steatohepatitis; and/or non-hepatic causes (e.g., rhabdomyolysis, hemolysis).
[0051] Prior to receiving sotorasib, the baseline liver function of the patient can be assessed by various means known in the art, such as blood chemistry tests measuring biomarkers of liver function. In some embodiments, the methods described herein comprise monitoring liver biomarkers in the patient and withholding sotorasib administration in patients having > Grade 2 abnormal liver function, as assessed by levels of AST and/or ALT. In such embodiments, sotorasib administration is paused until the AST and/or ALT levels in the patient improve(s) to Grade 1 or better (baseline).
[0052] Adverse effect Grades for abnormal liver function are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 1 . See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017, by the National Cancer Institute, incorporated herein by reference in its entirety.
[0053] Table 1.
Figure imgf000013_0001
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal; WNL= within normal limits
[0054] Grade 0 levels are characterized by biomarker levels within normal limits (WNL). "Normal" liver function, as used herein, refers to Grade 0 adverse effects. "Abnormal" liver function, as used herein, refers to Grade 1 and above adverse effects.
[0055] "Grade 1 liver function abnormalities" include elevations in ALT or AST greater than the ULN and less than or equal to 3-times the ULN if baseline was normal; 1.5 - 3. O x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of bilirubin levels greater than the ULN and less than or equal to 1.5-times the ULN if baseline was normal; > 1.0 - 1.5 x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of ALP greater than the ULN and less than or equal to 2.5-times the ULN if baseline was normal; > 2.0 - 2.5 x baseline if baseline was abnormal.
[0056] "Grade 2 liver function abnormalities" include elevations in ALT or AST greater than 3-times and less than or equal to 5-times the upper limit of normal (ULN) if baseline was normal; >3.0 - 5.0 x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than 1 .5- times and less than or equal to 3-times the ULN if baseline was normal; > 1.5 - 3. O x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of ALP greater than 2.5-times and less than or equal to 5-times the ULN if baseline was normal; > 2.5 - 5.0 x baseline if baseline was abnormal.
[0057] "Grade 3 liver function abnormalities" include elevations in ALT, AST, or ALP greater than 5-times and less than or equal to 20-times the ULN if baseline was normal; >5.0 - 20.0 x baseline if baseline was abnormal. Grade 3 liver function abnormalities also include elevations of bilirubin levels greater than 3-times and less than or equal to 10-times the ULN if baseline was normal; > 3.0 - 10 x baseline if baseline was abnormal.
[0058] "Grade 4 liver function abnormalities" include elevations in ALT, AST, or ALP greater than 20-times the ULN if baseline was normal; > 20 x baseline if baseline was abnormal. Grade 4 liver function abnormalities also include elevations of bilirubin levels greater than 10 times the ULN if baseline was normal; > 10.0 x baseline if baseline was abnormal.
[0059] The ULN for various indicators of liver function depends on the assay used, the patient population, and each laboratory's normal range of values for the specified biomarker, but can readily be determined by the skilled practitioner. Exemplary values for normal ranges for a healthy adult population are set forth in Table 2 below.
See Cecil Textbook of Medicine, pp. 2317-2341, W.B. Saunders & Co. (1985).
[0060] Table 2. - Upper Limit of Normal (ULN) Values
Figure imgf000014_0001
[0061] In any of the methods described herein, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the AST and/or ALT level(s) in the patient is/are elevated, e.g., to a Grade 2 or Grade 3 level, where the baseline AST and/or ALT levels of the patient were below Grade 2 or Grade 3 levels. In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg), when the AST and/or ALT level(s) in the patient is/are elevated is to a Grade 1 level, wherein the baseline AST and/or ALT levels of the patient were below Grade 1 levels.
[0062] Alternatively, in any of the methods disclosed herein, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when (1) AST and bilirubin levels in the patient are elevated, or (2) when AST or ALP levels in the patient are elevated, or (3) when ALT and bilirubin levels in the patient are elevated, or (4) when ALT and ALP levels in the patient are elevated, or (5) when bilirubin and ALP levels in the patient are elevated, e.g., to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline AST, bilirubin, ALP, and/or ALT levels of the patient were below Grade 1 , Grade 2, Grade 3 or Grade 4 levels, respectively. Alternatively, in any of the methods disclosed herein, three biomarkers of liver function may be elevated in the patient (e.g., ALT and AST and bilirubin, or ALT and AST and ALP) to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline biomarker levels of the patient were below Grade 1, Grade 2, Grade 3 or Grade 4 levels, respectively.
[0063] In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 3 times compared to the upper limit of normal (ULN). In a related embodiment, the abnormal level of ALT and/or AST is greater than about 3- to about 5-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 2 abnormality is an abnormal level of ALT and/or AST greater than about 3-fold to about 5-fold increase compared to baseline. In some embodiments, the abnormal level of ALP is greater than about 2.5- to about 5-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 2 abnormality is an abnormal level of ALP greater than about 2.5-fold to about 5-fold increase compared to baseline. In some embodiments, the abnormal level of bilirubin is greater than about 1 .5- to about 3-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 2 abnormality is an abnormal level of bilirubin greater than about 1 .5-fold to about 3-fold increase compared to baseline.
[0064] In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 5 times compared to the upper limit of normal (ULN). In some embodiments, the total daily dose is reduced when the level of ALT, AST, or ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 3 abnormality is an abnormal level of ALT and/or AST greater than about 5-fold to about 20-fold increase compared to baseline. In some embodiments, the abnormal level of ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 3 abnormality is an abnormal level of ALP greater than about 5-fold to about 20- fold increase compared to baseline. In some embodiments, the total daily dose is reduced when the level of bilirubin is greater than about 3- to about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 3 abnormality is an abnormal level of bilirubin greater than about 3-fold to about 10-fold increase compared to baseline.
[0065] In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 20 times compared to the upper limit of normal (ULN) (i.e., a “Grade 4 abnormality”). In some embodiments, where the patient has an abnormal baseline, the Grade 4 abnormality is an abnormal level of ALT and/or AST greater than about 20-fold increase compared to baseline. In some embodiments, the abnormal level of ALP is greater than about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 4 abnormality is an abnormal level of ALP greater than about 20- fold increase compared to baseline. In some embodiments, the total daily dose is reduced when the level of bilirubin is greater than about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 4 abnormality is an abnormal level of bilirubin greater than about 10-fold increase compared to baseline.
[0066] In some embodiments, the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when liver biomarker(s) in the patient has improved to a Grade 1 or better (e.g., baseline).
[0067] NauseaA/omiting
[0068] In some embodiments, the adverse event is nausea or vomiting. In some embodiments, the nausea/vomiting is present despite appropriate supportive care (e.g., anti-emetic therapy). “Nausea” as used herein refers to a disorder characterized by a queasy sensation and/or the urge to vomit.
[0069] Adverse effect Grades for nausea and vomiting are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 3. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017, by the National Cancer Institute, incorporated herein by reference in its entirety. [0070] Table 3.
Figure imgf000017_0001
[0071] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having ³ Grade 3 nausea until the patient has improved to £ Grade 1 or baseline. In some embodiments, once the patient has improved to £ Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
[0072] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having ³ Grade 3 vomiting until the vomiting improves to £ Grade 1 or baseline. In some embodiments, once the patient has improved to £ Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
[0073] In some embodiments, the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when nausea in the patient has improved to a Grade 1 or better (e.g., baseline).
[0074] Diarrhea
[0075] In some embodiments, the adverse event is diarrhea. In some embodiments, the diarrhea is present despite appropriate supportive care (e.g., anti-diarrheal therapy). An anti-diarrheal therapy can be administration of an anti-diarrheal agent, such as loperamide or atropine/diphenoxylate.
[0076] Adverse effect Grades for diarrhea are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 4. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017, by the National Cancer Institute, incorporated herein by reference in its entirety.
[0077] Table 4.
Figure imgf000018_0001
[0078] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having ³ Grade 3 diarrhea until the patient has improved to £ Grade 1 or baseline. In some embodiments, once the patient has improved to £ Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient. In some embodiments, the methods described herein comprise administering an anti-diarrheal agent to the patient. In some embodiments, the anti-diarrheal agent is loperamide or atropine/diphenoxylate.
[0079] In some embodiments, the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when diarrhea in the patient has improved to a Grade 1 or better (e.g., baseline).
[0080] Interstitial Lung Disease
[0081] In some embodiments, the adverse event is interstitial lung disease (ILD) or pneumonitis. In cases where ILD or pneumonitis is suspected at any grade level, sotorasib is withheld. In cases where ILD or pneumonitis is confirmed, and no other causes of the ILD or pneumonitis is identified, sotorasib is permanently discontinued.
[0082] Response to Sotorasib and Trametinib (and optionally anti-EGFR antibody) Therapy
[0083] Response rates or results for patients administered the therapy (i.e., sotorasib and trametinib (and optionally an anti-EGFR antibody)) in the methods disclosed herein can be measured in a number of ways, after the patient has been taking the therapy for a suitable length of time. In various embodiments, a patient is administered the therapy for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, e.g., for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months. In various embodiments, the patient is administered the therapy for at least 1 month. In various embodiments, the patient is administered the therapy for at least 3 months. In various embodiments, the patient is administered the therapy for at least 6 months.
[0084] The patient can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). An at least stable disease is one that is a stable disease, has shown a partial response (PR) or has shown a complete response (CR) (i.e., “at least SD” = SD+PR+CR, often referred to as disease control). In various embodiments, the stable disease is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD). In various embodiments, the patient exhibits at least a partial response (i.e., “at least PR” = PR+CR, often referred to as objective response).
[0085] Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases. In various embodiments, the progression of a patient’s disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof.
[0086] Progression free survival (PFS) can be assessed as described in the RECIST 1.1 protocol. In various embodiments, the patient exhibits a PFS of at least 1 month. In various embodiments, the patient exhibits a PFS of at least 3 months. In some embodiments, the patient exhibits a PFS of at least 6 months.
[0087] Additional means for assessing response are described in detail in the examples below and can generally be applied to the methods disclosed herein.
[0088] KRAS G12C Cancers
[0089] The methods described herein comprise treating a cancer with a KRAS G12C mutation in a patient, wherein the methods comprise administering to the patient sotorasib and trametinib (and optionally an anti-EGFR antibody) in amounts effective to treat the cancer. Without wishing to be bound by any particular theory, the following is noted: sotorasib is a small molecule that specifically and irreversibly inhibits KRASG12C (Hong et al., 2020). Hong et al. report that “[pjreclinical studies showed that [sotorasib] inhibited nearly all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key down-stream effector of KRAS, leading to durable complete tumor regression in mice bearing KRAS p.G12C tumors.” (id., see also Canon et al., 2019, and Lanman et al., 2020). Thus, in various embodiments, sotorasib at a total daily dose of 240 mg is disclosed for use in treating cancer, wherein one or more cells express KRAS G12C mutant protein.
[0090] Sotorasib was evaluated in a Phase 1 dose escalation and expansion trial with 129 patients having histologically confirmed, locally advanced or metastatic cancer with the KRAS p.G12C mutation identified by local molecular testing on tumor tissues, including 59 patients with non-small cell lung cancer, 42 patients with colorectal cancer, and 28 patients with other tumor types (Hong et al., 2020, at page 1208-1209). Hong et al. report a disease control rate (95% Cl) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer and 75.0% for other tumor types (Hong et al., 2020, at page 1213, Table 3). The cancer types showing either stable disease (SD) or partial response (PR) as reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma (Hong et al., 2020, at page 1212 (Figure A), and Supplementary Appendix (page 59 (Figure S5) and page 63 (Figure S6)).
[0091] KRAS G12C mutations occur with the alteration frequencies shown in the table below (Cerami et al., 2012; Gao et al., 2013). For example, the table shows that 11.6% of patients with non-small cell lung cancer have a cancer, wherein one or more cells express KRAS G12C mutant protein. Accordingly, sotorasib, which specifically and irreversibly bind to KRASG12C is useful for treatment of patients having a cancer, including, but not limited to the cancers listed in Table 5 below.
[0092] Table 5.
Figure imgf000020_0001
Figure imgf000021_0001
[0093] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer. In some embodiments, the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer. In some embodiments, the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer.
In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is metastatic or locally advanced non-small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.
[0094] Methods of Detecting KRAS, STK11, KEAP1, EGFR, ALK, and/or ROS1 Mutation Status
[0095] The presence or absence of G12C, STK11, KEAP1, EGFR, ALK and/or ROS1 mutations in a cancer as described herein can be determined using methods known in the art. Determining whether a tumor or cancer comprises a mutation can be undertaken, for example, by assessing the nucleotide sequence encoding the protein, by assessing the amino acid sequence of the protein, or by assessing the characteristics of a putative mutant protein or any other suitable method known in the art. The nucleotide and amino acid sequences sequence of wild-type human KRAS (nucleotide sequence set forth in Genbank Accession No. BC010502; amino acid sequence set forth in Genbank Accession No. AGC09594 ), STK11 (Gene ID: 6794; available at www.ncbi.nlm.nih.gov/gene/6794; accessed January 2020), KEAP1 (Gene ID: 9817; available at www.ncbi.nlm.nih.gov/gene/9817; accessed January 2020), EGFR (Gene ID: 1956; available at www.ncbi.nlm.nih.gov/gene/1956; accessed March 2021), ALK (Gene ID: 238; available at www.ncbi.nlm.nih.gov/gene/238; accessed March 2021), and ROS1 (Gene ID: 6098; available at www.ncbi.nlm.nih. gov/gene/6098; accessed March 2021) are known in the art. [0096] Methods for detecting a mutation include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct and/or next generation-based sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for mutations, such as the KRAS G12C mutation, by real-time PCR. In real-time PCR, fluorescent probes specific for a certain mutation, such as the KRAS G12C mutation, are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the mutation is identified using a direct sequencing method of specific regions in the gene. This technique identifies all possible mutations in the region sequenced. In some embodiments, gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and/or arrays can be used to detect the presence or absence of insertion mutations. In some embodiments, the methods include, but are not limited to, detection of a mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.
