WO2023049363A1 - Sotorasib and afatinib for treating cancer comprising a kras g12c mutation - Google Patents

Sotorasib and afatinib for treating cancer comprising a kras g12c mutation Download PDF

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WO2023049363A1
WO2023049363A1 PCT/US2022/044557 US2022044557W WO2023049363A1 WO 2023049363 A1 WO2023049363 A1 WO 2023049363A1 US 2022044557 W US2022044557 W US 2022044557W WO 2023049363 A1 WO2023049363 A1 WO 2023049363A1
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patient
sotorasib
cancer
afatinib
administering
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PCT/US2022/044557
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French (fr)
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Gregory Friberg
Haby HENARY
Brett E. Houk
Omar MATHER
Gataree Ngarmchamnanrith
Sandeep Dutta
Wendy J. Snyder
Neelesh Soman
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Amgen Inc.
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Publication of WO2023049363A1 publication Critical patent/WO2023049363A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
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    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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.
  • 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.
  • compositions comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and afatinib in amounts effective to treat the cancer.
  • administration of two or more therapeutics e.g., sotorasib, afatinib
  • 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.
  • combination therapy of two or more therapeutics as discussed herein include both concomitant and sequential administration.
  • 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-c/]pyrimidin-2(1 H)-one and has the following structure:
  • 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.
  • Afatinib is a pan-ErbB tyrosine kinase inhibitor.
  • Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling.
  • Afatinib (GILOTRIF®) is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant EGFR mutations as detected by a Food and Drug Administration (FDA)-approved test.
  • NSCLC metastatic non-small cell lung cancer
  • GILOTRIF is also indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy. See also, Afatinib (GILOTRIF®), US Prescribing Information, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877 (revision 10/2019), which is herein incorporated by reference in its entirety.
  • the methods comprise administering sotorasib in an amount ranging from 120 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 720 mg sotorasib to the patient once daily. In some embodiments, the methods comprise administering 480 to the patient once daily. In some embodiments, the methods comprise administering 240 mg to the patient once daily. In some embodiments, the methods comprises administering 120 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 afatinib to the patient once daily.
  • the methods comprise administering panitumumab in an amount ranging from 20 mg to 40 mg (e.g., 20 mg, 25 mg, 30 mg, 35 mg, 40 mg) once daily.
  • the methods comprise administering 40 mg afatinib.
  • the methods further comprise administering 30 mg afatinib.
  • the methods further comprise administering 20 mg afatinib.
  • the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 40 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 30 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 20 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg sotorasib daily; and (b) 30 mg afatinib daily.
  • the methods described herein comprise administering to the patient (a) 240 mg sotorasib daily; and (b) 20 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg sotorasib daily; and (b) 30 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg sotorasib daily; and (b) 20 mg afatinib daily.
  • the methods further comprise administering an anti-diarrheal agent to the patient.
  • the anti-diarrheal agent is loperamide or atropine/diphenoxylate.
  • the methods comprise administering the sotorasib and afatinib for a treatment period of at least 21 days, at least 3 months, at least 6 months, or at least 1 year.
  • sotorasib and afatinib are administered under fasted conditions. In various embodiments, sotorasib is administered before afatinib.
  • the patient is in further need of treatment with an acid-reducing agent.
  • Acidreducing 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.
  • 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 .
  • 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,
  • the patient is in further need of treatment with a P-glycoprotein (P-gp) substrate.
  • 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.
  • 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 the 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.
  • 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 therapy, 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-PD L1 therapy, platinum based chemotherapy and anti-EGFR therapy.
  • 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).
  • platinum based chemotherapies include, but are not limited to, carboplatin, oxaliplatin, cisplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin, ProLindac, and aroplatin.
  • anti-EGFR therapy include, but are not limited to, cetuximab and panitumumab.
  • 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 (ALA), and/or ROS proto-oncogene 1 (ROS1).
  • Targeted therapies for EGFR mutations include, but are not limited to, erlotinib, gefitinib, and afatinib.
  • Targeted therapies for ALK mutations include, but are not limited to, crizotinib, entrectinib, lorlatinib, repotrecti nib, brigatinib, alkotinib, alectinib, ensartinib, and ceritinib.
  • Targeted therapies for ROS1 mutations include, but are not limited to, crizotinib, entrecetinib, ensartinib, alkotinib, brigatinib, taletrectinib, cabozantinib, repotrecti nib, 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)Zpneumonitis, diarrhea, and/or nausea/vomiting.
  • hepatotoxicity e.g., elevation of liver enzymes
  • ILD interstitial lung disease
  • 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. [0042] In some embodiments, 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 antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson
  • 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 - 3.0 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. See Cecil Textbook of Medicine, pp. 2317-2341, W.B. Saunders & Co. (1985).
  • 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
  • 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 (U LN), i.e., a "Grade 3 abnormality".
  • U LN upper limit of normal
  • 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 480 mg, 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 480 mg, 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 a Grade 3 nausea until the patient has improved to s 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 a Grade 3 vomiting until the vomiting improves to s 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 a Grade 3 diarrhea until the patient has improved to s Grade 1 or baseline. In some embodiments, once the patient has improved to s 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.
  • 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 patient is administered the
  • 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.
  • sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C (Hong et al., 2020). Hong et al.
  • 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, esophageal 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 (Gerami 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, or melanoma.
  • 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.
  • the cancer is non- small cell lung cancer, and in some specific embodiments, metastatic or locally advanced non-small cell lung cancer.
  • the cancer is colorectal cancer.
  • 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 sequence of wildtype 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.
  • 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 PGR assays, PGR sequencing, mutant allele-specific PGR 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
  • MASA mutant allele-specific PGR amplification
  • samples are evaluated for mutations, such as the KRAS G12C mutation, by real-time PGR.
  • 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
  • amplicons produced using multiplex PCR-based sequencing can include nucleic acids having a length of about 33 bp.
  • 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.
  • 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).
  • the presence of one or more mutations present in a sample obtained from a patient is detected using droplet digital PGR (ddPCR), a method that is known to be highly sensitive for mutation detection.
  • ddPCR droplet digital PGR
  • 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
  • BAG 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 or CRC 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. 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.
  • 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. Staining can show PD-L1 expression from 0% to 100%.
  • 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-Meyers 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-LI Clone SP263
  • Ventana SP142 Assay developed by Ventana in collaboration with Genentech/Roche
  • 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%, 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 50%, or less than or equal to 1 %.
  • 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%.
  • 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%.
  • the patient has a PD-L1 TPS score in the range of more than or equal to 0% and less than 1 %.
  • the patient has a PD-L1 TPS score in the range of more than 50% and less than or equal to 100%.
  • 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%).
  • a method of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and afatinib in amounts effective to treat the cancer.
  • 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.
  • 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.
  • NSCLC non-small cell lung cancer
  • CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoid, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, or troglitazone.
  • 57 The method of embodiment 55 or 56, 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, criz
  • the study will include a dose exploration phase (Part 1) and expansion phase (Part 2) and will be conducted at approximately 99 sites globally.
  • Part 1 of the study will assess the safety of the selected starting dose of afatinib in combination with sotorasib.
  • the starting dose of sotorasib is the recommended phase 2 dose (RP2D) of 960 mg orally daily.
  • the starting dose of afatinib (30 mg orally daily) is based on available safety data (GILOTRIF® Prescribing Information, 2019).
  • Subjects in Part 1 will be treated with sotorasib and afatinib.
  • the term “subject” is used throughout the Examples interchangeably with “patient.”
  • the planned dose levels are:
  • Dose Level 2 sotorasib 960 mg and afatinib 40 mg orally daily
  • Dose Level -1 sotorasib 960 mg and afatinib 20 mg orally daily
  • Dose exploration will begin with 3 to 6 subjects treated at Dose Level 1 .
  • the study DLT period is 21 days.
  • a Dose Level Review Team (DLRT) meeting will be convened.
  • the following may occur: 1) dose escalation to Dose Level 2 and initiation of enrollment in Part 2, Group A Dose Level 1, 2) additional enrollment to Dose Level 1 , 3) dose de-escalation to Dose Level -1 , or 4) initiation of enrollment in Part 2 Group B at the same dose level with loperamide primary prophylaxis.
  • Part 1 will end once any of the following events occur:
  • -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 unsafe and intolerable
  • dose escalation may be halted or modified by the Sponsor as deemed appropriate.
  • Part 2 will consist of Group A and Group B.
  • Subjects enrolled in Part 2 Group A and Group B will include at least 5 subjects who received prior KRAS p.G12C inhibitor therapy.
  • Part 2 Group A Based on the dose escalation/de-escalation outcome in Part 1 , selected dose levels in Part 2 Group A that are equal to or lower than the safe and tolerable dose level from Part 1 (Dose Level 1 : sotorasib 960 mg and afatanib 30 mg) will start to enroll up to 40 subjects at each dose level beginning at Dose Level -1 a.
  • Dose Level 1 sotorasib 960 mg and afatanib 30 mg
  • Dose Level 1 sotorasib 960 mg and afatinib 30 mg orally daily
  • Dose Level 1a sotorasib 240 mg and afatinib 30 mg orally daily
  • Dose Level 2 sotorasib 960 mg and afatinib 40 mg orally daily
  • Dose Level -1 sotorasib 960 mg and afatinib 20 mg orally daily
  • Dose Level 1 in Part 1 is deemed safe and tolerable, Dose Level 1 in Part 2 Group A will commence enrollment in parallel to additional dose exploration in Part 1 .
  • Part 2 Group B will be treated with sotorasib and afatinib at a Dose Level that are equal to or lower than the safe and tolerable Dose Level from Part 1 (Dose Level 1 : sotorasib 960 mg and afatinib 30 mg) with loperamide primary prophylaxis for diarrhea management with enrollment of up to 40 subjects at each dose level, starting with dose level 1 for Group B.
  • the planned dose levels for Part 2, Group B are:
  • Dose Level 1 sotorasib 960 mg and afatinib 30 mg orally daily
  • Dose Level - 1 a sotorasib 240 mg and afatinib 30 mg orally daily
  • Dose Level - 1 a sotorasib 120 mg and afatinib 30 mg orally daily
  • Interim safety analyses will be done after approximately 20 subjects have been enrolled at the same dose level and have had the opportunity to be on treatment for at least 21 days. Based on these interim safety and efficacy results and after reviewing the updated estimate of the MTD or recommended safe combination doses using all available data including data from dose exploration and expansion subjects, the DLRT may modify the dose level of treated subjects. A final estimate of the MTD or RP2D will use all data from dose exploration and dose expansion.
  • sotorasib and afatinib may continue until evidence of disease progression, intolerance to study medication, withdrawal of consent, or end of study.
  • intolerance or toxicity to afatinib the subject may continue on sotorasib alone until evidence of disease progression, withdrawal of consent, or end of study.
  • Loperamide is indicated for the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease.
  • the recommended initial dose is 4 mg (2 capsules) followed by 2 mg (1 capsule) after each unformed stool.
  • loperamide is administered as needed, and the total daily dose should not exceed 16 mg.
  • loperamide is administered prophylactically in cycles 1 and 2, and as needed in cycles 3 and beyond, similar to the loperamide primary prophylaxis guidelines in the Neratinib Regional Prescribing Information (NERLYNX® Prescribing Information, 2020).
  • KRAS p.G12C mutation must be identified by an approved diagnostic device for detection of KRAS p.G12C in NSCLC or be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
  • CLIA Clinical Laboratory Improvement Amendments
  • Subjects must be willing to undergo pretreatment tumor biopsy if medically feasible. If a tumor biopsy prior to treatment is not medically feasible, subjects must be willing to provide archived tumor tissue samples (formalin-fixed paraffin-embedded [FFPE] sample) collected within the past 3 years. Subjects who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator and the Medical Monitor if a tumor biopsy is not feasible.
  • FFPE paraffin-embedded
  • QTc Corrected QT interval
  • Adequate renal laboratory assessments include measured creatinine clearance or estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation 60 mL/min/1.73 m 2 .
  • PT Prothrombin time
  • PTT activated partial thromboplastin time
  • INR International normalized ratio
  • 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.
  • 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 study day 1 ; concurrent use of hormone deprivation therapy for hormone-refractory prostate cancer or breast cancer is permitted. Exception: subjects who receive prior tyrosine kinase inhibitor monotherapy, sotorasib monotherapy or conventional chemotherapy within 14 days of study day 1 are eligible.
  • Therapeutic or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity.
  • cytochrome P450 (CYP) 3A4 sensitive substrates or P-glycoprotein (P-gp) substrates e.g., with a narrow therapeutic window
  • CYP3A4 or P-gp substrate or its major active metabolite whichever is longer, prior to start of therapy.
  • CYP3A4 sensitive substrates include abemaciclib, buspirone, isavuconazole, ridaforolimus, ABT-384, capravirine, itacitinib, saquinavir, acalabrutinib, casopitant, ivabradine, sildenafil, alfentanil, cobimetinib, ivacaftor, simeprevir, alisporivir, conivaptan, L-771,688, simvastatin, almorexant, danoprevir, levomethadyl (LAAM), sirolimus, alpha dihydroergocryptine, darifenacin, lomitapide, tacrolimus, aplaviroc, darunavir, lopinavir, terfenadine, aprepitant, dasatinib, lovastatin, ticagrelor, asunaprevir, dronedarone, lumefantrine, tilidine
  • Strong inducers of CYP3A4 include rifampin, phenytoin, mitotane, carbamazepine, avasimibe, enzalutamide, rifapentine, St John's Wort extract, apalutamide, lumacaftor, ivosidenib, and phenobarbital.
  • 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 1 month after the last dose of afatinib.
  • the dose limiting toxicity (DLT) window (i.e., DLT-evaluable period) will be the first 21 days of sotorasib and afatinib treatment (starting cycle 1 , day 1).
  • the grading of adverse events (AEs) will be based on the guidelines provided in the CTCAE version 5.0.
  • a subject will be DLT evaluable if the subject has completed the DLT window as described above and received > 80% of the planned dose of sotorasib and afatinib or experienced a DLT any time during the DLT window.
  • a subject will not be DLT evaluable if he/she drops out before completion of the DLT-evaluable period for reasons other than a DLT.
  • DLT is defined as any adverse event meeting the criteria listed below occurring during the first treatment cycle and attributable to sotorasib and/or afatinib.
  • 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 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.
  • 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 above. If day 1 of a cycle is delayed, day 1 of subsequent cycles should be adjusted accordingly to maintain the 21 -day cycle duration. However, if a within-cycle dose is held the missed dose will not be made up and day 1 of subsequent cycles should not be adjusted.
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • CTCAE Common Terminology Criteria for Adverse Events
  • INR international normalized ratio
  • LFT liver function test
  • TBL total bilirubin
  • ULN upper limit of normal 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.
  • 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 If the sotorasib starting dose is 960 mg, dose decrements below 240 mg are not allowable. If the sotorasib starting dose is 240 mg or 120 mg, dose decrements below 120 mg are not allowable..
  • 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 (I NR) 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
  • I NR international normalized ratio
  • 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
  • Dose modification for specific adverse reactions attributed to afatinib should be made according to the Afatinib (GILOTRIF®), US Prescribing Information, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877 (revision 10/2019), or regional prescribing information, as applicable.
  • GLOTRIF® Afatinib
  • US Prescribing Information Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877 (revision 10/2019)
  • regional prescribing information as applicable.
  • Withhold afatinib for any adverse reactions of:
  • Subjects with Grade 3 or Grade 4 ALT or AST elevations who are deriving clinical benefit may resume treatment with afatinib when sotorasib is resumed and after discussion with the Medical Monitor.
  • the dose must be 10 mg per day less than the dose at which the adverse reaction occurred.
  • 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 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. [0275] 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.
  • 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 and afatinib. Subsequently, brain scans may be performed at any time if, in the judgment 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 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 > 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 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: 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; Biopsied lesions; Categorically, clusters of small lesions, bone lesions, inflammatory breast disease, and leptomeningeal disease are non-measurable.
  • 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 s 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 a 15 mm) may be identified as target lesions. All other pathological nodes (those with short axis 10 mm but ⁇ 15 mm) should be considered non-target lesions. [0296] 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 nontarget disease and also take into consideration the appearance of new lesions.