[0097] In some embodiments, multiplex PCR-based sequencing is used for mutation detection and can include a number of amplicons that provides improved sensitivity of detection of one or more genetic biomarkers. For example, multiplex PCR-based sequencing can include about 60 amplicons (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 amplicons). In some embodiments, multiplex PCR-based sequencing can include 61 amplicons. Amplicons produced using multiplex PCR-based sequencing can include nucleic acids having a length from about 15 bp to about 1000 bp (e.g., from about 25 bp to about 1000 bp, from about 35 bp to about 1000 bp, from about 50 bp to about 1000 bp, from about 100 bp to about 1000 bp, from about 250 bp to about 1000 bp, from about 500 bp to about 1000 bp, from about 750 bp to about 1000 bp, from about 15 bp to about 750 bp, from about 15 bp to about 500 bp, from about 15 bp to about 300 bp, from about 15 bp to about 200 bp, from about 15 bp to about 100 bp, from about 15 bp to about 80 bp, from about 15 bp to about 75 bp, from about 15 bp to about 50 bp, from about 15 bp to about 40 bp, from about 15 bp to about 30 bp, from about 15 bp to about 20 bp, from about 20 bp to about 100 bp, from about 25 bp to about 50 bp, or from about 30 bp to about 40 bp). For example, amplicons produced using multiplex PCR-based sequencing can include nucleic acids having a length of about 33 bp.
[0098] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using sequencing technology (e.g., a next-generation sequencing technology). A variety of sequencing technologies are known in the art. For example, methods for detection and characterization of circulating tumor DNA in cell-free DNA can be described elsewhere (see, e.g., Haber and Velculescu, 2014). Non-limiting examples of such techniques include SafeSeqs (see, e.g., Kinde et al., 2011), OnTarget (see, e.g., Forshew et al., 2012), and TamSeq (see, e.g., Thompson et al., 2012).
[0099] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using droplet digital PCR (ddPCR), a method that is known to be highly sensitive for mutation detection. In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using other sequencing technologies, including but not limited to, chain-termination techniques, shotgun techniques, sequencing-by-synthesis methods, methods that utilize microfluidics, other capture technologies, or any of the other sequencing techniques known in the art that are useful for detection of small amounts of DNA in a sample (e.g., ctDNA in a cell-free DNA sample).
[00100] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using array-based methods. For example, the step of detecting a genetic alteration (e.g., one or more genetic alterations) in cell-free DNA is performed using a DNA microarray. In some embodiments, a DNA microarray can detect one more of a plurality of cancer cell mutations. In some embodiments, cell-free DNA is amplified prior to detecting the genetic alteration. Non-limiting examples of array-based methods that can be used in any of the methods described herein, include: a complementary DNA (cDNA) microarray (see, e.g., Kumar et al. 2012; Laere et al. 2009; Mackay et al. 2003; Alizadeh et al. 1996), an oligonucleotide microarray (see, e.g., Kim et al. 2006; Lodes et al. 2009), a bacterial artificial chromosome (BAC) clone chip (see, e.g., Chung et al. 2004; Thomas et al. 2005), a single-nucleotide polymorphism (SNP) microarray (see, e.g., Mao et al. 2007; Jasmine et al. 2012), a microarray-based comparative genomic hybridization array (array-CGH) (see, e.g., Beers and Nederlof, 2006; Pinkel et al. 2005; Michels et al. 2007), a molecular inversion probe (MIP) assay (see, e.g., Wang et al. 2012; Lin et al. 2010). In some embodiments, the cDNA microarray is an Affymetrix microarray (see, e.g., Irizarry 2003; Dalma-Weiszhausz et al. 2006), a NimbleGen microarray (see, e.g., Wei et al. 2008; Albert et al. 2007), an Agilent microarray (see, e.g., Hughes et al. 2001), or a BeadArray array (see, e.g., Liu et al. 2017). In some embodiments, the oligonucleotide microarray is a DNA tiling array (see, e.g., Mockler and Ecker, 2005; Bertone et al. 2006). Other suitable array-based methods are known in the art.
[00101] Methods for determining whether a tumor or cancer comprises a mutation can use a variety of samples. In some embodiments, the sample is taken from a patient having a tumor or cancer. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded (FFPE) sample. In some embodiments, the sample is a circulating cell-free DNA and/or circulating tumor cell (CTC) sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA. In a certain embodiment, the sample is acquired by resection, core needle biopsy (CNB), fine needle aspiration (FNA), collection of urine, or collection of hair follicles. In some embodiments, a liquid biopsy test using whole blood or cerebral spinal fluid may be used to assess mutation status.
[00102] In various embodiments, a test approved by a regulatory authority, such as the US Food and Drug Administration (FDA), is used to determine whether the patient has a mutation, e.g., a KRAS G12C mutated cancer, or whether the tumor or tissue sample obtained from such patient contains cells with a mutation. In some embodiments, the test for a KRAS mutation used is therascreen® KRAS RGQ PCR Kit (Qiagen). The therascreen® KRAS RGQ PCR Kit is a real-time qualitative PCR assay for the detection of 7 somatic mutations in codons 12 and 13 of the human KRAS oncogene (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) using the Rotor-Gene Q MDx 5plex HRM instrument. The kit is intended for use with DNA extracted from FFPE samples of NSCLC samples acquired by resection, CNB, or FNA. Mutation testing for STK11, KEAP1, EGFR, ALK and/or ROS1 can be conducted with commercially available tests, such as the Resolution Bioscience Resolution ctDx LungTM assay that includes 24 genes (including those actionable in NSCLC). Tissue samples may be tested using Tempus xT 648 panel.
[00103] In some embodiments, the cancer has been identified as having a KRAS G12C mutation. In some embodiments, the cancer has been identified as having a mutation of STK11, e.g., a loss-of-function mutation.
In some embodiments, the cancer has been identified as having a mutation of KEAP1, e.g., a loss-of-function mutation. In some embodiments, the cancer has been identified as having wild-type STK11. In some embodiments, the cancer has been identified as having wild-type KEAP1.
[00104] In various embodiments, the cancer has been identified as having a loss-of-function mutation of STK11 and wild-type KEAP1. In some embodiments, the cancer has been identified as having a loss-of-function mutation of STK11 and a loss-of-function mutation of KEAP1. In some embodiments, the cancer has been identified as having wild-type of STK11 and wild-type KEAP1. In some embodiments, the cancer has been identified as having wild-type of STK11 and a loss-of-function mutation of KEAP1.
[00105] The term “loss-of-function mutation” as used herein refers to a mutation (e.g., a substitution, deletion, truncation, or frameshift mutation) that results in expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological activity or enzymatic activity), results in expression of only a fragment of the protein that no longer exhibits wild-type activity, or results in no expression of the wild-type protein. For example, a loss-of-function mutation affecting the STK11 gene in a cell may result in the loss of expression of the STK11 protein, expression of only a fragment of the STK11 protein, or expression of the STK11 protein that exhibits diminished or no enzymatic activity (e.g., no serine/threonine kinase enzymatic activity) in the cancerous cell. Similarly, a loss-of-function mutation affecting the KEAP1 gene in a cell may result in the loss of expression of the KEAP1 protein, expression of only a fragment of the KEAP1 protein, or expression of a KEAP1 protein that exhibits diminished or no activity (e.g., inability to interact with or activate Nuclear factor erythroid 2-related factor 2 (NRF2)) in the cell.
Methods of Detecting PD-L1 Protein Expression
[00106] PD-L1 expression can be determined by methods known in the art. For example, PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with pembrolizumab. This is qualitative assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 PD-L1 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in FFPE samples, such as human non-small cell lung cancer tissue. Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. Staining can show PD-L1 expression from 0% to 100%. [00107] PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, the FDA- approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Myers Squibb as a companion test for treatment with nivolumab. This qualitative assay uses the Monoclonal rabbit anti-PD-L1, Clone 28-8 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissue.
[00108] Other commercially available tests for PD-L1 detection include the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca) that utilizes monoclonal rabbit anti- PD-L1, Clone SP263 and the Ventana SP142 Assay (developed by Ventana in collaboration with Genentech/Roche) that uses rabbit monoclonal anti-PD-L1 clone SP142.
[00109] In some embodiments, a test approved by a regulatory authority, such as the US Food and Drug Administration (FDA), is used to determine the PD-L1 TPS of a cancer as disclosed herein. In various embodiment, the PD-L1 TPS is determined using a immunohistochemistry (IHC) test. In some embodiments, the IHC test is the PD-L1 IHC 22C3 pharmDx test. In various embodiments, the IHC test conducted with samples acquired by, for example, resection, CNB, or FNA.
[00110] In various embodiment, the patient has a PD-L1 TPS of less than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In various embodiments, the patient has a PD-L1 TPS of less than 50%, or less than 1%. In various embodiments, the patient has a PD-L1 TPS of more than or equal to 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In various embodiments, the patient has a PD-L1 TPS of less than or equal to 100%, 95%, 90%, 85%, 80%,
75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,
4%, 3%, 2%, or 1%. In various embodiments, the patient has a PD-L1 TPS of less than or equal to 50%, or less than or equal to 1%. In various embodiments, the patient has a PD-L1 TPS of more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,
4%, 3%, 2%, or 1%. In various embodiments, the patient has a PD-L1 TPS score a range bound by any of the values cited in the foregoing embodiments. For example, the patient has a PD-L1 TPS score in the range of less than 50% and more than or equal to 1 %, less than or equal to 50% and more than 1 %, less than or equal to 50% and more than or equal to 1%, or less than 50% and more than 1%.
[00111] In various embodiments, the patient has a PD-L1 TPS score in the range of less than 50% and more than or equal to 1%. In some embodiments, the patient has a PD-L1 TPS score in the range of more than or equal to 0% and less than 1%. In some embodiments, the patient has a PD-L1 TPS score in the range of more than 50% and less than or equal to 100%. In some embodiments, the patient has a PD-L1 TPS score of less than 1%. In some embodiments, the patient as a PD-L1 TPS score of 1-49%. In some embodiments, the patient has a PD-L1 TPS score of 50% or greater (i.e., 50%-100%). Embodiments
1. A method of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and trametinib once daily, wherein the sotorasib and trametinib are administered to the patient in amounts effective to treat the cancer.
2. The method of embodiment 1, comprising administering 960 mg sotorasib to the patient.
3. The method of embodiment 1, comprising administering 240 mg sotorasib to the patient.
4. The method of any one of embodiments 1-3, comprising administering 1 mg trametinib to the patient.
5. The method of any one of embodiments 1-3, comprising administering 2 mg trametinib to the patient.
6. The method of any one of embodiments 1-3, comprising administering 0.5 mg trametinib to the patient.
7. The method of embodiment 1 , comprising orally administering 960 mg sotorasib and 1 mg trametinib once daily to the patient.
8. The method of embodiment 1 , comprising orally administering 960 mg sotorasib and 2 mg trametinib once daily to the patient.
9. The method of embodiment 1 , comprising orally administering 960 mg sotorasib and 0.5 mg trametinib once daily to the patient.
10. The method of any one of embodiments 1-9, wherein two subsequent doses of trametinib are administered about 24 hours apart.
11 . The method of any one of embodiments 1-10, wherein the patient is treated for one or more treatment cycles, wherein the treatment cycle is a 21 day treatment cycle.
12. The method of any one of embodiments 1-11, further comprising administering an anti- epidermal growth factor receptor (EGFR) antibody to the patient every two weeks.
13. The method of embodiment 12, wherein the anti-EGFR antibody comprises a heavy chain variable region comprising HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.
14. The method of embodiment 13, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 4 and the light chain variable region comprises the sequence of SEQ ID NO: 9.
15. The method of embodiment 14, wherein the anti-EGFR antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 5 and a light chain comprising the sequence of SEQ ID NO: 10. 16. The method of embodiment 12, wherein the anti-EGFR antibody is panitumumab.
17. The method of any one of embodiments 12-16, wherein , wherein the patient is treated for one or more treatment cycles, wherein the treatment cycle is a 28 day treatment cycle.
18. The method of any one of embodiments 12-17, comprising administering 4.8 mg/kg panitumumab via IV administration to the patient.
19 The method of any one of embodiments 12-17, comprising administering 6 mg/kg panitumumab via IV administration to the patient.
20. The method of any one of embodiments 12-17, comprising administering 3.6 mg/kg panitumumab via IV administration to the patient.
21. The method of any one of embodiments 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and
(b) 4.8 mg/kg panitumumab via IV administration every two weeks.
22. The method of any one of embodiments 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and
(b) 6 mg/kg panitumumab via IV administration every two weeks.
23. The method of any one of embodiments 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and
(b) 6 mg/kg panitumumab via IV administration every two weeks.
24. The method of any one of embodiments 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 2 mg trametinib orally once daily; and
(b) 6 mg/kg IV panitumumab via IV administration every two weeks.
25. The method of any one of embodiments 12-17 comprising administering to the patient
(a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and
(b) 4.8 mg/kg panitumumab via IV administration every two weeks.
26. The method of any one of embodiments 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and
(b) 3.6 mg/kg panitumumab via IV administration every two weeks.
27. The method of any one of embodiments 12-17, comprising administering to the patient (a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and (b) 3.6 mg/kg panitumumab via IV administration every two weeks.
28. The method of any one of embodiments 1 -27, wherein the patient is resistant to therapy with a KRASG12C inhibitor.
29. The method of any one of embodiments 1-28, wherein the cancer is a solid tumor.
30. The method of any one of embodiments 1-29, wherein the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
31 . The method of any one of embodiments 1-29, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer (CRC).
32. The method of any one of embodiments 1-31, wherein the patient, prior to start of sotorasib and trametinib therapy and optionally panitumumab, had undergone at least one other systemic cancer therapy.
33. The method of embodiment 32, wherein the patient had undergone at least two other systemic cancer therapies.
34. The method of embodiment 32 or 33, wherein at least one systemic cancer therapy is selected from therapy with a KRASG12C inhibitor, anti-PD-1 therapy, anti-PD-L1 therapy, and platinum-based chemotherapy.