  • CR complete response
  • NE Not evaluable
  • PD progressive disease
  • PR partial response
  • SD stable disease
  • 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.
  • 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.
  • 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.
  • Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea.
  • Class II Slight limitation of physical activity Comfortable at rest, but ordinary physical activity results in 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.
  • TRAEs treatment-related adverse events
  • Grade 3 TRAEs occurred in 30% pts within each dose cohort, with diarrhea being the most common.
  • Eight patients (24.2%) discontinued sotorasib and/or afatinib due to an AE, with diarrhea leading to discontinuation in 5 patients.
  • sotorasib and a pan-ErbB inhibitor, combining sotorasib with afatinib was feasible, and demonstrated clinical activity, in a heavily pre-treated KRAS p.G12C mutated NSCLC population that included 15% who progressed on prior sotorasib.
  • the AEs observed are not new or novel to either agent, with diarrhea being the most common.
  • TRAE treatment-related adverse events
  • the most common TRAEs included diarrhea (23 pts (69.7%) all grades, 8 pts (24.2%) grade S3), nausea (9 pts (27.3%), all grade ⁇ 2), vomiting (7 pts (21.2%), all grade ⁇ 2), increased alanine aminotransferase (4 pts (12.1%) all grades, 3 pts (9.1 %) grade S3), increased aspartate aminotransferase (4 pts (12.1%) all grades, 3 pts (9.1%) grade S3), increased blood alkaline phosphatase (4 pts (12.1 %) all grades, 3 pts (9.1 %) grade S3), and acute kidney injury (3 pts (9.1 %) all grades, 3 pts
  • TRAEs grade 3 TRAEs reported included 1 each of dehydration, dyspnea, hyperbilirubinemia, hypotension, hypokalemia, hypovolemia, respiratory failure, and stomatitis. No new or novel TRAEs to either sotorasib or afatinib were observed.
  • ORR analysis set includes all patients who received &1 dose of investigational products, have &1 measurable lesions at baseline assessed using RECIST 1.1 , and have the opportunity to be followed for 7 weeks starting from day 1
  • T Patient 2 received prior osimertinib and progressed on osimertinib prior to enrollment.
  • PK data are 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 doseproportional 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; 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 tmax and tic, 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.
  • 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-so torasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
  • Example 4 Contraindication with co-administration of sotorasib with acid-reducing agents under fed conditions
  • Geometric least-square mean ratios of sotorasib AUCint 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 AUCint 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 AUCw 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 AUCint 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 AUCint 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. [0350] Digoxin median time to maximal plasma concentration (t ma x) and mean terminal half-life (ti/2) were similar following coadministration of digoxin with sotorasib compared to those of digoxin alone.
  • Geometric mean digoxin AUCint (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.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events v5.0

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Abstract

Provided herein are methods of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and afatinib in amounts effective to treat the cancer.

Description

SOTORASIB AND AFATINIB FOR TREATING CANCER COMPRISING A KRAS G12C MUTATION
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/248,107, filed September 24, 2021 , which is incorporated herein by reference in its entirety.
BACKGROUND
[0002] 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
[0003] Described herein are methods of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and afatinib in amounts effective to treat the cancer.
[0004] 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
[0005] 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.
[0006] 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
[0007] Provided herein are methods of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and afatinib in amounts effective to treat the cancer. [0008] The methods of treatment disclosed herein regarding administration of two or more therapeutics (e.g., sotorasib, afatinib) 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.
[0009] Sotorasib
[0010] 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-c/]pyrimidin-2(1 H)-one and has the following structure:
Figure imgf000003_0001
[0011] 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.
[0012] Afatinib
[0013] Afatinib is a pan-ErbB tyrosine kinase inhibitor. Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Afatinib (GILOTRIF®) is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant EGFR mutations as detected by a Food and Drug Administration (FDA)-approved test. GILOTRIF is also indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy. See also, Afatinib (GILOTRIF®), US Prescribing Information, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877 (revision 10/2019), which is herein incorporated by reference in its entirety.
[0014] Dosing Regimens
[0015] In some embodiments, the methods comprise administering sotorasib in an amount ranging from 120 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 720 mg sotorasib to the patient once daily. In some embodiments, the methods comprise administering 480 to the patient once daily. In some embodiments, the methods comprise administering 240 mg to the patient once daily. In some embodiments, the methods comprises administering 120 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.
[0016] In some embodiments, the methods comprise administering afatinib to the patient once daily. In some embodiments, the methods comprise administering panitumumab in an amount ranging from 20 mg to 40 mg (e.g., 20 mg, 25 mg, 30 mg, 35 mg, 40 mg) once daily. In some embodiments, the methods comprise administering 40 mg afatinib. In some embodiments, the methods further comprise administering 30 mg afatinib. In some embodiments, the methods further comprise administering 20 mg afatinib.
[0017] In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 40 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 30 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 20 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg sotorasib daily; and (b) 30 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg sotorasib daily; and (b) 20 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg sotorasib daily; and (b) 30 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg sotorasib daily; and (b) 20 mg afatinib daily.
[0018] In some embodiments, the methods further comprise administering an anti-diarrheal agent to the patient. In some embodiments, the anti-diarrheal agent is loperamide or atropine/diphenoxylate.
[0019] In some embodiments, the methods comprise administering the sotorasib and afatinib for a treatment period of at least 21 days, at least 3 months, at least 6 months, or at least 1 year.
[0020] In various embodiments, sotorasib and afatinib are administered under fasted conditions. In various embodiments, sotorasib is administered before afatinib.
[0021] In various embodiments, the patient is in further need of treatment with an acid-reducing agent. Acidreducing 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.
[0022] 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 .
[0023] 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, 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, ribocidib, 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.
[0024] 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.
[0025] 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.
[0026] In some embodiments, the patient administered the 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 therapy, such that the sotorasib therapy as provided herein is a third line therapy.
[0027] 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.
[0028] 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.
[0029] 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-PD L1 therapy, platinum based chemotherapy and anti-EGFR therapy. 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). Some examples of platinum based chemotherapies include, but are not limited to, carboplatin, oxaliplatin, cisplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin, ProLindac, and aroplatin. Some examples of anti-EGFR therapy include, but are not limited to, cetuximab and panitumumab.
[0030] 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 (ALA), and/or ROS proto-oncogene 1 (ROS1). Targeted therapies for EGFR mutations include, but are not limited to, erlotinib, gefitinib, and afatinib. Targeted therapies for ALK mutations include, but are not limited to, crizotinib, entrectinib, lorlatinib, repotrecti nib, brigatinib, alkotinib, alectinib, ensartinib, and ceritinib. Targeted therapies for ROS1 mutations include, but are not limited to, crizotinib, entrecetinib, ensartinib, alkotinib, brigatinib, taletrectinib, cabozantinib, repotrecti nib, lorlatinib, and ceritinib.
[0031] 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.
[0032] Adverse Events [0033] 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.
[0034] 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.
[0035] In some embodiments, the adverse event is hepatotoxicity (e.g., elevation of liver enzymes), interstitial lung disease (ILD)Zpneumonitis, diarrhea, and/or nausea/vomiting.
[0036] Hepatotoxicity
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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. [0042] 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).
[0043] 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).
[0044] 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.
[0045] Table 1.
Figure imgf000009_0001
Figure imgf000010_0001
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal; WNL= within normal limits
[0046] 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.
[0047] "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 - 3.0 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.
[0048] "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.
[0049] "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.
[0050] "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.
[0051] 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).
[0052] Table 2. - Upper Limit of Normal (ULN) Values
Figure imgf000010_0002
Figure imgf000011_0001
[0053] 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.
[0054] 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.
[0055] 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.
[0056] 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 (U LN), 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.
[0057] 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.
[0058] In some embodiments, the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480 mg, 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).
[0059] NauseaA/omiting
[0060] 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.
[0061] 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.
[0062] Table 3.
Figure imgf000012_0001
Figure imgf000013_0001
[0063] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having a Grade 3 nausea until the patient has improved to s Grade 1 or baseline. In some embodiments, once the patient has improved to s 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.
[0064] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having a Grade 3 vomiting until the vomiting improves to s Grade 1 or baseline. In some embodiments, once the patient has improved to s 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.
[0065] 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).
[0066] Diarrhea
[0067] 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.
[0068] 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.
[0069] Table 4.
Figure imgf000013_0002
[0070] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having a Grade 3 diarrhea until the patient has improved to s Grade 1 or baseline. In some embodiments, once the patient has improved to s 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.
[0071] 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).
[0072] Interstitial Lung Disease
[0073] 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.
[0074] Response to Sotorasib and Afatinib Combination Therapy
[0075] Response rates or results for patients administered the therapy (i.e., sotorasib and afatinib) as 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.
[0076] 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).
[0077] 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.
[0078] 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.
[0079] Additional means for assessing response are described in detail in the examples below and can generally be applied to the methods disclosed herein.
[0080] KRAS G12C Cancers
[0081] The methods described comprising treating a cancer with a KRAS G12C mutation in a patient, wherein the method comprises administering to the patient sotorasib and afatinib 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 “[p]reclinical 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).
[0082] 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, esophageal 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)).
[0083] KRAS G12C mutations occur with the alteration frequencies shown in the table below (Gerami 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.
Table 5
Figure imgf000015_0001
Figure imgf000016_0001
[0084] 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, or melanoma. In some 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. In various embodiments, the cancer is non- small cell lung cancer, and in some specific embodiments, metastatic or locally advanced non-small cell lung cancer. In various embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.
[0085] Methods of Detecting KRAS, STK11, KEAP1, EGFR, ALK, and/or ROS1 Mutation Status
[0086] 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 sequence of wildtype 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.
[0087] 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 PGR assays, PGR sequencing, mutant allele-specific PGR 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 PGR. In real-time PGR, 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.
[0088] 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. [0089] 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).
[0090] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using droplet digital PGR (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).
[0091] 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 (BAG) 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.
[0092] 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.
[0093] 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 or CRC 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.
[0094] 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.
[0095] 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.
[0096] 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 [0097] 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%.
[0098] 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-Meyers 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.
[0099] 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-LI, Clone SP263 and the Ventana SP142 Assay (developed by Ventana in collaboration with Genentech/Roche) that uses rabbit monoclonal anti-PD-L1 clone SP142.
[0100] 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.
[0101] 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%. [0102] 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%).
[0103] Embodiments
[0104] 1. A method of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and afatinib in amounts effective to treat the cancer.
[0105] 2. The method of embodiment 1, comprising administering 960 mg sotorasib to the patient.
[0106] 3. The method of embodiment 1, comprising administering 720 mg sotorasib to the patient
[0107] 4. The method of embodiment 1, comprising administering 480 mg sotorasib to the patient.
[0108] 5. The method of embodiment 1, comprising administering 240 mg sotorasib to the patient.
[0109] 6. The method of embodiment 1, comprising administering 120 mg sotorasib to the patient.
[0110] 7. The method of any one of embodiments 1-6, comprising administering sotorasib to the patient once daily.
[0111] 8. The method of any one of embodiments 1-6, comprising administering sotorasib to the patient twice daily.
[0112] 9. The method of any one of embodiments 1-6, comprising administering afatinib to the patient once daily.
[0113] 10. The method of any one of embodiments 1-9, comprising administering 40 mg afatinib to the patient.
[0114] 11. The method of any one of embodiments 1-9, comprising administering 30 mg afatinib to the patient.
[0115] 12. The method of any one of embodiments 1-9, comprising administering 20 mg afatinib to the patient.
[0116] 13. The method of any one of embodiments 1 and 7-9, comprising administering to the patient (a) 960 mg sotorasib daily; and (b) 40 mg afatinib daily.
[0117] 14. The method of any one of embodiments 1 and 7-9, comprising administering to the patient (a) 960 mg sotorasib daily; and (b) 30 mg afatinib daily.
[0118] 15. The method of any one of embodiments 1 and 7-9, comprising administering to the patient (a) 960 mg sotorasib daily; and (b) 20 mg afatinib daily. [0119] 16. The method of any one of embodiments 1 and 7-9, comprising administering to the patient (a) 240 mg sotorasib daily; and (b) 30 mg afatinib daily.
[0120] 17. The method of any one of embodiments 1 and 7-9, comprising administering to the patient (a) 240 mg sotorasib daily; and (b) 20 mg afatinib daily.
[0121] 18. The method of any one of embodiments 1 and 7-9, comprising administering to the patient (a) 120 mg sotorasib daily; and (b) 30 mg afatinib daily.
[0122] 19. The method of any one of embodiments 1 and 7-9, comprising administering to the patient (a) 120 mg sotorasib daily; and (b) 20 mg afatinib daily.
[0123] 21 ., The method of embodiment 20, wherein the anti-diarrheal agent is loperamide or atropine/diphenoxylate.
[0124] 22. The method of any one of embodiments 1-21, comprising administering the sotorasib and afatinib for a treatment period of at least 21 days, at least 3 months, at least 6 months, or at least 1 year.
[0125] 23. The method of any one of embodiments1-21 , wherein the sotorasib and afatinib are administered to the patient under fasted conditions.
[0126] 24. The method of any one of embodiments 1-23, wherein sotorasib is administered before afatinib.
[0127] 25. The method of any one of embodiments 1-24, wherein the cancer is a solid tumor.
[0128] 26. The method of any one of embodiments 1-25, 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 tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
[0129] 27. The method of any one of embodiments 1-25, wherein the cancer is non-small cell lung cancer (NSCLC).
[0130] 28. The method of any one of embodiments 1-27, 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.
[0131] 29. The method of any one of embodiments 1-27, 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.
[0132] 30. The method of any one of embodiments 1-29, wherein the patient has previously undergone therapy with a KRASG12C inhibitor. [0133] 31 . The method of any one of embodiments 1-30, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2.
[0134] 32. The method of any one of embodiments 1-31, wherein the patient does not have spinal compression or an active brain metastases from a non-brain tumor.
[0135] 33. The method of any one of embodiments 1-32, wherein the patient does not have interstitial lung disease or active, non-infectious pneumonitis.
[0136] 34. The method of any one of embodiments 1-33, wherein the patient did not have a myocardial infarction 6 months before beginning treatment.
[0137] 35. The method of any one of embodiments 1-34, wherein the patient was not administered an anti-tumor therapy less than 28 days before beginning treatment.
[0138] 36. The method of any one of embodiments 1-35, wherein the patient was not administered a tyrosine kinase inhibitor monotherapy less than 14 days before beginning treatment.
[0139] 37. The method of any one of embodiments 1-36, wherein the patient was not administered sotorasib monotherapy less than 14 days before beginning treatment.
[0140] 38. The method of any one of embodiments 1-37, wherein the patient exhibits at least a stable disease (SD) after 1, 3, or 6 months of sotorasib and afatinib therapy, as measured by RECIST 1.1 protocol.
[0141] 39. The method of any one of embodiments 1-37, wherein the patient exhibits at least a partial response (PR) after 1 , 3, or 6 months of sotorasib and afatinib therapy, as measured by RECIST 1.1 protocol.
[0142] 40. The method of any one of embodiments 1-37, wherein the patient exhibits a progression free survival (PFS) of at least 3 months.
[0143] 41 . The method of any one of embodiments 1-40, wherein the patient is not suffering from a hepatitis B infection, or a hepatitis C infection.
[0144] 42. The method of any one of embodiments 1-41, wherein the patient is in further need of treatment with an acid-reducing agent.
[0145] 43. The method of embodiment 42, wherein the acid-reducing agent is a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), or a locally acting antacid.
[0146] 44. The method of embodiment 42 or embodiment 43, 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.
[0147] 45. The method of embodiment 43 or embodiment 44, wherein the locally acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide.
[0148] 46. The method of any one of embodiments 1-45, wherein the patient is in further need of treatment with a proton pump inhibitor (PPI) or H2 receptor antagonist (H2RA). [0149] 47. The method of embodiment 46, wherein the patient is not administered a PPI or a H2RA in combination with sotorasib.
[0150] 48. The method of any one of embodiments 43, 46, or 47, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole.
[0151] 49. The method of any one of embodiments 43, 46, or 47, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine.