35. The method of embodiment 34, wherein the patient has previously undergone (i) an EGFR, ALK or ROS1 targeted therapy if the cancer also exhibited a mutation in EGFR, ALK, or ROS1, and (ii) an anti- PD1 therapy or anti-PD-L1 therapy, unless contraindicated, or a platinum-based chemotherapy.
36. The method of embodiment 34, wherein the patient has previously undergone (i) an EGFR, ALK or ROS1 targeted therapy if the cancer also exhibited a mutation in EGFR, ALK, or ROS1, and (ii) an anti- PD1 therapy or anti-PD-L1 therapy, unless contraindicated, and a platinum-based chemotherapy.
37. The method of embodiment 34, wherein the patient has previously undergone at least one platinum-based chemotherapy.
38. The method of embodiment 37, wherein the platinum-based chemotherapy comprises fluoropyrimidine, oxaliplatin, or irinotecan.
39. The method of any one of embodiments 1 -38, wherein the patient exhibits at least a stable disease (SD) after 1, 3, or 6 months of sotorasib and trametinib therapy, as measured by RECIST 1.1 protocol.
40. The method of any one of embodiments 1 -38, wherein the patient exhibits at least a partial response (PR) after 1 , 3, or 6 months of sotorasib therapy, as measured by RECIST 1.1 protocol. 41 . The method of any one of embodiments 1 -40, wherein the patient exhibits a progression free survival (PFS) of at least 3 months.
42. The method of any one of embodiments 1-41, wherein the patient does not have an active brain metastases or leptomeningeal disease from a non-brain tumor.
43. The method of any one of embodiments 1 -42, wherein the patient is not suffering from a hepatitis A infection, a hepatitis B infection or a hepatitis C infection.
44. The method of any one of embodiments 1-43, wherein the patient is not suffering from retinal vein occlusion (RVO) or retinal pigment epithelial detachment or unresolved keratitis.
45. The method of any one of embodiments 1 -44, wherein the patient is not suffering from interstitial pneumonitis or pulmonary fibrosis.
46. The method of any one of embodiment 1 -45, wherein the patient is in further need of treatment with an acid-reducing agent.
47. The method of embodiment 46, wherein the acid-reducing agent is a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), or a locally acting antacid.
48. The method of embodiment 46 or embodiment 47, wherein the acid-reducing agent is a locally acting antacid, and wherein sotorasib is administered about 4 hours before or about 10 hours after the locally acting antacid.
49. The method of embodiment 47 or 48, wherein the locally acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide.
50. The method of any one of embodiments 1 -49, wherein the patient is in further need of treatment with a proton pump inhibitor (PPI) or H2 receptor antagonist (H2RA).
51 . The method of embodiment 50, wherein the patient is not administered a PPI or a H2RA in combination with sotorasib.
52. The method of any one of embodiments 47, 50 or 51, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole.
53. The method of any one of embodiments 47, 50 or 51, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine or lafutidine.
54. The method of any one of embodiments 1 -53, wherein the patient is in further need of treatment with a CYP3A4 inducer.
55. The method of embodiment 54, wherein the patient is not administered a CYP3A4 inducer in combination with sotorasib. 56. The method of embodiment 54 or 55, wherein the CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, or troglitazone.
57. The method of embodiment 54 or embodiment 55, wherein the patient is not administered a strong CYP3A4 inducer in combination with sotorasib.
58. The method of embodiment 57, wherein the strong CYP3A4 inducer is phenytoin or rifampin.
59. The method of any one of embodiments 1 -58, wherein the patient is in further need of treatment with a CYP3A4 substrate.
60. The method of embodiment 59, wherein the patient is not administered a CYP3A4 substrate in combination with sotorasib.
61 . The method of embodiment 59 or 60, wherein the CYP3A4 substrate is abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib, cyclosporine, dabrafenib, daclatasvir, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, dolutegravir, domperidone, doxepin, elagolix, elbasvir/grazoprevir, eliglustat, enzalutamide, eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, gleevec, haloperidol, hydrocortisone, ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isavuconazonium, ivabradine, ivacaftor, lansoprazole, lenvatinib, lercanidipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, midazolam, naldemedine, naloxegol, nateglinide, nelfinavir, neratinib, netupitant/palonosetron, nevirapine, nifedipine, nisoldipine, nitrendipine, olaparib, omeprazole, ondansetron, osimertinib, ospemifene, palbociclib, panobinostat, pantoprazole, perampanel, pimavanserin, pimozide, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, ribociclib, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast, rolapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus, sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus(fk506), tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, vilazodone, vincristine, vorapaxar, voriconazole, zaleplon, or ziprasidone.
62. The method of any one of embodiments 1-61, wherein the patient is in further need of treatment with a P-glycoprotein (P-gp) substrate.
63. The method of embodiment 62, wherein the patient is not administered a P-gp substrate in combination sotorasib. 64. The method of embodiment 62 or embodiment 63, wherein the P-gp substrate is etexilate, digoxin, fexofenadine, , everolimus, cyclosporine, sirolimus, or vincristine.
65. The method of any one of embodiments 1-64, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of 1-49%.
66. The method of any one of embodiments 1-64, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of less than 1%.
67. The method of any one of embodiments 1-64, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of 50-100%.
68. The method of any one of embodiments 1-67, wherein the cancer further comprises a BRAF V600E or V600K mutation.
69. The method of any one of embodiments 1-68, wherein the cancer further comprises a STK11 mutation.
70. The method of any one of embodiments 1 -68, wherein the cancer further comprises a KEAP1 mutation.
71 . The method of any one embodiment 1-68 and 70, wherein the cancer further comprises a STK11 wild type.
72. The method of any one of embodiments 1-69, wherein the caner further comprises a KEAP1 wild type.
73. The method of embodiment 69 or embodiment 70, wherein the mutation is a loss-of-function mutation.
EXAMPLES
Example 1 - Sotorasib in combination with trametinib and optionally panitumumab
[00112] Without wishing to be bound by any particular theory, the following is noted: Sotorasib at 960 mg QD was shown to be safe and effective under study conditions under Study 20170543 (CodeBreaklOO). The addition of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, to sotorasib, a targeted therapy against mutant KRAS p.G12C, may lead to significant inhibition of rat sarcoma viral oncogene homolog/RAF proto oncogene serine/threonine protein kinase/MEK/extracellular signal regulated kinase (RAS/RAF/MEK/ERK) signaling pathway and enhance the anti-tumor activity. Since resistance to sotorasib may be mediated by upregulation of signaling through epidermal growth factor receptor (EGFR) pathway, adding an EGFR inhibitor to the combination of sotorasib and trametinib may block bypass activation of the mitogen activated kinase (MAPK) signaling and lead to improved anti-tumor activity. This study will therefore explore sotorasib in combination with trametinib (MEK inhibitor) and sotorasib in combination with trametinib and panitumumab (EGFR targeted monoclonal antibody). The term “subject” is used herein interchangeably with “patient.” [00113] Overall Design:
[00114] A multicenter, open label study is set up to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of sotorasib in combination with trametinib in subjects with KRAS G12C mutant advanced solid tumors or in combination with trametinib and panitumumab in subjects with KRAS G12C mutant advanced solid tumors. Overall, approximately 140 subjects will be enrolled in the study. Sotorasib is administered orally once daily (QD), and trametinib is administered orally QD. Panitumumab is administered as a 60 minute (£ 1000 mg) or 90 minute (> 1000 mg) intravenous (IV) infusion on day 1 every 2 weeks (Q2W). Sotorasib in combination with trametinib is evaluated in Part 1 (dose exploration) and Part 2 (dose expansion). Sotorasib in combination with trametinib and panitumumab is evaluated in Part 3 (dose exploration) and Part 4 (dose expansion).
[00115] Trial Treatments:
[00116] Sotorasib is administered orally QD, and trametinib is administered orally QD.
[00117] The sotorasib dose is 960 mg/day. Sotorasib is administered orally QD continuously with or without food for treatment cycles which are defined as 21 days (Part 1 and Part 2) or 28 days (Part 3). Subjects take all of the sotorasib dose as oral tablets at approximately the same time every day. The sotorasib dose should not be taken more than 2 hours earlier than the target time based on previous day’s dose. The sotorasib dose should not be taken more than 6 hours after the dosing time. Take the next dose as prescribed. If vomiting occurs after taking sotorasib, an additional dose should not be taken. The next dose should be taken as prescribed. Administration to subjects who have difficulty swallowing solids: disperse tablets in 120 mL (4 ounces) of non- carbonated, room temperature water without crushing. No other liquids should be used. Stir until tablets dispersed into small pieces (the tablets will not completely dissolve) and drink immediately, or within 2 hours. The appearance of the mixture may range from pale yellow to bright yellow. Swallow the tablet dispersion. Do not chew pieces of the tablet. Rinse the container with an additional 120 mL (4 ounces) of water, and drink. If the mixture is not consumed immediately, stir the mixture again to ensure that tablets are dispersed.
[00118] The trametinib dose is 0.5 to 2 mg/day. Trametinib is administered orally QD continuously with or without food for a treatment cycle of 21 days or 28 days (when administered in combination with panitumumab).
[00119] The panitumumab dose is 3.6 to 6 mg/kg Q2W. Panitumumab is administered as a 60 minute (£
1000 mg) or 90 minute (> 1000 mg) IV infusion Q2W.
[00120] Procedures:
[00121] Sotorasib is administered orally QD, and trametinib is administered orally QD. Panitumumab is administered as 60 minute (£ 1000 mg) or 90 minute (> 1000 mg) IV infusion Q2W.
[00122] Part i :
[00123] Part 1 of the study assesses the safety of the selected starting dose of sotorasib in combination with trametinib. The starting dose for sotorasib and trametinib is based on the review of the safety, PK and pharmacodynamic data from the first in human study exploring sotorasib as a monotherapy and the available safety data for trametinib.
[00124] The dose levels for trametinib with a fixed dose of sotorasib (960 mg orally daily) are:
-Dose Level 1 : 1 mg orally QD -Dose Level 2: 2 mg orally QD -Dose Level -1: 0.5 mg orally QD
[00125] Dose exploration begins with 2-4 subjects treated at Dose Level 1. The study dose limiting toxicity (DLT) period is 21 days. Once all subjects enrolled at a certain dose level are DLT evaluable, a Dose Level Review Team (DLRT) meeting is convened. Depending on observed safety data, the following occurs: (1) dose escalation to Dose Level 2 or (2) additional enrollment to Dose Level 1 or (3) dose de-escalation to Dose Level -1 . Rules for dose-escalation/de-escalation are derived using a modified Toxicity Probability Interval-2 (mTPI-2) model (Guo et al, 2017) with a target toxicity probability of 0.30.
[00126] Guidelines for Dose Escalation/De-escalation for Part 1
Figure imgf000033_0001
DLT = dose-limiting toxicity a A subject is evaluable if subject experiences a DLT or completes 21 days on treatment and receives > 80% of planned dose of both sotorasib and trametinib. A subject without a DLT will not be DLT evaluable if the date of decision to end both investigational products is before the completion of the DLT window. b De-escalate guideline applies only when current dose level is either Dose Level 1 or Dose Level 2 and enrollment is allowed to a lower dose level. Re-escalation to Dose Level 1 or Dose Level 2 may be allowed, as appropriate, only in the following instances: 1) 1 of 2 or 1 of 3 evaluable subjects experience a DLT at the applicable dose level 2) 2 of 5 or 2 of 6 evaluable subjects experience a DLT 3) 3 of 8 or 3 of 9 subjects experience a DLT or 4) 4 of 10 subjects experience a DLT. c As appropriate to better understand safety profile for a dose level, the number of evaluable subjects may be expanded up to 10.
[00127] In addition to the planned dose levels, further degree of dose modification (e.g., intermediate doses) and/or schedule of administration (e.g., alternate dosing) is decided based on analysis of emerging safety and PK data. The maximum tolerated dose (MTD) is estimated using isotonic regression (Ji et al, 2010) and the MTD is the dose level with the estimated DLT rate closest to 0.30. In order to consider a certain Dose Level as the MTD or recommended safe combination dose for Part 2, at least 6 DLT evaluable subjects must be enrolled at that dose level. No more than 10 DLT evaluable subjects are enrolled at any specific dose level in Part 1.
[00128] Part 1 ends once any of the following events occur:
-Dose Level 2 is determined to be safe and tolerable (minimum of 6 evaluable subjects overall).
-Either Dose Level 1 or Dose Level -1 is determined to be safe and tolerable (minimum of 6 evaluable subjects) and the next higher dose level is determined to be un-safe and intolerable.
-All planned dose levels are determined to be un-safe and intolerable.
-On the basis of a review of real-time safety data and available preliminary PK data, dose escalation may be halted or modified by the Sponsor as deemed appropriate.
[00129] Part 2:
[00130] Upon completing the dose exploration part of the study and depending on data obtained, enrollment will commence in the dose expansion phase (Part 2) to confirm the safety and tolerability of the selected dose and to further evaluate anti-tumor activity. Part 2 consists of 3 groups:
-Group 2a consists of subjects with advanced NSCLC with KRAS G12C mutation -Group 2b consists of subjects with advanced CRC with KRAS G12C mutation -Group 2c consists of subjects with advanced solid tumors (except NSCLC and CRC) with KRAS G12C mutation
[00131] Interim safety analyses are done after n = 10 and after n = 20 subjects in Part 2 have had the opportunity to be on treatment for at least 21 days. Based on these interim safety results and after reviewing the updated estimate of the MTD or recommended safe combination dose using all available data including data from dose exploration and expansion subjects, the DLRT may modify the dose level. A final estimate of the MTD or recommended phase 2 dose (RP2D) will use all data from dose exploration and dose expansion. For both Part 1 and Part 2, administration of sotorasib and trametinib may continue until evidence of disease progression, intolerance to study medication, withdrawal of consent, or end of study.
[00132] Part 3:
[00133] Part 3 of the study assesses the safety of the selected starting dose of sotorasib in combination with trametinib and panitumumab.