[0152] 50. The method of any one of embodiments 1-49, wherein the patient is in further need of treatment with a CYP3A4 inducer.
[0153] 51 . The method of embodiment 48, wherein the patient is not administered a CYP3A4 inducer in combination with sotorasib.
[0154] 52. The method of embodiment 50 or 51 , wherein the CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoid, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, or troglitazone.
[0155] 53. The method of embodiment 50 or embodiment 51, wherein the patient is not administered a strong CYP3A4 inducer in combination with sotorasib.
[0156] 54. The method of embodiment 53, wherein the strong CYP3A4 inducer is phenytoin or rifampin.
[0157] 55. The method of any one of embodiments 1-54, wherein the patient is in further need of treatment with a CYP3A4 substrate.
[0158] 56. The method of embodiment 55, wherein the patient is not administered a CYP3A4 substrate in combination with sotorasib.
[0159] 57. The method of embodiment 55 or 56, 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.
[0160] 58. The method of any one of embodiments 1-57, wherein the patient is in further need of treatment with a P-glycoprotein (P-gp) substrate.
[0161] 59. The method of embodiment 58, wherein the patient is not administered a P-gp substrate in combination with sotorasib.
[0162] 60. The method of embodiment 58 or embodiment 59, wherein the P-gp substrate is dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine.
[0163] 61 . The method of any one of embodiments 1-60, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of 1-49%.
[0164] 62. The method of any one of embodiments 1-61, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of less than 1%.
[0165] 63. The method of any one of embodiments 1-62, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of 50-100%.
[0166] 64. The method of any one of embodiments 1-63, wherein the cancer further comprises a STK11 mutation.
[0167] 65. The method of any one of embodiments 1-64, wherein the cancer further comprises a KEAP1 mutation.
[0168] 66. The method of embodiment 64 or embodiment 65, wherein the mutation is a loss-of-function mutation.
EXAMPLES
Example 1 - Sotorasib in combination with afatinib
[0169] This is a phase 1b multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of sotorasib in combination with afatinib in subjects with KRAS p.G12C mutant advanced NSCLC. Both sotorasib and afatinib will be administered orally once daily (QD). The cycle duration will be 21 days. The study will include a dose exploration phase (Part 1) and expansion phase (Part 2) and will be conducted at approximately 99 sites globally.
[0170] Part 1 of the study will assess the safety of the selected starting dose of afatinib in combination with sotorasib. The starting dose of sotorasib is the recommended phase 2 dose (RP2D) of 960 mg orally daily. The starting dose of afatinib (30 mg orally daily) is based on available safety data (GILOTRIF® Prescribing Information, 2019). Subjects in Part 1 will be treated with sotorasib and afatinib. [0171] The term “subject” is used throughout the Examples interchangeably with “patient.”
[0172] The planned dose levels are:
[0173] Dose Level 2: sotorasib 960 mg and afatinib 40 mg orally daily
[0174] Dose Level 1 : sotorasib 960 mg and afatinib 30 mg orally daily
[0175] Dose Level -1 : sotorasib 960 mg and afatinib 20 mg orally daily
[0176] Dose exploration will begin with 3 to 6 subjects treated at Dose Level 1 . The study DLT period is 21 days. Once at least 3 subjects enrolled at a certain dose level are DLT evaluable, a Dose Level Review Team (DLRT) meeting will be convened. Depending on observed safety data, the following may occur: 1) dose escalation to Dose Level 2 and initiation of enrollment in Part 2, Group A Dose Level 1, 2) additional enrollment to Dose Level 1 , 3) dose de-escalation to Dose Level -1 , or 4) initiation of enrollment in Part 2 Group B at the same dose level with loperamide primary prophylaxis.
[0177] Up to 120 subjects will be enrolled in this study, across both Part 1 and Part 2. It is anticipated that the number of subjects enrolled in Part 1 (dose exploration) will be approximately 20 with no more than 10 dose limiting toxicity (DLT) evaluable subjects at each dose level. Up to 100 subjects will be enrolled across Part 2 with up to 40 subjects at each dose level of Part 2 Group A and Part 2 Group B.
[0178] Part 1 will end once any of the following events occur:
[0179] -Dose Level 2 is determined to be safe and tolerable (minimum of 6 evaluable subjects overall).
[0180] -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 unsafe and intolerable
[0181] -All planned dose levels (including any intermediate doses or alternate dosing schedules) are determined to be unsafe and intolerable.
[0182] -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.
[0183] Part 2:
[0184] Once any Dose Level is deemed safe and tolerable by the DLRT and depending on the data obtained, enrollment will commence in the dose expansion phase (Part 2) to confirm the safety and tolerability of that Dose Level or a lower Dose Level and to further evaluate anti-tumor activity. Part 2 will consist of Group A and Group B.
[0185] Subjects enrolled in Part 2 Group A and Group B will include at least 5 subjects who received prior KRAS p.G12C inhibitor therapy.
[0186] Based on the dose escalation/de-escalation outcome in Part 1 , selected dose levels in Part 2 Group A that are equal to or lower than the safe and tolerable dose level from Part 1 (Dose Level 1 : sotorasib 960 mg and afatanib 30 mg) will start to enroll up to 40 subjects at each dose level beginning at Dose Level -1 a. [0187] The planned dose levels for Part 2, Group A as follows:
[0188] Dose Level 1 : sotorasib 960 mg and afatinib 30 mg orally daily
[0189] Dose Level 1a: sotorasib 240 mg and afatinib 30 mg orally daily
[0190] Dose Level -1 b: sotorasib 120 mg and afatinib 30 mg orally daily
[0191] Dose Level 2: sotorasib 960 mg and afatinib 40 mg orally daily
[0192] Dose Level -1 : sotorasib 960 mg and afatinib 20 mg orally daily
[0193] If Dose Level 1 in Part 1 is deemed safe and tolerable, Dose Level 1 in Part 2 Group A will commence enrollment in parallel to additional dose exploration in Part 1 .
[0194] Part 2 Group B will be treated with sotorasib and afatinib at a Dose Level that are equal to or lower than the safe and tolerable Dose Level from Part 1 (Dose Level 1 : sotorasib 960 mg and afatinib 30 mg) with loperamide primary prophylaxis for diarrhea management with enrollment of up to 40 subjects at each dose level, starting with dose level 1 for Group B.
[0195] The planned dose levels for Part 2, Group B are:
[0196] Dose Level 1 : sotorasib 960 mg and afatinib 30 mg orally daily
[0197] Dose Level - 1 a: sotorasib 240 mg and afatinib 30 mg orally daily
[0198] Dose Level - 1 a: sotorasib 120 mg and afatinib 30 mg orally daily
[0199] Interim safety analyses will be done after approximately 20 subjects have been enrolled at the same dose level and have had the opportunity to be on treatment for at least 21 days. Based on these interim safety and efficacy results and after reviewing the updated estimate of the MTD or recommended safe combination doses using all available data including data from dose exploration and expansion subjects, the DLRT may modify the dose level of treated subjects. A final estimate of the MTD or RP2D will use all data from dose exploration and dose expansion.
[0200] For both Part 1 and Part 2, administration of sotorasib and afatinib may continue until evidence of disease progression, intolerance to study medication, withdrawal of consent, or end of study. In case of intolerance or toxicity to afatinib, the subject may continue on sotorasib alone until evidence of disease progression, withdrawal of consent, or end of study.
[0201] Loperamide is indicated for the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. The recommended initial dose is 4 mg (2 capsules) followed by 2 mg (1 capsule) after each unformed stool. For subjects in Group A, loperamide is administered as needed, and the total daily dose should not exceed 16 mg. For subjects in Group B, loperamide is administered prophylactically in cycles 1 and 2, and as needed in cycles 3 and beyond, similar to the loperamide primary prophylaxis guidelines in the Neratinib Regional Prescribing Information (NERLYNX® Prescribing Information, 2020). [0202] Objectives and Endpoints
Figure imgf000028_0001
[0203] Summary of Subject Eligibility Criteria:
[0204] Adult subjects (>18 years old) with advanced solid tumors with KRAS p.G12C mutation as assessed by molecular testing are eligible to participate in the study.