[00134] The dose levels for trametinib and panitumumab with sotorasib are as follows:
-Dose Level 1: Sotorasib 960 mg QD + trametinib 1.5 mg orally QD + panitumumab 4.8 mg/kg IV Q2W -Dose Level 2k. Sotorasib 960 mg QD + trametinib 1 mg orally QD + panitumumab 6 mg/kg IV Q2W -Dose Level 2B: Sotorasib 960 mg QD + trametinib 1.5 mg orally QD + panitumumab 6 mg/kg IV Q2W -Dose Level 3: Sotorasib 960 mg QD + trametinib 2 mg orally QD + panitumumab 6 mg/kg IV Q2W -Dose Level -1 A: Sotorasib 960 mg QD + trametinib 1 mg orally QD + panitumumab 4.8 mg/kg IV Q2W -Dose Level -1 B: Sotorasib 960 mg QD + trametinib 1.5 mg orally QD + panitumumab 3.6 mg/kg IV Q2W -Dose Level -2: Sotorasib 960 mg QD + trametinib 1 mg orally QD + panitumumab 3.6 mg/kg IV Q2W.
[00135] Dose exploration begins with 3 to 6 subjects treated at Dose Level 1 . The DLT period is 28 days.
Once all subjects enrolled at a certain dose level are DLT evaluable, a DLRT meeting will be convened. Depending on observed safety data, the following may occur: 1) dose escalation to both Dose Level 2A and/or 2B, 2) additional enrollment to Dose Level 1 or 3) dose de-escalation to both Dose Level -1A and/or -1B.
[00136] If enrollment to Dose Level 2A and/or 2B is initiated, depending on observed safety data, the following may occur: 1) dose escalation to Dose Level 3 if Dose Level 2B is deemed safe and tolerable, 2) additional enrollment to both Dose Level 2A and/or 2B, or 3) de-escalation to Dose Level 1 if Dose Level 2A is deemed not tolerable.
[00137] If Dose Level -1A and/or -1 B is initiated, depending on observed safety data, the following occurs: 1) additional enrollment to Dose Level -1 A and/or -1 B, 2) dose de-escalation to Dose Level -2 if both Dose Level - 1A and -1 B are not tolerable, or 3) re-escalation to Dose Level 1 .
[00138] Rules for dose escalation/de-escalation are derived using a mTPI-2 model (Guo et al, 2017) with a target toxicity probability of 0.30.
[00139] Guidelines for Dose Escalation/De-escalation for Part 3
Figure imgf000035_0001
Figure imgf000036_0001
DLT - dose limiting toxicity a A subject is evaluable if subject experiences a dose limiting toxicity (DLT) or completes 28 days on treatment and receives D 80% of planned dose of sotorasib, trametinib and panitumumab. A subject without a DLT will not be DLT evaluable if the date of decision to end both investigational products is before the completion of the DLT window. b De-escalate guideline applies only when enrollment is allowed to a lower dose level. Re-escalation to a higher dose level may be allowed, as appropriate, only in the following instances: 1) 2 of 5 or 2 of 6 evaluable subjects experience a DLT or 2) 3 of 8 or 3 of 9 subjects experience a DLT. If a higher dose level is not allowed, then the current dose level can be expanded or if at least 6 subjects are DLT evaluable at that dose level, it can be declared the maximum tolerated dose (MTD) if deemed safe. c As appropriate to better understand safety profile for a dose level, the number of evaluable subjects may be expanded up to 10.
[00140] In addition to the dose levels described above, further degree of dose modification (e.g., intermediate doses) and/or schedule of administration (e.g., alternate dosing) is decided based on analysis of emerging safety and PK data. The maximum tolerated dose (MTD) is estimated using isotonic regression (Ji et al, 2010) and the MTD will be the dose level with the estimated DLT rate closest to 0.30. In order to consider a certain Dose Level as the MTD or recommended safe combination dose for Part 4, at least 6 DLT evaluable subjects must be enrolled at that Dose Level. No more than 10 DLT evaluable subjects will be enrolled at any specific Dose Level in Part 3.
[00141] Part 3 ends once any of the following events occur:
-Dose Level 3 is determined to be safe and tolerable (minimum of 6 evaluable subjects overall).
-Any Dose Level (including any intermediate dose level) Is determined to be safe and tolerable (minimum of 6 evaluable subjects) and the next higher Dose Level (if any) is deemed unsafe and intolerable.
-All dose levels (including any intermediate dose levels) are deemed unsafe and intolerable. -On the basis of a review of real-time safety data and available preliminary PK data, dose escalation may be halted or modified by the Sponsor as deemed appropriate.
[00142] Part 4:
[00143] Upon completing the dose exploration Part 3 of the study and depending on data obtained, enrollment commences in the dose expansion phase (Part 4) to confirm the safety and tolerability of the selected dose and to further evaluate anti-tumor activity.
[00144] Interim safety analyses will be done after n = 10 and after n = 20 subjects in Part 4 have had the opportunity to be on treatment for at least 28 days. Based on these interim safety results and after reviewing the updated estimate of the MTD or recommended safe combination dose using all available data including data from dose exploration and expansion subjects, the DLRT may modify the dose level. A final estimate of the MTD or RP2D will use all data from dose exploration and dose expansion.
[00145] For both Part 3 and Part 4, administration of sotorasib, trametinib and panitumumab continues until evidence of disease progression, withdrawal of consent, or end of study.
[00146] Summary of Subject Eligibility Criteria:
[00147] Men and women age ³18 years old
[00148] Pathologically documented locally-advanced or metastatic malignancy with KRAS p.G12C mutation identified through molecular testing.
[00149] - For NSCLC, subjects must have received anti-PD1 or anti PD (L)1 immunotherapy (unless contraindicated) AND/OR platinum-based combination chemotherapy AND targeted therapy (if actionable oncogenic driver mutations were identified [e.g., EGFR, ALK, and ROS1]), or if subject refused standard therapy. Prior neoadjuvant/adjuvant chemotherapy are considered for eligibility only if the subject progressed on or within 6 months of completion of the therapy. KRAS p.G12C mutation is identified by an approved diagnostic device for detection of KRAS p.G12C in NSCLC or is performed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory.
[00150] - For CRC, subjects must have received at least 1 prior systemic regimen for advanced or metastatic
CRC including fluoropyrimidine, oxaliplatin, and irinotecan-based regimens. For those CRC subjects with tumors that are MSI-H, at least 1 of the prior systemic regimens must be treatment with either nivolumab or pembrolizumab if they were clinically able to receive inhibitors and 1 of these agents is approved for that indication in the region or country, or if subject refused standard therapy.
[00151] - For advanced solid tumor types other than NSCLC or CRC, subjects must have received at least 1 prior systemic therapy and be intolerant or ineligible for available therapies known to provide clinical benefit.
[00152] Subjects must be willing to undergo tumor biopsy, if medically feasible, before start of treatment and between week 2 to week 5 after starting treatment. If a tumor biopsy prior to treatment is not medically feasible, subjects must be willing to provide archived tissue samples (formalin fixed embedded [FFPR] sample) collected within the past 5 years). Subject who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator if a tumor biopsy is not feasible.
[00153] Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria.
[00154] Eastern Cooperative Oncology Group (ECOG) Performance Status of £ 2.
[00155] Life expectancy of > 3 months, in the opinion of the investigator.
[00156] Ability to take oral medications and willing to record daily adherence to investigational product.
[00157] Corrected QT interval (QTc) £ 470 msec for women and £ 450 msec for men (based on average of screening triplicates).
[00158] Subjects have adequate hematological, renal and hepatic function and coagulation. Adequate hematological laboratory assessments, are as follows:
-Absolute neutrophil count (ANC) ³ 1 .5 x 109/L -Platelet count ³ 75 x 109/L -Flemoglobin ³ 9 x g/dL
[00159] Adequate renal laboratory assessments include measured creatinine clearance or estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation ³ 60 mL/min/1 .73 m2.
[00160] Adequate hepatic laboratory assessments are as follows:
-AST < 2.5 x upper limit of normal (ULN) (if liver metastases are present, £ 5 x ULN)
-ALT < 2.5 x ULN (if liver metastases are present, £ 5 x ULN)
-Total bilirubin < 1 .5 x ULN (<2.0 x ULN for subjects with documented Gilbert’s syndrome or < 3.0 x ULN for subjects for whom the indirect bilirubin level suggests an extrahepatic source of elevation)
[00161] Adequate coagulation laboratory assessments are as follows:
- Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x ULN, OR International normalized ratio (INR) < 1 .5 or within target range if on prophylactic anticoagulation therapy.
[00162] Cardiac ejection fraction ³50%, with no evidence of pericardial effusion as determined by an echocardiogram (ECFIO) or multigated acquisition scan (MUGA).
[00163] Exclusion criteria:
[00164] Primary brain tumor.
[00165] Active brain metastases or leptomeningeal disease from non-brain tumors. Subjects who have had brain metastases resected or have received whole brain radiation therapy ending at least 4 weeks (or stereotactic radiosurgery ending at least 2 weeks) prior to study day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms grade £2; b) on stable doses of dexamethasone, if applicable; and c) follow-up MRI performed within 28 days shows no new or enlarging lesions appearing. For determining the grade of any neurological symptom attributable to an intracranial lesion, see National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017, by the National Cancer Institute, incorporated herein by reference in its entirety. Active brain metastases can be assessed by the presence of intracranial lesions. It is to be understood that while “metastases” is plural, patients exhibiting only one intracranial lesion under the criteria noted below is a patient who has “active brain metastases.”
[00166] History or presence of hematological malignancies unless curatively treated with no evidence of disease for ³ 2 years.
[00167] History of other malignancy within the past 2 years, with the following exceptions:
- Malignancy treated with curative intent and with no known active disease present for ³ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician;
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
- Adequately treated cervical carcinoma in situ without evidence of disease;
- Adequately treated breast ductal carcinoma in situ without evidence of disease;
- Prostatic intraepithelial neoplasia without evidence of prostate cancer;
- Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ.
[00168] Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or clinically significant findings on electrocardiogram (ECG).
[00169] Gastrointestinal (Gl) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for IV alimentation, uncontrolled inflammatory Gl disease (e.g., Crohn’s disease, ulcerative colitis).
[00170] Exclusion of hepatitis infection based on the following results and/or criteria:
- Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute hepatitis B);
- Negative HepBsAg with a positive for hepatitis B core antibody. Undetectable anti-hepatitis B antibody suggests unclear and possible infection and needs exclusion.;
- Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. Detectable Hepatitis C virus RNA suggests chronic hepatitis C.
[00171] Known positive test for human immunodeficiency virus (HIV).
[00172] Subjects with retinal vein occlusion (RVO) or retinal pigment epithelial detachment or unresolved keratitis.
[00173] History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis. [00174] Prior/Concomitant Therapy
[00175] Anti-tumor therapy* (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with breast cancer], or investigational agent) within 28 days of start of study day 1 ; concurrent use of hormone deprivation therapy for hormone refractory prostate cancer or breast cancer is permitted.
-Exception: subjects who receive prior small molecule targeted therapy, sotorasib monotherapy, or conventional chemotherapy within 14 days of study day 1 .
[00176] Therapeutic or palliative radiation therapy within 2 weeks of study day 1 . Subjects must have recovered from all radiotherapy related toxicity.
[00177] Use of known cytochrome P450 (CYP) 3A4 sensitive substrates or P-glycoprotein (P-gp) substrates (both with a narrow therapeutic window or index), within 14 days or 5 half lives of the CYP3A4 or P-gp substrate or its major active metabolite, whichever is longer, prior to study day 1 . CYP3A4 sensitive substrates with a narrow therapeutic index include alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, primozide, quinidine, tacrolimus, and sirolimus. P-gp substrates with a narrow therapeutic index include digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, or vincristine.
[00178] Use of strong inducers of CYP3A4 (including herbal supplements such as St. John’s wort) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 . Strong inducers of CYP3A4 include rifampin, phenytoin, mitotane, carbamazepine, avasimibe, enzalutamide, rifapentine, St John's Wort extract, apalutamide, lumacaftor, and ivosidenib.
[00179] Active infection requiring IV antibiotics within 1 week of study enrollment.
[00180] Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia (grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible [defined as having been present and stable for >6 months], such as ifosfamide related proteinuria or neuropathy, may be allowed if they are not otherwise described in the exclusion criteria.
[00181] Subject unable to receive both iodinated contrast for CT scans and gadolinium contrast for MRI scans.
[00182] Prior KRAS G12C inhibitor therapy (applicable to Part 3). Any dose reduction, ³ grade 3 treatment- related adverse event, or treatment discontinuation for any adverse event related to the previous treatment with MEK inhibitor or KRAS G12C inhibitor or (for Part 3 and 4 only) EGFR targeted antibody.
[00183] Prior/Concurrent Clinical Study Experience
[00184] Currently receiving treatment in another investigational device or drug study, or less than 28 days (or 14 days as described in exclusion criterion regarding anti-tumor therapy above, marked with (*)) since last intervention on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.
[00185] Other Exclusions
[00186] Subject has known sensitivity to any of the products or components to be administered during dosing.
[00187] Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (e.g., Clinical Outcome Assessments) to the best of the subject and investigator’s knowledge.
[00188] History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
[00189] Female subjects of childbearing potential with a positive pregnancy test assessed at Screening by a serum pregnancy test and/or urine pregnancy test.
[00190] Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 7 days after the last dose of sotorasib.
[00191] Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 7 days after the last dose of sotorasib.
[00192] Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 4 months after the last dose of trametinib.
[00193] Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 4 months after the last dose of trametinib.
[00194] Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 7 days after the last dose of sotorasib.
[00195] Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 7 days after the last dose of sotorasib.
[00196] Male subjects unwilling to abstain from donating sperm during treatment with sotorasib and for an additional 7 days after the last dose of sotorasib.
[00197] Male subjects (including those who have had vasectomies) with a female partner of childbearing potential who are unwilling to practice abstinence or use a condom during treatment and for an additional 4 months after the last dose of trametinib.
[00198] Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 4 months after the last dose of trametinib. [00199] Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and an additional 2 months after the last dose of panitumumab, when relevant.
[00200] Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 2 months after the last dose of panitumumab, when relevant.
[00201] Statistical considerations:
[00202] The primary analysis for sotorasib in combination with trametinib (Part 1 and Part 2) and sotorasib in combination with trametinib and panitumumab (Part 3 and Part 4) occurs when target enrollment for all parts is complete, and each subject either completes at least 6 months on study or withdraws from the study.
[00203] Objectives and Endpoints
Figure imgf000042_0001
Figure imgf000043_0001
[00204] Dose Limiting Toxicities:
[00205] The DLT window (i.e., DLT-evaluable period) will be the first 21 days of sotorasib and trametinib treatment (starting cycle 1 , day 1) for Part 1 or the first 28 days of sotorasib, trametinib, and panitumumab treatment (Part 3). The grading of AEs will be based on the guidelines provide din the CTCAE version 5.0. A subject is DLT evaluable if the subject has completed the DLT window as described above and received ³80% of the planned dose of sotorasib and trametinib (and panitumumab, if applicable) or experienced a DLT any time during the DLT window. A subject without a DLT will not be DLT evaluable if the date of decision to end both investigational products is before the completion of the DLT window.
[00206] DLT is defined as any adverse event meeting the criteria listed below occurring during the first treatment cycle and attributable to sotorasib and/or trametinib and/or panitumumab, if applicable.
[00207] (1) An adverse event that results in permanent discontinuation of any investigational product (except infusion reactions for panitumumab for subjects enrolled in Part 3 and Part 4)
(2) Febrile neutropenia
(3) Neutropenic infection
(4) Grade 4 neutropenia of any duration
(5) Grade 3 neutropenia lasting > 7 days
(6) Grade 3 thrombocytopenia for > 7 days
(7) Grade 3 thrombocytopenia with grade ³ 2 bleeding
(8) Grade 4 thrombocytopenia
(9) Grade 4 anemia
(10) Grade ³ 4, vomiting or diarrhea
(11) Grade 3 vomiting or grade 3 diarrhea lasting more than 3 days despite optimal medical support
(12) Grade ³ 3 nausea lasting 3 days or more despite optimal medical support
(13) Grade 3 ALT or AST elevations lasting more than 5 days
(14) Grade ³ 4 elevations of ALT or AST of any duration
(15) Grade ³ 3 bilirubin elevation
(16) Retinal vein occlusion, interstitial lung disease (ILD)/pneumonitis, symptomatic congestive heart failure, absolute decrease in LVEF of greater than 20% from baseline that is below the lower limit of normal, and life threatening pulmonary embolism
(17) Any other grade ³ 3 AE with the following exceptions:
- DLT Exemption: grade 3 fatigue < 1 week
-DLT Exemption: Asymptomatic grade 3 electrolyte abnormalities that last < 72 hours, are not clinically complicated, and resolve spontaneously or respond to medical interventions
-DLT Exemption: grade 3 amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitis
-DLT Exemption: Other select lab abnormalities that do not appear to be clinically relevant or harmful to the patient and/or can be corrected with replacement or modifications (e.g., grade 3 lymphopenia, grade 3 hypoalbuminemia)
(18) Grade 3 skin toxicity related to panitumumab and/or trametinib in the opinion of the Investigator that improves to < grade 3 within 3 weeks (only applicable to Part 3 and Part 4)
[00208] Any subject meeting the criteria for Hy’s Law case (i.e., severe drug-induced liver injury [DILI]) will be considered a DLT. A Hy’s Law case is defined as: AST or ALT values of ³ 3 x ULN AND with serum total bilirubin level (TBL) of > 2 x ULN without signs of cholestasis and with no other clear alternative reason to explain the observed liver related laboratory abnormalities.
[00209] Sotorasib Dose Modifications:
[00210] Dose reduction levels of sotorasib for toxicity management of individual subjects is provided in the following table. Up to two reductions are allowed. Dose reductions below 240 mg are not allowed.
Figure imgf000044_0001
QD = once daily
[00211] Sotorasib will be discontinued, or dosage reduced, in the event of a toxicity that, in the opinion of the investigator, warrants the discontinuation, or dose reduction as indicated in the table below (Sotorasib dose modification guidelines for hematologic and non-hematologic toxicities). Subjects who experience an adverse event requiring dose reductions below 240 mg should be permanently discontinued from sotorasib treatment.
[00212] Sotorasib dose modification guidelines for hematologic and non-hematologic toxicities.
Figure imgf000045_0002
3 Subjects may be resumed at a dose lower than the recommended restarting dose after discussion with the Medical Monitor bFor subjects with hepatotoxicity, see below
[00213] If sotorasib is held, panitumumab should be held as well. Trametinib treatment can be continued if sotorasib is held.
[00214] Hepatotoxicity Guidelines for Sotorasib: Guidelines for management and monitoring of subjects with increased AST, ALT, or alkaline phosphatase (ALP) are presented in the table below
Figure imgf000045_0001
Figure imgf000046_0001
Common Terminology Criteria for Adverse Events; INR = international normalized ratio; LFT = liver function test; TBL = total bilirubin; ULN = upper limit of normal; ULOQ = upper limits of quantification a If increase in AST/ALT is likely related to alternative agent, discontinue causative agent and await resolution to baseline or grade 1 prior to resuming sotorasib. b For example: prednisone 1 to 2 mg/kg/day, dexamethasone equivalent, or methylprednisone equivalent followed by a taper. The taper may occur after restarting sotorasib. c Close monitoring at restart (e.g., daily LFTs x 2, then weekly x 4). Sotorasib dose may be increased after discussion with Medical Monitor. d There is no limit to the number of sotorasib re-challenges for isolated alkaline phosphatase elevations that resolve to baseline or grade 1. e Dose decrements below 240 mg are not allowable. Subjects may restart at same dose without dose reduction. [00215] Hepatotoxicity Response: Subjects with abnormal hepatic laboratory values (i.e., alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBL)) and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as described below) may meet the criteria for withholding or permanent discontinuation of sotorasib or other protocol-required therapies, as specified in the Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009.
[00216] The following stopping and/or withholding rules apply to subjects for whom another cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been identified. Important alternative causes for elevated AST/ALT and/or TBL values include, but are not limited to: Hepatobiliary tract disease; Viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); Right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; Heritable disorders causing impaired glucuronidation (e.g., Gilbert’s syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); Alpha-one antitrypsin deficiency; Alcoholic hepatitis; Autoimmune hepatitis; Wilson’s disease and hemochromatosis; Nonalcoholic fatty liver disease including steatohepatitis; and/or Non-hepatic causes (e.g., rhabdomyolysis, hemolysis).
[00217] Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and/or the laboratory abnormalities resolve to normal or baseline, as described in the below.
Figure imgf000047_0002
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal
[00218] Panitumumab Dose Modifications:
[00219] For subjects who experience toxicities while on study, 1 or more doses of panitumumab are withheld, reduced, or delayed (administered at > 14 day intervals). Exemplary panitumumab dose reductions are listed in the table below.
Figure imgf000047_0001
[00220] Criteria for Withholding and Discontinuing Dose Modification [00221] Dermatological Toxicity
[00222] Exemplary panitumumab dose modification guidelines due to dermatological toxicities are provided in the table below.
Figure imgf000048_0001
[00223] In the event of severe or life-threatening inflammatory or infectious complications, consider withholding or discontinuing panitumumab as clinically appropriate.
[00224] Management of Skin Toxicities
[00225] It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving panitumumab as sunlight can exacerbate any skin reactions that may occur. Proactive skin treatment including skin moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) may be useful in the management of skin toxicities. Subjects may be advised to apply moisturizer and sunscreen to face, hands, feet, neck, back and chest every morning during treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every night. Treatment of skin reactions should be based on severity and may include a moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics, as prescribed by a physician.
[00226] Pulmonary Toxicity
[00227] In the event of acute onset or worsening of pulmonary symptoms, consider withholding panitumumab. If interstitial lung disease is confirmed, discontinue panitumumab.
[00228] Ocular Toxicity [00229] Monitor for keratitis or ulcerative keratitis. In the event of acute or worsening keratitis, withhold or discontinue panitumumab.
[00230] Other Toxicity
[00231] For toxicities other than dermatologic, pulmonary or ocular, withhold panitumumab for any grade 3 or 4 panitumumab-related toxicity with the following exceptions:
[00232] - Panitumumab will only be withheld for symptomatic grade 3 or 4 hypomagnesemia and/or hypocalcemia that persists despite aggressive magnesium and/or calcium replacement
[00233] - Panitumumab will only be withheld for grade 3 or 4 nausea, diarrhea, or vomiting that persists despite maximum supportive care.
[00234] Criteria for Re-T reatment with Panitumumab
[00235] For dermatological toxicities, see above. For toxicities other than dermatologic: If panitumumab was withheld, administration may recommence once the adverse event has improved to £ grade 1 or returned to baseline.
[00236] Episodes of visual changes have been observed in subjects receiving trametinib and panitumumab.
An ophthalmologist should be consulted if changes in vision develop. However, if the visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic examination.
[00237] Special attention should be given to retinal findings (e.g., retinal pigment epithelial detachment (RPED) or retinovascular abnormalities (i.e., branch or central retinal vein occlusions (RVO). For events of visual changes (regardless of severity) for which an ophthalmic examination is conducted, a blood sample for PK analysis must be drawn as close as possible to the time of the event. Guidelines regarding management and dose reduction for visual changes and/or ophthalmic examination findings considered to be related to study treatment are provided in the following table.
Figure imgf000049_0001
Figure imgf000050_0001
[00238] Recommended dose modifications for trametinib for retinal pigment epithelial detachments (RPED) are as follows:
Figure imgf000050_0002
ADL = activities of daily living; CTCAE = Common Terminology Criteria for Adverse Events; RPED = retinal pigment epithelial detachment. a Refers to CTCAE Version 4.0 'Retinopathy
[00239] Concomitant treatment
[00240] Avoid co-administration of sotorasib with proton pump inhibitors and H2 receptor antagonists. If an acid-reducing agent cannot be avoided, administered sotorasib 4 hours before of 10 hours after a local antacids.
[00241] Breast cancer resistance protein (BCRP) substrates should be used with caution when co administered with sotorasib, which may increase the circulating concentrations of BCRP substrates.
[00242] Efficacy Assessments / Radiological Imaging Assessment [00243] The extent of disease will be evaluated by contrast-enhanced MRI/CT according to RECIST v1.1. In order to reduce radiation exposure for subjects, the lowest dose possible should be utilized whenever possible.
[00244] The screening scans must be performed within 28 days prior to enrollment and will be used as baseline. Imaging performed as part of standard of care that falls within the 28 day screening window given for scans may be used for the baseline scan as long as it meets the scan requirements for screening. All subsequent scans will be performed in the same manner as at screening, with the same contrast, preferably on the same scanner. Radiological assessment must include CT of the chest, and contrast-enhanced CT or MRI of the abdomen and pelvis, as well as assessment of all other known sites of disease as detailed within the Site Imaging Manual.
[00245] The same imaging modality, MRI field strength and IV and oral contrast agents should be used at screening should be used for all subsequent assessments. Liver specific MRI contrast agents should not be used. To reduce potential safety concerns, macrocyclic gadolinium contrast agents are recommended per National Health Institute guidelines or follow local standards if more rigorous.
[00246] During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, as well as all other known sites of disease, will be performed independent of treatment cycle every 6 ± 1 weeks for the first 4 response assessments. After 4 (6 week) response assessments, radiological imaging and tumor assessment will be performed every 12 + 1 weeks. Radiologic imaging and tumor assessment will be performed until disease progression, start of new anti-cancer treatment, death, withdrawal of consent or until end of study. Imaging may also be performed more frequently if clinically necessitated at the discretion of the managing physician. Radiographic response (CR, PR) requires confirmation by a repeat, consecutive scan at least 4 weeks after the first documentation of response and may be delayed until the next scheduled scan to avoid unnecessary procedures.
[00247] All subjects must have MRI of the brain performed within 28 days prior to first dose of sotorasib. Subsequently, brain scans may be performed at any time if clinically indicated, in the judgement of the managing physician. All brain scans on protocol are required to be MRI unless MRI is contraindicated, and then CT with contrast is acceptable.
[00248] Radiological imaging assessment at the end of the study or during the end of treatment (EOT) visit should be performed only for subjects that discontinue treatment for a reason other than disease progression per RECIST v1.1 guidelines.
[00249] Determination of disease response for clinical management of subjects will be assessed at the clinical sites per RECIST v1 .1 . Scans may be submitted to a central imaging core laboratory for archival and (if necessary) independent response assessment utilizing RECIST v1 .1 criteria. Exploratory imaging analyses may be performed centrally and may include tumor volumetries, viable tumor measurements, tissue necrosis ratios, and lesion texture analysis (radiomics). [00250] Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
[00251] Definitions [00252] Measurable Lesions
[00253] Measurable Tumor Lesions - Non-nodal lesions with clear borders that can be accurately measured in at least 1 dimension with longest diameter ³ 10 mm in CT/MRI scan with slice thickness no greater than 5 mm. When slice thickness is greater than 5 mm, the minimum size of measurable lesion should be twice the slice thickness.
[00254] Nodal Lesions - Lymph nodes are to be considered pathologically enlarged and measurable, a lymph node must be ³ 15 mm in short axis when assessed by CT/MRI (scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis is measured and followed. Nodal size is normally reported as two dimensions in the axial plane. The smaller of these measures is the short axis (perpendicular to the longest axis).
[00255] Irradiated Lesions - Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are not measurable unless there has been demonstrated progression in the lesion prior to enrollment.
[00256] Non-measurable Lesions: All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes with ³ 10 mm but to < 15 mm short axis with CT scan slice thickness no greater than 5 mm) are considered non-measurable and characterized as non-target lesions.
[00257] Other examples of non-measurable lesions include:
[00258] -Lesions with prior local treatment: tumor lesions situated in a previously irradiated area, or an area subject to other loco-regional therapy, should not be considered measurable unless there has been demonstrated progression in the lesion.
[00259] -Biopsied lesions.
[00260] Categorically, clusters of small lesions, bone lesions, inflammatory breast disease, and leptomeningeal disease are non-measurable.