[0205] Pathologically documented, locally-advanced or metastatic NSCLC with KRAS p.G12C mutation identified through molecular testing. Subjects must have received anti-PD1 or anti-programmed death-ligand 1 (PD-L1) immunotherapy (unless contraindicated) AND/OR platinum-based combination chemotherapy AND targeted therapy (if actionable oncogenic driver mutations were identified [i.e.; EGFR, ALK, and ROS1]), or if subject refused standard therapy. Prior neoadjuvant/adjuvant chemotherapy will be considered for eligibility only if the subject progressed on or within 6 months of completion of the therapy. KRAS p.G12C mutation must be identified by an approved diagnostic device for detection of KRAS p.G12C in NSCLC or be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. For Part 1 and Part 2, subjects who have received prior KRAS p.G12C-targeted therapy must have progressed.
[0206] Subjects must be willing to undergo pretreatment tumor biopsy if medically feasible. If a tumor biopsy prior to treatment is not medically feasible, subjects must be willing to provide archived tumor tissue samples (formalin-fixed paraffin-embedded [FFPE] sample) collected within the past 3 years. Subjects who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator and the Medical Monitor if a tumor biopsy is not feasible.
[0207] Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1 .1) criteria.
[0208] Eastern Cooperative Oncology Group (ECOG) Performance Status of s 2.
[0209] Life expectancy of > 3 months, in the opinion of the investigator.
[0210] Ability to take oral medications and willing to record daily adherence to investigational product.
[0211] Corrected QT interval (QTc) s 470 msec for females and s 450 msec for males (based on average of screening electrocardiogram triplicates).
[0212] Subjects have adequate hematological, renal and hepatic function and coagulation. Adequate hematological laboratory assessments, are as follows:
-Absolute neutrophil count (ANC) > 1.5 x 109/L
-Platelet count > 75 x 109/L
-Hemoglobin 9 x g/dL
[0213] Adequate renal laboratory assessments include measured creatinine clearance or estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation 60 mL/min/1.73 m2.
[0214] 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)
[0215] Adequate coagulation laboratory assessments are as follows:
- Prothrombin time (PT) or activated partial thromboplastin time (PTT) or activated PTT < 1 .5 x ULN, OR International normalized ratio (INR) < 1.5 x ULN or within target range if on prophylactic anticoagulation therapy.
[0216] Exclusion criteria:
[0217] Disease Related [0218] Spinal cord compression or active brain metastases from non-brain tumors. Subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms grade s 2; b) on stable doses of dexamethasone, if applicable; and c) follow-up MRI performed within 30 days shows no new or enlarging lesions appearing.
[0219] Other Medical Conditions
[0220] Evidence of interstitial lung disease or active, non-infectious pneumonitis.
[0221] History or presence of hematological malignancies unless curatively treated with no evidence of disease for 2 years.
[0222] 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 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.
[0223] 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 ECG.
[0224] 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).
[0225] 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;
- 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.
[0226] Positive test for human immunodeficiency virus (HIV).
[0227] Prior/Concomitant Therapy
[0228] 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 study day 1 ; concurrent use of hormone deprivation therapy for hormone-refractory prostate cancer or breast cancer is permitted. Exception: subjects who receive prior tyrosine kinase inhibitor monotherapy, sotorasib monotherapy or conventional chemotherapy within 14 days of study day 1 are eligible. [0229] Therapeutic or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity.
[0230] Use of known cytochrome P450 (CYP) 3A4 sensitive substrates or P-glycoprotein (P-gp) substrates (e.g., with a narrow therapeutic window), within 14 days or 5 half-lives of the CYP3A4 or P-gp substrate or its major active metabolite, whichever is longer, prior to start of therapy. CYP3A4 sensitive substrates include abemaciclib, buspirone, isavuconazole, ridaforolimus, ABT-384, capravirine, itacitinib, saquinavir, acalabrutinib, casopitant, ivabradine, sildenafil, alfentanil, cobimetinib, ivacaftor, simeprevir, alisporivir, conivaptan, L-771,688, simvastatin, almorexant, danoprevir, levomethadyl (LAAM), sirolimus, alpha dihydroergocryptine, darifenacin, lomitapide, tacrolimus, aplaviroc, darunavir, lopinavir, terfenadine, aprepitant, dasatinib, lovastatin, ticagrelor, asunaprevir, dronedarone, lumefantrine, tilidine, atazanavir, ebastine, lurasidone, tipranavir, atorvastatin, eletriptan, maraviroc, tolvaptan, avanafil, eliglustat (in subjects CYP2D6 poor metabolizers (PMs)), midazolam, triazolam, AZD1305, elvitegravir, midostaurin, ulipristal, BIRL 355, entrectinib, naloxegol, vardenafil, blonanserin, eplerenone, neratinib, venetoclax, bosutinib, everolimus, nisoldipine, vicriviroc, brecanavir, felodipine, paritaprevir, vilaprisan, brotizolam, ibrutinib, perospirone, vodosporin, budesonide, indinavir, and quetiapine. P- gp substrates with a narrow therapeutic window include digoxin, everolimus, cyclosporine, sirolimus, and vincristine.
[0231] 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 start of therapy. Strong inducers of CYP3A4 include rifampin, phenytoin, mitotane, carbamazepine, avasimibe, enzalutamide, rifapentine, St John's Wort extract, apalutamide, lumacaftor, ivosidenib, and phenobarbital.
[0232] Active infection requiring IV antibiotics within 1 weeks of study enrollment (day 1).
[0233] 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 and there is agreement to allow by both the investigator and sponsor).
[0234] Subject unable to receive both iodinated contrast for CT scans and gadolinium contrast for MRI scans.
[0235] Any dose reduction, grade 3 treatment-related adverse event, or treatment discontinuation for any adverse event related to the previous treatment with EGFR targeted therapy or KRAS p.G12C targeted therapy.
[0236] Major surgical procedures s 28 days or non-study-related minor procedures s 7 days prior to cycle 1 day 1 . In all cases, the subjects must be sufficiently recovered and stable before treatment administration.
[0237] Prior/Concurrent Clinical Study Experience [0238] Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.
[0239] Other Exclusions
[0240] Subject has known sensitivity to any of the products or components to be administered during dosing.
[0241] 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.
[0242] 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.
[0243] Female subjects of childbearing potential with a positive pregnancy test assessed at Screening or day 1 prior to first dose by a serum pregnancy test and/or urine pregnancy test.
[0244] 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.
[0245] 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.
[0246] Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 1 month after the last dose of afatinib.
[0247] Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 1 month after the last dose of afatinib.
[0248] 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.
[0249] 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.
[0250] Male subjects unwilling to abstain from donating sperm during treatment and for an additional 7 days after the last dose of sotorasib.
[0251] Dose Limiting Toxicities:
[0252] The dose limiting toxicity (DLT) window (i.e., DLT-evaluable period) will be the first 21 days of sotorasib and afatinib treatment (starting cycle 1 , day 1). The grading of adverse events (AEs) will be based on the guidelines provided in the CTCAE version 5.0. A subject will be DLT evaluable if the subject has completed the DLT window as described above and received > 80% of the planned dose of sotorasib and afatinib or experienced a DLT any time during the DLT window. A subject will not be DLT evaluable if he/she drops out before completion of the DLT-evaluable period for reasons other than a DLT. DLT is defined as any adverse event meeting the criteria listed below occurring during the first treatment cycle and attributable to sotorasib and/or afatinib.
[0253] (1) An adverse event that results in permanent discontinuation of any investigational product
(2) An adverse event that results in delay of initiation of cycle 2 by > 2 weeks
(3) Febrile neutropenia
(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 2 bleeding
(8) Grade 4 thrombocytopenia
(9) Grade 4 anemia
(10) Grade >4, vomiting or diarrhea
(11) Grade 3 vomiting or grade 3 diarrhea lasting more than 3 days despite optimal medical support
(12) Grade 3 nausea lasting 3 days or more despite optimal medical support
(13) Grade 3 ALT or AST elevations lasting more than 5 days or Grade 4 elevations of ALT or AST of any duration)
(14) Grade 3 bilirubin elevation
(15) Any other grade > 3 AE with the following exceptions:
- DLT Exemption: fatigue
-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, grade 3 hypomagnesemia)
(16) 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 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.