[00261] Methods of Measurement
[00262] Measurement of Lesions - The longest diameter of selected lesions should be measured in the plane in which the images were acquired (axial plane). All measurements should be taken and recorded in metric notation. All baseline evaluations should be performed as closely as possible to the beginning of treatment and not more than 4 weeks before study Day 1 .
[00263] Methods of Assessment - The same method of assessment and the same technique should be used to characterize each identified and reported lesion throughout the trial. [00264] CT / MRI - Contrast-enhanced CT or MRI should be used to assess all lesions. Optimal visualization and measurement of metastasis in solid tumors requires consistent administration (dose and rate) of IV contrast as well as timing of scanning. CT and MRI should be performed with £ 5 mm thick contiguous slices.
[00265] Baseline documentation of “Target” and “Non-target” lesions
[00266] Target Lesions - All measurable lesions up to a maximum of two (2) lesions per organ and five (5) lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline.
[00267] Target lesions should be selected on the basis of their size (lesions with the longest diameter) and suitability for accurate repeated measurements.
[00268] Pathologic lymph nodes (with short axis ³ 15 mm) may be identified as target lesions. All other pathological nodes (those with short axis ³ 10 mm but < 15 mm) should be considered non-target lesions.
[00269] A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions are calculated and reported as the baseline sum of diameters. The baseline sum of diameters are used as reference by which to characterize objective tumor response.
[00270] Non-T arget Lesions - All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, and these lesions should be followed as “present”, “absent”, or “unequivocal progression” throughout the study. In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case report form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).
[00271] Response Criteria
Evaluation of Target Lesions
Figure imgf000053_0001
Evaluation of Non-target Lesions
Figure imgf000054_0001
To achieve “unequivocal progression” on the basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for unequivocal progression status.
[00272] Evaluation of Overall Response
[00273] The best overall response is the best response recorded from the start of the study treatment until the end of treatment or disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
[00274] In general, the subject's best response assignment depends on the findings of both target and non target disease and also take into consideration the appearance of new lesions.
Time Point response: Subjects with Target (+/- Non-target) Disease
Figure imgf000054_0002
vIE = Not evaluable Time Point Response: Subjects with Non-Target Disease Only
Figure imgf000055_0002
1 “Non-CR/non-PD” is preferred over “SD” for non-target disease since SD is increasingly used as endpoint for assessment of efficacy in some trials so as to assign this category when no lesions can be measured is not advised.
Overall Response: Confirmation of Complete Response (CR) and Partial Response (PR) required
Figure imgf000055_0001
1 1f a CR is truly met at first time point, then any disease at a subsequent time point, even if disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend upon whether minimum duration for SD was met. However, sometimes “CR” may be claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
[00275] Special Notes on Response Assessment
[00276] Nodal lesions - Lymph nodes identified as target lesions should always have the actual short axis measurement recorded, even if the nodes regress to below 10 mm on study. In order to qualify for CR, each node must achieve a short axis < 10 mm, NOT total disappearance. Nodal target lesion short axis measurements are added together with target lesion’ longest diameter measurements to create the sum of target lesion diameters for a particular assessment (time point).
[00277] Target lesions that become “too small to measure” - While on study, all lesions (nodal and non-nodal) recorded at baseline should have their measurements recorded at each subsequent evaluation. If a lesion becomes less than 5 mm, the accuracy of the measurement becomes reduced. Therefore, lesions less than 5 mm are considered as being “too small to measure” and are not measured. With this designation, they are assigned a default measurement of 5mm. No lesion measurement less than 5mm should be recorded, unless a lesion totally disappears and “0” can be recorded for the measurement.
[00278] New lesions - The term “new lesion” always refers to the presence of a new finding that is definitely tumor. New findings that only may be tumor, but may be benign (infection, inflammation, etc.) are not selected as new lesions, until that time when the review is certain they represent tumor.
[00279] If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date of the initial scan.
[00280] A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression, regardless of any response that may be seen in target or non-target lesions present from baseline.
[00281] Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having “symptomatic deterioration.” Every effort should be made to document the objective progression with an additional imaging assessment even after discontinuation of treatment.
[00282] In some circumstances it may be difficult to distinguish residual disease from scar or normal tissue. When the evaluation of complete response (CR) depends on this determination, it is recommended that the residual lesion be further investigated by fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET/computed tomography (PET/CT), or possibly fine needle aspirate/biopsy, to confirm the CR status.
[00283] Confirmation Measurement / Duration of Response
[00284] Response Confirmation - In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is required to ensure responses identified are not the result of measurement error.
[00285] Duration of overall response -The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date the recurrent or progressive disease is objectively documented or death, whichever is earlier.
[00286] Duration of Stable Disease - SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started, or death, whichever is earlier.
[00287] ECOG Performance and NYHA Classification
Figure imgf000057_0001
Source: Oken et al, 1982; ECOG = Eastern Cooperative Oncology Group;
[00288] New York Heart Association Functional Classification
[00289] Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea.
[00290] Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnea.
[00291] Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation or dyspnea.
[00292] Class IV Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest. If any physical activity is undertaken, discomfort is increased.
[00293] Preliminary results: [00294] Patients with pretreated, KRAS G^C-mutated NSCLC, CRC or other types of solid tumors were enrolled. In part 1 , sotorasib was given as a fixed oral daily dose of 960 mg. The planned oral daily doses of trametinib were 1 mg (dose level 1), 2 mg (dose level 2), and 0.5 mg (dose level -1). Primary endpoint was safety, including dose-limiting toxicities and adverse events; secondary endpoint was efficacy, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), etc.
[00295] Among 18 NSCLC patients receiving treatment with sotorasib (960 mg) and trametinib (1 mg or 2 mg), 3 patients exhibited a best overall response of partial response (PR), 12 patients exhibited a stable disease (SD) and 2 had a progressive disease (PD). For NSCLC, of 3 patients that had received prior treatment with a KRAS G12C inhibitor, 2 patients exhibited clinically meaningful tumor shrinkage compared to baseline.
[00296] Among 17 CRC patients receiving treatment with sotorasib (960 mg) and trametinib (1 mg or 2 mg), 2 patients exhibited a best overall response of PR, 11 patients exhibited SD, and 3 exhibited PD. Finally, of the 6 patients having other cancers (appendiceal, appendix, endometrial, other solid tumor, pancreatic, and papillary adenocarcinoma) receiving treatment with sotorasib (960 mg) and trametinib (1 mg or 2 mg), all exhibited a best overall response of SD.
[00297] Results also showed that the combination of sotorasib and trametinib was safe and tolerable.
[00298] Preliminary results (September 1, 2021 data cut)
[00299] Patients with pretreated, KRAS G^C-mutated NSCLC, CRC or other types of solid tumors were enrolled. In part 1 , sotorasib was given as a fixed oral daily dose of 960 mg. The planned oral daily doses of trametinib were 1 mg or 2 mg. Primary endpoint was safety, including dose-limiting toxicities and adverse events; secondary endpoint was efficacy, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS) per RECIST 1.1.
[00300] A total of 41 patients were enrolled. Among the 18 CRC patients (7 of which were previously treated with a KRASG12C inhibitor), 3 patients received treatment with sotorasib 960 mg and trametinib 1 mg, and 15 patients received sotorasib 960 mg and trametinib 2 mg. Among the 18 NSCLC patients (3 of which were previously treated with a KRASG12C inhibitor), all received sotorasib 960 mg and trametinib 2 mg. Among the 5 patients with other solid tumors (2 of which were previously treated with a KRASG12C inhibitor), 3 received sotorasib 960 mg and trametinib 2 mg. The baseline characteristics were as follows:
Figure imgf000059_0001
[00301] Median treatment duration of the combination therapy was 2.8 months (range 0.3 to 12.9 months). No drug interactions between sotorasib and trametinib were observed.
[00302] Treatment-related adverse events (TRAE) occurred in 95.1% of all patients (39 of 41), with 34.1 %
(14 patients) exhibiting a grade ³ 3 TRAE and 2.4% (1 patient) exhibiting a grade ³ 4 TRAE. The most common TRAEs (which include TRAEs with >20% patient incidence across all grades and/or grade ³3 with >5% patient incidence) included diarrhea (all grades 43.9%, 18 patients, and ³3 grade 4.9%, 2 patients); rash (34.1%, 14 patients, all grade £2); dermatitis acneiform (all grades 31.7%, 13 patients, and ³3 grade 2.4%, 1 patient); nausea (29.3%, 12 patients, all grade £2); vomiting (22.0%, 9 patients, all grade £2); peripheral edema (19.5%,
8 patients, all grade £2); ejection fraction decreased (all grades 17.1%, 7 patients, and ³3 grade 7.3%, 3 patients); and blood creatine phosphokinase increased (all grades 14.6%, 6 patients, and ³3 grade 7.3%, 3 patients). Other grade 3 TRAEs reported included dyspnea, erythema muliforme, fatigue, hypertension, hypokalemia, neutropenia, and maculo-papular rash. No new or unexpected toxicities were identified.
[00303] In patients that received treatment with a prior KRASG12C inhibitor, 6 of 7 patients (86%) with CRC and 2 of 3 (67%) with NSCLC achieved disease control. A summary of the tumor response in all patients is provided in the table below.
Figure imgf000060_0001
*Number of patients in objective response rate (ORR) analysis set who received ³ 1 dose of investigational products, have ³ 1 measurable lesion at baseline assessed using RECIST 1.1 and have the opportunity to be followed for ³ 7 weeks starting from day 1. For the 5 patients with other solid tumor treated with sotorasib 960 mg/trametinib 2 mg PO QD, all had stable disease. †Not evaluable due to death before first scan.
[00304] For CRC, decrease in target lesion size was observed in the majority (12/18; 67%) of patients.
Disease control was achieved in 6/7 patients (86%) with prior KRASG12C inhibitor therapy; 1 with partial response.
[00305] For NSCLC, decrease in target lesion size was observed in 15/17 (88%) patients. Disease control was achieved in 2 of 3 patients with prior KRASG12C inhibitor therapy (2 SD; 1 PD). 7 patients had disease control for more than 6 months, 4 are ongoing at the time of cut-off.
[00306] In conclusion, the results showed that the combination of sotorasib and trametinib was safe in patients with heavily pre-treated KRASG12C mutated solid tumors. No new or unexpected toxicities were identified. Antitumor activity was observed in patients with and without prior KRASG12C inhibitor therapy. A partial and durable response (progression-free > 8 months) was observed in a CRC patient who had received prior KRASG12C inhibitor therapy. Disease control was achieved by the majority of patients previously treated with a KRASG12C inhibitor (86% disease control rate for CRC, 67% disease control rate for NSCLC).
[00307] Preliminary data (March 14, 2022 data cut)
[00308] Patients with pretreated, KRAS G12C-mutated NSCLC, CRC or other types of solid tumors were enrolled in Part 3. A total of eight (8) patients were treated at Dose Level 1 . At Dose Level 1 , all 8 patients were treated with daily sotorasib 960 mg and trametinib 1 .5 mg oral tablets, plus panitumumab 4.8 mg/kg intravenously Q2W. Endpoints included partial response (PR), progressive disease (PD), and stable disease (SD) per RECIST 1.1. [00309] The following table provides interim efficacy data from patients treated with the triplet drug combination of sotorasib/trametinib/panitumumab (n=8).
Figure imgf000061_0001
Example 2 - Pharmacokinetic Analysis of 960 mg, 360 mg, 180 mg, and 240 mg Sotorasib
[00310] Preliminary pharmacokinetic (PK) data were available for subjects with advanced solid tumors with the specific KRAS G12C mutation, with doses ranging from 180 to 960 mg PO QD. Dose-related increases in exposure on day 1 from 180 to 960 mg PO QD were observed. Increases in exposure were less than dose- proportional on day 1. There was no accumulation with multiple PO QD dosing for 8 days. The change in exposure from 180 to 960 mg PO QD was less than dose-proportional on day 8. Rapid absorption was observed with tmax between 1 to 2 hours after PO administration. Figure 1 shows the mean plasma concentration time profile after oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1. Figure 2 shows the concentrations after once daily dosing for 8 days (Day 8). The table below provides the pharmacokinetic parameters, where AUCo-24h is the area under the concentration-time curve from time 0 to 24 hr postdose; Cmax is the maximum observed drug concentration during a dosing interval; ti/2,z is the terminal elimination half-life; tmax is the time to reach Cmax. Data reported are presented as geometric mean (arithmetic CV%) except ax and , which are reported as a median (range) and arithmetic mean (SD), respectively. Values are reported to three significant figures, except CV% and tmax, which are reported to 0 decimal places and 2 significant figures, respectively.
Pharmacokinetic Parameter
AUCo-24h
Dose N (hr) (pg/mL) (hr· pg/mL) (hr)
180 mg Day 1 6 1.0 (0.50-2.0) 6.88 (51%) 44.0 (56%) 5.95 (1.08)3 Day 8 6 0.75 (0.50-1.0) 6.44 (67%) 33.5 (85%) 5.96 (2.76)b 360 mg Day 1 25 1.0 (0.50-24) 5.86 (68%) 56.8 (84%) 6.56 (1.81)3 Day 8 25 1.0 (0.25-4.0) 5.97 (46%) 37.4 (50%) 5.71 (1.59)d 720 mg Day 1 11 1.0 (0.50-4.0) 7.57 (59%) 64.0 (68%) 7.06 (1.59)3 Day 8 11 1.0 (0.50-4.0) 5.45 (50%) 43.9 (49%) 5.06 (1.24)' 960 mg
Day 1 25 2.0 (0.25-6.0) 8.33 (59%) 68.0 (77%) 6.00 (2.20)9
Day 8 25 1.0 (0.50-24) 4.91 (69%) 32.7 (70%)h 5.19 (1.12)' aN=5; bN=6; cN=17;dN=19; eN=8; fN=9;9|\|=18; hN=24; 'N=16;
Example 3 - Acquired resistance to sotorasib can be reversed with combination therapy with a MEK inhibitor
[00311] Briefly, a patient with stage IV NSCLC was initially treated with carboplatin/pemetrexed/pembrolizumab followed by maintenance pemetrexed/pembrolizumab. This regimen lead to a partial radiologic response lasting for nearly one year. After progressing on first-line therapy, the patient was treated with sotorasib 960mg and had a confirmed partial response lasting 5.6 months. After sotorasib monotherapy (ending on day 168) the patient was briefly treated with several lines of standard therapy, including ipilimumab/nivolumab, gemcitabine/vinorelbine and docetaxel/ramumirumab, without experiencing significant clinical or radiologic benefit. On day 308, the patient started sotorasib (960 mg) in combination with trametinib (2 mg) and had a partial response to therapy (unconfirmed timepoint response). The treatment has been well- tolerated without any adverse events leading to dose modifications.
Example 4 - Contraindication with co-administration of sotorasib with acid-reducing agents under fasted conditions
[00312] This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Subjects received 960 mg sotorasib on Day 1, 40 mg omeprazole once daily on Days 4 to 8, and 40 mg omeprazole followed by 960 mg sotorasib on Day 9. All doses were administered under fasted conditions. Blood samples for sotorasib PK were collected predose and up to 48 hours post-sotorasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods. [00313] Coadministration of sotorasib with omeprazole delayed sotorasib time to maximal plasma concentration (tmax) by 0.75 hours. Mean terminal half-life (tic) of sotorasib was similar following coadministration of sotorasib with omeprazole compared to administration of sotorasib alone. Geometric mean sotorasib AUCM (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) following coadministration of sotorasib with omeprazole (17000 h*ng/mL and 3100 ng/mL, respectively) were lower compared to administration of sotorasib alone (29300 h*ng/mL and 7200 ng/mL, respectively). Sotorasib was safe and well tolerated when coadministered with 40mg omeprazole or administered alone to healthy subjects.
[00314] Results indicated that coadministration of sotorasib with omeprazole, in the fasted state, decreased sotorasib AUCinf by 42% and Cmax by 57% compared with administration of sotorasib alone.
Example 5 - Contraindication with co-administration of sotorasib with acid-reducing agents under fed conditions
[00315] This was a phase 1 , open-label, fixed sequence, crossover, single-center study to explore mitigation strategies to limit the impact of acid-reducing agents on the exposure of sotorasib. This study evaluated the PK of sotorasib administered alone and in combination with famotidine or omeprazole in healthy men and women (a total of 14 subjects) underfed conditions. Subjects received a single dose of sotorasib on day 1, an evening dose of famotidine on day 3 (10 hours prior to sotorasib administration), a single dose of sotorasib on day 4 followed by another dose of famotidine 2 hours later, daily doses of omeprazole on day 6 through day 10, and a single dose of both omeprazole and sotorasib on day 11. All sotorasib administrations occurred following consumption of a standard calorie moderate fat meal. Blood was collected at predetermined timepoints to characterize plasma concentrations of sotorasib. Safety and tolerability monitoring was performed throughout the study.
[00316] A total of 15 healthy subjects (1 woman and 13 men) were enrolled in the study. Thirteen out of the 14 subjects received all treatments and completed the study.
[00317] Geometric least-square mean ratios of sotorasib AUCinf and Cmax were 0.622 and 0.654, respectively when comparing sotorasib coadministered with famotidine and sotorasib alone under fed conditions. Geometric least-square mean ratios of sotorasib AUCM and Cmax were 0.430 and 0.349, respectively, when comparing sotorasib coadministered with omeprazole and sotorasib alone. Doses of 960 mg sotorasib were safe and well tolerated with coadmnistered with a single dose of 40 mg famotidine and following multiple daily dosing of 40 mg omeprazole under fed conditions to healthy subjects.
[00318] In summary, coadministration of a single dose of famotidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after a single dose of sotorasib underfed conditions decreased sotorasib Cmax by 35% and AUC by 38%. In addition, co-administration of repeat doses of omeprazole (PPI) with a single dose of sotorasib decreased sotorasib Cmax by 65% and AUC by 57% under fed conditions. Example 6 - Contraindication with coadministration of sotorasib with strong CYP34A4 inducers
[00319] This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 960 mg sotorasib on Days 1, 3 and 18, and 600 mg rifampin on Day 3 and Days 5 to 19. Blood samples for sotorasib PK were collected predose and up to 48 hours post-sotorasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
[00320] Results:
[00321] Geometric mean sotorasib AUCM (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) following coadministration of single dose of rifampin with sotorasib (19600 h*ng/mL and 5340 ng/mL, respectively), were similar to those of sotorasib alone (25600 h*ng/mL and 6350 ng/mL, respectively). Geometric mean sotorasib AUCM and Cmax following coadministration of multiple doses of rifampin with sotorasib (12400 h*ng/mL and 4110 ng/mL, respectively), were lower compared to those of sotorasib alone (25600 h*ng/mL and 6350 ng/mL, respectively).
[00322] Sotorasib was safe and well tolerated when coadministered with 600 mg rifampin or administered alone to healthy subjects. Single dose of rifampin did not have a clinically meaningful effect on sotorasib PK indicating sotorasib is not a substrate of OATP1 B1. Multiple doses of rifampin decreased sotorasib AUCinf by 51% and Cmaxby 35%, indicating sotorasib is a CYP3A4 substrate, consistent with in vitro data.
Example 7 - Contraindication with coadministration of sotorasib with CYP34A substrates
[00323] This Phase 1 , open-label, fixed-sequence study enrolled 5 subjects with previously untreated NSCLC who received a single, oral dose of 2 mg midazolam alone of day -1, 960 mg sotorasib orally on days 1 through 14, and a single oral dose of 2 mg midazolam at approximately the same time as an oral dose of 960 mg sotorasib on day 15. Blood samples for sotorasib PK were collected predose and up to 48 hours post-sotorasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
[00324] Single dose plasma midazolam PK data were obtained from 5 subjects who received midazolam alone and midazolam coadministered with sotorasib following 14 days of multiple daily dosing of sotorasib. Results indicated that exposure to midazolam decreased when coadministered with sotorasib following multiple daily dosing with sotorasib. Coadministration of sotorasib with midazolam (a sensitive CYP3A4 substrate) decreased midazolam Cmax by 48% and AUV by 53%.
Example 8 - Contraindication with coadministration of sotorasib and P-gp substrates
[00325] This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 0.5 mg digoxin on Day 1 and 960 mg sotorasib followed by 0.5 mg digoxin on Day 7. Blood samples for digoxin PK were collected predose and up to 144 hours post-digoxin dose. Samples were measured using validated high-performance liquid chromatography tandem mass spectrometry methods. PK parameters were estimated using non-compartmental methods. Safety and tolerability were monitored throughout the study. [00326] Digoxin median time to maximal plasma concentration (tmax) and mean terminal half-life (tic) were similar following coadministration of digoxin with sotorasib compared to those of digoxin alone. Geometric mean digoxin AUCinf (area under the curve from time zero to infinity) following coadministration of digoxin with sotorasib (40.3 h*ng/mL) was similar to that of digoxin alone (33.2 h*ng/mL). Geometric mean digoxin Cmax (maximal plasma concentration) following coadministration of digoxin with sotorasib (3.64 ng/mL) was higher compared to that of digoxin alone (1 .90 ng/mL). Single doses of 0.5 mg digoxin were safe and well tolerated when administered alone or coadministered with 960 mg sotorasib.
[00327] Results indicated that coadministration of digoxin with a single dose of sotorasib increased digoxin AUCinf and Cmax by approximately 21% and 91%, respectively, compared with digoxin alone.
[00328] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
[00329] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.
[00330] References:
Albert et al„ (2007) Nat. Methods 4:903-905.
Alizadeh et al„ (1996) Nat. Genet. 14:457-460.
Beers and Nederlof, (2006) Breast Cancer Res. 8(3):210.
Bertone et al., (2006) Genome Res. 16(2):271-281.
Canon, et al„ (2019) Nature, 575(7781), 217.
Cerami, et al., (2012) Cancer Discov., 2(5), 401.
Chung et al., (2004) Genome Res., 14(1):188-196.
Cully M, Downward J„ (2008) Cell, 133:1292.
Dalma-Weiszhausz et al.. (2006) Methods Enzymol., 410:3-28.
Eisenhauer, et al., (2009) Eur. J. Cancer, 45:228-247.
Falchook et al., (2012) Lancet Oncol., 13(8)782-789.
Flaherty et al., (2012) N. Eng. J. Med., 367(18):1694-1703.
Forshew et al., (2012) Sci. Transl. Med., 4:136ra68.
Gao, et al. (2013) Science Signaling, 6(269), pH. Gilmartin, et al., (2011) Clin. Cancer Res., 17(5):989-1000. Erratum in: (2012) Clin Cancer Res., 18(8):2413.
Guo et al., (2017) Contemp. Clin. Trials., 58:23-33.
Haber and Velculescu, (2014) Cancer Discov., 4:650-61.
Hong, et al., (2020) N. Engl. J. Med., 383, 1207.
Hughes et al., (2001) Nat. Biotechnol., 19(4):342-347.
Irizarry, (2003) Nucleic Acids Res., 31 :e15.
Janes et al., (2018) Cell, 172(3):578-589.
Jasmine et al., (2012) PLoS One 7(2):e31968.
Ji, et al., (2010) Clin Trials, 7(6):653-663.
Kim et al., (2006) Carcinogenesis, 27(3):392-404.
Kinde et al., (2011) Proc. Natl. Acad. Sci USA, 108:9530-5.
Kumar et al., (2012) J. Pharm. Bioallied Sci., 4(1):21-26.
Laere et al., (2009) Methods Mol. Biol., 512:71-98.
Lanman, et al., (2020) J. Med. Chem., 2020, 63, 52.
Lin et al., (2010) BMC Genomics, 11:712.
Liu et al., (2017) Biosens Bioelectron., 92:596-601.
Lodes et al., (2009) PLoS One 4(7):e6229.
LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision
5/2021)
Mackay et al., (2003) Oncogene, 22:2680-2688.
Mao et al., (2007) Curr. Genomics, 8(4):219-228.
McDonald et al., (2017) Cell, 170(3):577-592.
MEKINIST® US Prescribing Information. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, revision 5/2021)
Michels et al., (2007) Genet. Med., 9:574-584.
Mockler and Ecker, (2005) Genomics, 85(1): 1 -15.
Oken et al., (1982) Am. J. Clin. Oncol., 5(6):649-655.
Ostrem, et al., (2013) Nature, 503:548-551. Ostrem and Shokat., (2016) Nature Rev. Drug Discov., 15(11):771-785.
Patricelli et al., (2016) Cancer Discovery, 6:316-329.
Pinkel et al., (2005) Nat. Genetics, 37:S11-S17.
Simanshu et al., (2017) Cell, 170:17-33.
Thomas et al., (2005) Genome Res., 15(12): 1831-1837.
Thompson et al., (2012) PLoS ONE, 7:e31597.
VECTIBIX® US Prescribing Information. Amgen Inc., Thousand Oaks, California, 91320, revision/2017
Wang et al., (2012) Cancer Genet., 205(7-8) :341 -55.
Wei et al., (2008) Nucleic Acids Res., 36(9):2926-2938.
Xie et al., (2017), Front Pharmacol.; 8:823.
Zubrod et al., (1960), J. Chronic Disease, 11:7-33.

Claims

What is claimed is:
1. A method of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and trametinib once daily, wherein the sotorasib and trametinib are administered to the patient in amounts effective to treat the cancer.
2. The method of claim 1, comprising administering 960 mg sotorasib to the patient.
3. The method of claim 1, comprising administering 240 mg sotorasib to the patient.
4. The method of any one of claims 1-3, comprising administering 1 mg trametinib to the patient.
5. The method of any one of claims 1-3, comprising administering 2 mg trametinib to the patient.
6. The method of any one of claims 1-3, comprising administering 0.5 mg trametinib to the patient.
7. The method of claim 1 , comprising orally administering 960 mg sotorasib and 1 mg trametinib once daily to the patient.
8. The method of claim 1 , comprising orally administering 960 mg sotorasib and 2 mg trametinib once daily to the patient.
9. The method of claim 1 , comprising orally administering 960 mg sotorasib and 0.5 mg trametinib once daily to the patient.
10. The method of any one of claims 1-9, wherein two subsequent doses of trametinib are administered about 24 hours apart.
11 . The method of any one of claims 1-10, wherein the patient is treated for one or more treatment cycles, wherein the treatment cycle is a 21 day treatment cycle.
12. The method of any one of claims 1-11, further comprising administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient every two weeks.
13. The method of claim 12, wherein the anti-EGFR antibody comprises a heavy chain variable region comprising HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8
14. The method of claim 13, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 4 and the light chain variable region comprises the sequence of SEQ ID NO: 9.
15. The method of claim 14, wherein the anti-EGFR antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 5 and a light chain comprising the sequence of SEQ ID NO: 10.
16. The method of claim 12, wherein the anti-EGFR antibody is panitumumab.
17. The method of any one of claims 12-16, wherein , wherein the patient is treated for one or more treatment cycles, wherein the treatment cycle is a 28 day treatment cycle.
18. The method of any one of claims 12-17, comprising administering 4.8 mg/kg panitumumab via IV administration to the patient.
19 The method of any one of claims 12-17, comprising administering 6 mg/kg panitumumab via IV administration to the patient.
20. The method of any one of claims 12-17, comprising administering 3.6 mg/kg panitumumab via IV administration to the patient.
21. The method of any one of claims 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and
(b) 4.8 mg/kg panitumumab via IV administration every two weeks.
22. The method of any one of claims 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and
(b) 6 mg/kg panitumumab via IV administration every two weeks.
23. The method of any one of claims 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1 .5 mg trametinib orally once daily; and
(b) 6 mg/kg panitumumab via IV administration every two weeks.
24. The method of any one of claims 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 2 mg trametinib orally once daily; and
(b) 6 mg/kg IV panitumumab via IV administration every two weeks.
25. The method of any one of claims 12-17 comprising administering to the patient
(a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and
(b) 4.8 mg/kg panitumumab via IV administration every two weeks.