[0254] If a subject experiences a DLT during the DLT evaluation period, study treatment should be discontinued for that subject. Additionally, any treatment related toxicity meeting the DLT definition after day 21 should result in discontinuation of therapy. In subjects with PR, complete response (CR) or evidence of clinical benefit (as determined by the investigator), an option to continue at the same or at a reduced dose level can be considered once the toxicity returns to the subject’s baseline value or CTCAE grade s 1 if deemed appropriate by the investigator and Sponsor.
[0255] Dose reduction levels of sotorasib for toxicity management of individual subjects is provided in the following table.
Figure imgf000034_0001
[0256] QD = once daily
[0257] 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 above. If day 1 of a cycle is delayed, day 1 of subsequent cycles should be adjusted accordingly to maintain the 21 -day cycle duration. However, if a within-cycle dose is held the missed dose will not be made up and day 1 of subsequent cycles should not be adjusted.
[0258] Sotorasib dose modification guidelines for hematologic and non-hematologic toxicities.
Figure imgf000034_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
[0259] 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 imgf000035_0001
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; INR = international normalized ratio; LFT = liver function test; TBL = total bilirubin; ULN = upper limit of normal 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 0.25 to 1 .0 mg/kg/day or equivalent, followed by a taper. 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 If the sotorasib starting dose is 960 mg, dose decrements below 240 mg are not allowable. If the sotorasib starting dose is 240 mg or 120 mg, dose decrements below 120 mg are not allowable..
[0260] 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 (I NR) 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..
[0261] 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).
[0262] 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 imgf000036_0001
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal
[0263] Afatinib Dose Modifications:
[0264] Dose modification for specific adverse reactions attributed to afatinib should be made according to the Afatinib (GILOTRIF®), US Prescribing Information, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877 (revision 10/2019), or regional prescribing information, as applicable. [0265] Withhold afatinib for any adverse reactions of:
(1) NCI CTCAE Grade 3 or higher.
(2) Diarrhea of Grade 2 or higher persisting for 2 or more consecutive days while taking anti- diarrheal medication (For Group B subjects who experience diarrhea, refer to dose modification guidelines provided below).
(3) For subjects who develop prolonged Grade 2 diarrhea lasting more than 48 hours, or greater than or equal to Grade 3 diarrhea, withhold afatinib until diarrhea resolves to Grade 1 or less, and resume afatinib with appropriate dose reduction. Provide subjects with an anti-diarrheal agent (e.g., loperamide) for selfadministration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.
(4) Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable.
(5) For subjects who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold afatinib until the adverse reaction resolves to Grade 1 or less, and resume afatinib with appropriate dose reduction.
(6) Renal impairment of Grade 2 or higher.
(7) Grade 2 ALT or AST elevation with symptoms.
[0266] Resume treatment when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute afatinib at a reduced dose (i.e., 10 mg per day less than the dose at which the adverse reaction occurred).
[0267] Permanently discontinue afatinib for:
(1) Life-threatening bullous, blistering, or exfoliative skin lesions
(2) Confirmed interstitial lung disease
(3) Severe drug-induced hepatic impairment
(4) Subjects with Grade 3 or Grade 4 ALT or AST elevations who are deriving clinical benefit may resume treatment with afatinib when sotorasib is resumed and after discussion with the Medical Monitor. The dose must be 10 mg per day less than the dose at which the adverse reaction occurred.
(5) Gastrointestinal perforation
(6) Persistent ulcerative keratitis
(7) Withhold afatinib during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with afatinib should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
(8) Symptomatic left ventricular dysfunction
(9) Severe or intolerable adverse reaction occurring at a dose of 20 mg per day [0268] For subjects in Group B, where primary prophylaxis for management of diarrhea is required, the dose reduction levels of sotorasib and afatinib for diarrhea management of individual subjects is provided below.
[0269] Group B sotorasib and afatinib dose reduction for diarrhea management
Figure imgf000038_0001
a If the sotorasib starting dose is 240 mg (e.g . , . Group A Dose Level - 2), Step -1 will be 240 - 20.
[0270] If a subject in Group B is experiencing diarrhea that in the opinion of the investigator, warrants a dose reduction or discontinuation of either sotorasib or afatinib, reduction steps are indicated in the table below. Subjects who experience intolerable diarrhea following dose reduction guidance should be permanently discontinued from sotorasib and afatinib treatment. If day 1 of a cycle is delayed, day 1 of subsequent cycles should be adjusted accordingly to maintain the 21 -day cycle duration. However, if a within-cycle dose is held the missed dose will not be made up and day 1 of subsequent cycles should not be adjusted.
[0271] Group B sotorasib and afatinib dose modification guidelines for management of diarrhea
Figure imgf000038_0002
[0272] Radiological Imaging Assessment
[0273] 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.
[0274] 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 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. [0275] 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.
[0276] 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.
[0277] All subjects must have MRI of the brain performed within 28 days prior to first dose of sotorasib and afatinib. Subsequently, brain scans may be performed at any time if, in the judgment 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.
[0278] 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.
[0279] 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).
[0280] Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
[0281] Definitions
[0282] Measurable Lesions
[0283] Measurable Tumor Lesions - Non-nodal lesions with clear borders that can be accurately measured in at least 1 dimension with longest diameter 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.
[0284] Nodal Lesions - Lymph nodes are to be considered pathologically enlarged and measurable, a lymph node must be > 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).
[0285] 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.
[0286] Non-measurable Lesions: All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes with 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.
[0287] Other examples of non-measurable lesions include: 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; Biopsied lesions; Categorically, clusters of small lesions, bone lesions, inflammatory breast disease, and leptomeningeal disease are non-measurable.
[0288] Methods of Measurement
[0289] 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 .
[0290] 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.
[0291] 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 s 5 mm thick contiguous slices.
[0292] Baseline documentation of “Target” and “Non-target” lesions
[0293] 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.
[0294] Target lesions should be selected on the basis of their size (lesions with the longest diameter) and suitability for accurate repeated measurements.
[0295] Pathologic lymph nodes (with short axis a 15 mm) may be identified as target lesions. All other pathological nodes (those with short axis 10 mm but < 15 mm) should be considered non-target lesions. [0296] 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.
[0297] 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”).
[0298] Response Criteria
Evaluation of Target Lesions
Figure imgf000041_0001
0299] 1 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.
[0300] Evaluation of Overall Response
[0301] 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).
[0302] In general, the subject's best response assignment depends on the findings of both target and nontarget disease and also take into consideration the appearance of new lesions.
Time Point response: Subjects with Target (+/- Non-target) Disease
Figure imgf000042_0001
CR= complete response; NE = Not evaluable; PD = progressive disease; PR = partial response; SD = stable disease
Time Point Response: Subjects with Non-Target Disease Only
Figure imgf000042_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 imgf000042_0003
Figure imgf000043_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.
[0303] Special Notes on Response Assessment
[0304] 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).
[0305] 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.
[0306] 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.
[0307] -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.
[0308] -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. [0309] 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.
[0310] 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.
[0311] Confirmation Measurement / Duration of Response
[0312] 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.
[0313] 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.
[0314] 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.
[0315] ECOG Performance and NYHA Classification
Figure imgf000044_0001
Source: Oken et al, 1982; [0001] ECOG = Eastern Cooperative Oncology Group;
[0316] New York Heart Association Functional Classification
[0317] Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea.
[0318] Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnea. [0319] Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation or dyspnea.
[0320] 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.
[0321] Preliminary results (July 12, 2021 data cut):
[0322] Patients with advanced KRAS p.G12C mutated NSCLC who had disease progression on prior therapies, including KRASG12C inhibitors, were enrolled in this dose exploration/expansion study. Patients were treated with 960 mg sotorasib QD and afatinib (20 mg or 30mg QD). Primary endpoint was safety/tolerability. Secondary endpoint was efficacy, including objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1.