26. The method of any one of claims 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1.5 mg trametinib orally once daily; and
(b) 3.6 mg/kg panitumumab via IV administration every two weeks.
27. The method of any one of claims 12-17, comprising administering to the patient
(a) 960 mg sotorasib orally and 1 mg trametinib orally once daily; and
(b) 3.6 mg/kg panitumumab via IV administration every two weeks.
28. The method of any one of claims 1-27, wherein the patient is resistant to therapy with a KRASG12C inhibitor.
29. The method of any one of claims 1-28, wherein the cancer is a solid tumor.
30. The method of any one of claims 1-29, wherein the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
31 . The method of any one of claims 1-29, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer (CRC).
32. The method of any one of claims 1-31, wherein the patient, prior to start of sotorasib and trametinib therapy and optionally panitumumab, had undergone at least one other systemic cancer therapy.
33. The method of claim 32, wherein the patient had undergone at least two other systemic cancer therapies.
34. The method of claim 32 or 33, wherein at least one systemic cancer therapy is selected from therapy with a KRASG12C inhibitor, anti-PD-1 therapy, anti-PD-L1 therapy, and platinum-based chemotherapy.
35. The method of claim 34, wherein the patient has previously undergone (i) an EGFR, ALK or ROS1 targeted therapy if the cancer also exhibited a mutation in EGFR, ALK, or ROS1, and (ii) an anti-PD1 therapy or anti-PD-L1 therapy, unless contraindicated, or a platinum-based chemotherapy.
36. The method of claim 34, wherein the patient has previously undergone (i) an EGFR, ALK or ROS1 targeted therapy if the cancer also exhibited a mutation in EGFR, ALK, or ROS1, and (ii) an anti-PD1 therapy or anti-PD-L1 therapy, unless contraindicated, and a platinum-based chemotherapy.
37. The method of claim 34, wherein the patient has previously undergone at least one platinum- based chemotherapy.
38. The method of claim 37, wherein the platinum-based chemotherapy comprises fluoropyrimidine, oxaliplatin, or irinotecan.
39. The method of any one of claims 1-38, wherein the patient exhibits at least a stable disease (SD) after 1, 3, or 6 months of sotorasib and trametinib therapy, as measured by RECIST 1.1 protocol.
40. The method of any one of claims 1-38, wherein the patient exhibits at least a partial response (PR) after 1 , 3, or 6 months of sotorasib therapy, as measured by RECIST 1.1 protocol.
41 . The method of any one of claims 1 -40, wherein the patient exhibits a progression free survival (PFS) of at least 3 months.
42. The method of any one of claims 1-41, wherein the patient does not have an active brain metastases or leptomeningeal disease from a non-brain tumor.
43. The method of any one of claims 1-42, wherein the patient is not suffering from a hepatitis A infection, a hepatitis B infection or a hepatitis C infection.
44. The method of any one of claims 1-43, wherein the patient is not suffering from retinal vein occlusion (RVO) or retinal pigment epithelial detachment or unresolved keratitis.
45. The method of any one of claims 1-44, wherein the patient is not suffering from interstitial pneumonitis or pulmonary fibrosis.
46. The method of any one of claim 1 -45, wherein the patient is in further need of treatment with an acid-reducing agent.
47. The method of claim 46, wherein the acid-reducing agent is a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), or a locally acting antacid.
48. The method of claim 46 or claim 47, wherein the acid-reducing agent is a locally acting antacid, and wherein sotorasib is administered about 4 hours before or about 10 hours after the locally acting antacid.
49. The method of claim 47 or 48, wherein the locally acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide.
50. The method of any one of claims 1-49, wherein the patient is in further need of treatment with a proton pump inhibitor (PPI) or H2 receptor antagonist (H2RA).
51 . The method of claim 50, wherein the patient is not administered a PPI or a H2RA in combination with sotorasib.
52. The method of any one of claims 47, 50 or 51, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole.
53. The method of any one of claims 47, 50 or 51, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine or lafutidine.
54. The method of any one of claims 1-53, wherein the patient is in further need of treatment with a CYP3A4 inducer.
55. The method of claim 54, wherein the patient is not administered a CYP3A4 inducer in combination with sotorasib.
56. The method of claim 54 or 55, wherein the CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, or troglitazone.
57. The method of claim 54 or claim 55, wherein the patient is not administered a strong CYP3A4 inducer in combination with sotorasib.
58. The method of claim 57, wherein the strong CYP3A4 inducer is phenytoin or rifampin.
59. The method of any one of claims 1-58, wherein the patient is in further need of treatment with a CYP3A4 substrate.
60. The method of claim 59, wherein the patient is not administered a CYP3A4 substrate in combination with sotorasib.
61 . The method of claim 59 or 60, wherein the CYP3A4 substrate is abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib, cyclosporine, dabrafenib, daclatasvir, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, dolutegravir, domperidone, doxepin, elagolix, elbasvir/grazoprevir, eliglustat, enzalutamide, eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, gleevec, haloperidol, hydrocortisone, ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isavuconazonium, ivabradine, ivacaftor, lansoprazole, lenvatinib, lercanidipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, midazolam, naldemedine, naloxegol, nateglinide, nelfinavir, neratinib, netupitant/palonosetron, nevirapine, nifedipine, nisoldipine, nitrendipine, olaparib, omeprazole, ondansetron, osimertinib, ospemifene, palbociclib, panobinostat, pantoprazole, perampanel, pimavanserin, pimozide, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, ribociclib, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast, rolapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus, sonidegib, sorafenib, sunitinib, suvorexant, tacrol i m us(f k506) , tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, vilazodone, vincristine, vorapaxar, voriconazole, zaleplon, or ziprasidone.
62. The method of any one of claims 1-61, wherein the patient is in further need of treatment with a P-glycoprotein (P-gp) substrate.
63. The method of claim 62, wherein the patient is not administered a P-gp substrate in combination sotorasib.
64. The method of claim 62 or claim 63, wherein the P-gp substrate is etexilate, digoxin, fexofenadine, , everolimus, cyclosporine, sirolimus, or vincristine.
65. The method of any one of claims 1-64, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of 1-49%.
66. The method of any one of claims 1-64, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of less than 1%.
67. The method of any one of claims 1-64, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of 50-100%.
68. The method of any one of claims 1-67, wherein the cancer further comprises a BRAF V600E or !/600Kmutation.
69. The method of any one of claims 1-68, wherein the cancer further comprises a STK11 mutation.
70. The method of any one of claims 1-68, wherein the cancer further comprises a KEAP1 mutation.
71. The method of any one claim 1-68 and 70, wherein the cancer further comprises a STK11 wild type.
72. The method of any one of claims 1-69, wherein the caner further comprises a KEAP1 wild type.
73. The method of claim 69 or claim 70, wherein the mutation is a loss-of-function mutation.
PCT/US2022/032395 2021-06-07 2022-06-06 Methods of treating cancer with a combination of sotorasib and trametinib WO2022261025A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200121788A1 (en) * 2018-10-19 2020-04-23 Merck Patent Gmbh Abituzumab for the treatment of colorectal cancer
US20200222407A1 (en) * 2018-11-19 2020-07-16 Amgen Inc. Combination therapy including a kras g12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2021076655A1 (en) * 2019-10-15 2021-04-22 Amgen Inc. Combination therapy of kras inhibitor and shp2 inhibitor for treatment of cancers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200121788A1 (en) * 2018-10-19 2020-04-23 Merck Patent Gmbh Abituzumab for the treatment of colorectal cancer
US20200222407A1 (en) * 2018-11-19 2020-07-16 Amgen Inc. Combination therapy including a kras g12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2021076655A1 (en) * 2019-10-15 2021-04-22 Amgen Inc. Combination therapy of kras inhibitor and shp2 inhibitor for treatment of cancers

Non-Patent Citations (54)

* Cited by examiner, † Cited by third party
Title
"Cecil Textbook of Medicine", 1985, W.B. SAUNDERS & CO., pages: 2317 - 2341
"Genbank", Database accession no. AGC09594
ALBERT ET AL., NAT. METHODS, vol. 4, 2007, pages 903 - 905
ALIZADEH ET AL., NAT. GENET., vol. 14, 1996, pages 457 - 460
ANONYMOUS: "NCT04185883 Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation", 28 June 2021 (2021-06-28), XP055961487, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/history/NCT04185883?V_32=View#StudyPageTop> *
BEERSNEDERLOF, BREAST CANCER RES., vol. 8, no. 3, 2006, pages 210
BERTONE ET AL., GENOME RES, vol. 16, no. 2, 2006, pages 271 - 281
CANON ET AL., NATURE, vol. 575, no. 7781, 2019, pages 217
CERAMI ET AL., CANCER DISCOV., vol. 2, no. 5, 2012, pages 401
CHUNG ET AL., GENOME RES., vol. 14, no. 1, 2004, pages 188 - 196
CULLY M, DOWNWARD J., CELL, vol. 133, 2008, pages 1292
DALMA-WEISZHAUSZ ET AL., METHODS ENZYMOL., vol. 410, 2006, pages 3 - 28
DIANA BRAUSWETTER ET AL: "Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers", PLOS ONE, vol. 12, no. 9, 28 September 2017 (2017-09-28), pages e0185687, XP055572028, DOI: 10.1371/journal.pone.0185687 *
EISENHAUER ET AL., EUR. J. CANCER, vol. 45, 2009, pages 228 - 247
ERRATUM, CLIN CANCER RES., vol. 18, no. 8, 2012, pages 2413
FALCHOOK ET AL., LANCET ONCOL., vol. 13, no. 8, 2012, pages 782 - 789
FLAHERTY ET AL., N. ENG. J. MED., vol. 367, no. 18, 2012, pages 1694 - 1703
FORSHEW ET AL., SCI. TRANSL. MED., vol. 4, 2012
GAO ET AL., SCIENCE SIGNALING, vol. 6, no. 269, 2013
GILMARTIN ET AL., CLIN. CANCER RES., vol. 17, no. 5, 2011, pages 989 - 1000
GUO ET AL., CONTEMP. CLIN. TRIALS., vol. 58, 2017, pages 23 - 33
HABERVELCULESCU, CANCER DISCOV., vol. 4, 2014, pages 650 - 61
HONG DAVID S. ET AL: "KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 383, no. 13, 24 September 2020 (2020-09-24), US, pages 1207 - 1217, XP055911440, ISSN: 0028-4793, Retrieved from the Internet <URL:https://www.nejm.org/doi/pdf/10.1056/NEJMoa1917239?articleTools=true> DOI: 10.1056/NEJMoa1917239 *
HONG ET AL., N. ENGL. J. MED., vol. 383, 2020, pages 1207
HUGHES ET AL., NAT. BIOTECHNOL., vol. 19, no. 4, 2001, pages 342 - 347
IRIZARRY, NUCLEIC ACIDS RES., vol. 31, 2003, pages e15
JANES ET AL., CELL, vol. 172, no. 3, 2018, pages 578 - 589
JASMINE ET AL., PLOS ONE, vol. 7, no. 2, 2012, pages e31968
JI ET AL., CLIN TRIALS, vol. 7, no. 6, 2010, pages 653 - 663
KIM ET AL., CARCINOGENESIS, vol. 27, no. 3, 2006, pages 392 - 404
KINDE ET AL., PROC. NATL. ACAD. SCI USA, vol. 108, 2011, pages 9530 - 5
KITAZAWA MASATO ET AL: "Drug sensitivity profile of minor KRAS mutations in colorectal cancer using mix culture assay: The effect of AMG-510, a novel KRAS G12C selective inhibitor, on colon cancer cells is markedly enhanced by the combined inhibition of MEK and BCL-XL", MOLECULAR AND CLINICAL ONCOLOGY, vol. 15, no. 1, 28 May 2021 (2021-05-28), GR, XP055961549, ISSN: 2049-9450, DOI: 10.3892/mco.2021.2310 *
KUMAR ET AL., J. PHARM. BIOALLIED SCI., vol. 4, no. 1, 2012, pages 21 - 26
LAERE ET AL., METHODS MOL. BIOL., vol. 512, 2009, pages 71 - 98
LANMAN ET AL., J. MED. CHEM., vol. 63, 2020, pages 52
LIN ET AL., BMC GENOMICS, vol. 11, 2010, pages 712
LIU ET AL., BIOSENS BIOELECTRON., vol. 92, 2017, pages 596 - 601
LODES ET AL., PLOS ONE, vol. 4, no. 7, 2009, pages e6229
MACKAY ET AL., ONCOGENE, vol. 22, 2003, pages 2680 - 2688
MAO ET AL., CURR. GENOMICS, vol. 8, no. 4, 2007, pages 219 - 228
MICHELS ET AL., GENET. MED., vol. 9, 2007, pages 574 - 584
MOCKLERECKER, GENOMICS, vol. 85, no. 1, 2005, pages 1 - 15
OKEN ET AL., AM. J. CLIN. ONCOL., vol. 5, no. 6, 1982, pages 649 - 655
OSTREM ET AL., NATURE, vol. 503, 2013, pages 548 - 551
OSTREMSHOKAT, NATURE REV. DRUG DISCOV., vol. 15, no. 11, 2016, pages 771 - 785
PATRICELLI ET AL., CANCER DISCOVERY, vol. 6, 2016, pages 316 - 329
PINKEL ET AL., NAT. GENETICS, vol. 37, 2005, pages S11 - S17
SIMANSHU ET AL., CELL, vol. 170, no. 3, 2017, pages 577 - 592
THOMAS ET AL., GENOME RES., vol. 15, no. 12, 2005, pages 1831 - 1837
THOMPSON ET AL., PLOS ONE, vol. 7, 2012, pages e31597
WANG ET AL., CANCER GENET., vol. 205, no. 7-8, 2012, pages 341 - 55
WEI ET AL., NUCLEIC ACIDS RES., vol. 36, no. 9, 2008, pages 2926 - 2938
XIE ET AL., FRONT PHARMACOL., vol. 8, 2017, pages 823
ZUBROD ET AL., J. CHRONIC DISEASE, vol. 11, 1960, pages 7 - 33

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