[0323] 33 patients with NSCLC (median age: 65.0 yrs) were enrolled. Ten patients received 20 mg afatinib/960 mg sotorasib QD (cohort 1) and 23 pts received 30 mg afatinib/960 mg sotorasib QD (cohort 2). Across both cohorts, the median number of prior therapies was 2 (range 0-7; 66.7% ^2 prior lines) and 5 pts (15.2%) received prior sotorasib therapy. The most common treatment-related adverse events (TRAEs) included diarrhea (23 pts [69.7%], 7 pts [21.2%] grade ^3), nausea (7 pts [21.2%], all grade =£2), and vomiting (6 pts [18.2%], all grade £2). Grade 3 TRAEs occurred in 30% pts within each dose cohort, with diarrhea being the most common. Eight patients (24.2%) discontinued sotorasib and/or afatinib due to an AE, with diarrhea leading to discontinuation in 5 patients.
[0324] Median treatment duration of sotorasib/afatinib combination was 64.0 days (Q1 , 29.0; Q3, 128.0) at the data cut off point. For cohort 1 (N=10 that includes 4 patients who received prior sotorasib), the ORR was 20.0% and DCR was 70.0% (2-confirmed partial response (PR), 5-stable disease (SD), 1 -progressive disease (PD), 2- not available). Among the KRASG12C inhibitor-naive patients, the ORR was 33.3%. For cohort 2 (N=23 that includes 1 patient who received prior sotorasib), the ORR was 34.8% and DCR was 73.9% (8-confirmed PR, 9- SD, 4-PD, 2-not available). Among 5 patients receiving prior sotorasib, 3 had SD, 1 PD, and 1 withdrew from study due to an AE prior to any scan. EGFR co-mutation at baseline was detected in 4 of 24 pts; 2 of 4 pts responded to combination therapy.
[0325] The combination of sotorasib and a pan-ErbB inhibitor, combining sotorasib with afatinib was feasible, and demonstrated clinical activity, in a heavily pre-treated KRAS p.G12C mutated NSCLC population that included 15% who progressed on prior sotorasib. The AEs observed are not new or novel to either agent, with diarrhea being the most common.
[0326] Preliminary results (September 17, 2021 data cut)
[0327] Patients with locally advanced or metastatic NSCLC with a KRAS p.G12C mutation as assessed by molecular testing, who had disease progression on prior therapies, including KRASG12C inhibitors, were enrolled in this dose exploration/expansion study (Clinicaltrials.gov, NCT04185883). Patients were treated with 960 mg sotorasib QD and afatinib (20 mg or 30mg QD). Primary endpoint was dose-limiting toxicities and adverse events. Secondary endpoint was pharmacokinetics and efficacy, including objective response rate (ORR), disease control rate (DCR), and duration of response (DOR), progression-free survival (PFS), per RECIST 1.1.
[0328] 33 patients (pts) with NSCLC (9 male, 24 female; median age: 65 yrs (range 49-86)) were enrolled. Ten patients received 20 mg afatinib/960 mg sotorasib QD (cohort 1) and 23 pts received 30 mg afatinib/960 mg sotorasib QD (cohort 2). Across both cohorts, the median number of lines of prior therapies was 2 (range 0-7) and 5 pts (15.2%) received prior sotorasib therapy (4 patients in cohort 1 and one patient in cohort 2). The majority of patients had an ECOG performance score of 1 (26 pts (78.8%)). 4 pts (12.1 %) had and ECOG performance score of 0 and 3 pts (9.1 %) had an ECOG performance score of 2. 9 pts (27.3%) had brain metastasis and 4 pts (12.1%) had liver metastasis.
[0329] Median treatment duration of combination treatment was 2.7 months (range 0.5 -11.3) at the data cut off point. There was no observed drug interaction between afatinib and sotorasib.
[0330] Greater than or equal to grade 3 treatment-related adverse events (TRAE) occurred in approximately a third of patients within each dose cohort. The most common TRAEs (which include TRAEs with > 20% patient incidence across all grades and/or grade 3 with > 5% patient incidence) included diarrhea (23 pts (69.7%) all grades, 8 pts (24.2%) grade S3), nausea (9 pts (27.3%), all grade ^2), vomiting (7 pts (21.2%), all grade ^2), increased alanine aminotransferase (4 pts (12.1%) all grades, 3 pts (9.1 %) grade S3), increased aspartate aminotransferase (4 pts (12.1%) all grades, 3 pts (9.1%) grade S3), increased blood alkaline phosphatase (4 pts (12.1 %) all grades, 3 pts (9.1 %) grade S3), and acute kidney injury (3 pts (9.1 %) all grades, 3 pts (9.1%) grade >3). Other grade 3 TRAEs reported included 1 each of dehydration, dyspnea, hyperbilirubinemia, hypotension, hypokalemia, hypovolemia, respiratory failure, and stomatitis. No new or novel TRAEs to either sotorasib or afatinib were observed.
[0331] The tumor response rate is shown in the below table:
Figure imgf000046_0001
Figure imgf000047_0001
Includes 4 patients who had received prior sotorasib therapy
Includes 1 patient who had received prior sotorasib therapy t ORR - objective response rate; ORR analysis set includes all patients who received &1 dose of investigational products, have &1 measurable lesions at baseline assessed using RECIST 1.1 , and have the opportunity to be followed for 7 weeks starting from day 1
[0332] Overall, across both cohorts, 10 of 33 (30%) of patients achieved partial response and 25 of 33 (76%) achieved disease control. For patients receiving prior KRASG12C inhibitor therapy, 3 had SD, 1 had PD, and 1 withdrew due to an adverse event. Decrease in target lesion size was observed in 24 of 29 (83%) of patients across both cohorts. At the time of cut-off, 11 of 33 patients remain on treatment, with 9 patients remaining on treatment without PD after 6 months, and one patient with prior KRASG12C inhibitor therapy (sotorasib) has stable disease for over 8 months. The median PFS (mPFS) was 4.1 months (range 0.0+, 8.2+) with a median follow-up time of 5.4 months.
[0333] Further, patients with pathogenic EGFR co-mutation or amplification responded to the combination therapy (see table below). 4 of 24 patients with available NGS data from baseline tumor tissue or plasma had a pathogenic EGFR mutation or amplification. 2 of the 4 patients with EGFR co-mutation or amplification at baseline responded to sotorasib+afatinib combination. For the 2 patients who did not respond, additional mutations in multiple genes/pathways were detected. Furthermore, KEAP1 mutations were also observed.
Figure imgf000047_0002
T Patient 2 received prior osimertinib and progressed on osimertinib prior to enrollment.
[0334] In conclusion, a combination of sotorasib and a pan-ErbB inhibitor (afatinib), in heavily pre-treated KRAS p.G12C mutated patients with NSCLC, including 5 patients (15%) who had progressed on prior sotorasib was feasible, but efficacy may have been limited by tolerability. Overall, 10 of 33 patients (30%) achieved confirmed partial response and 25 of 33 patients (76%) achieved disease control including some with durable and deep responses. Stable disease was observed in patients with prior KRASG12C inhibitor (sotorasib) therapy, including one patient with durable control. Partial responses were observed in 2 of 4 patients who presented with EGFR co-mutation or amplification at study entry. Example 2 - Pharmacokinetic Analysis of 960 mg, 360 mg, 180 mg, and 240 mg Sotorasib
[0335] Preliminary pharmacokinetic (PK) data are 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 doseproportional 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 tmax and tic, 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
Figure imgf000048_0001
Example 3 - Contraindication with co-administration of sotorasib with acid-reducing agents under fasted conditions
[0336] 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-so torasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
[0337] 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 AUCint (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.
[0338] Results indicated that coadministration of sotorasib with omeprazole, in the fasted state, decreased sotorasib AUCint by 42% and Cmax by 57% compared with administration of sotorasib alone.
Example 4 - Contraindication with co-administration of sotorasib with acid-reducing agents under fed conditions
[0339] 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) under fed 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.
[0340] 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.
[0341] Geometric least-square mean ratios of sotorasib AUCint 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 AUCint 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.
[0342] 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 under fed conditions decreased sotorasib Cmax by 35% and AUG by 38%. In addition, co-administration of repeat doses of omeprazole (PPI) with a single dose of sotorasib decreased sotorasib Cmax by 65% and AUG by 57% under fed conditions. Example 5 - Contraindication with coadministration of sotorasib with strong CYP34A4 inducers
[0343] 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.
[0344] Results:
[0345] Geometric mean sotorasib AUCw (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 AUCint 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).
[0346] 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 AUCint by 51 % and Cmax by 35%, indicating sotorasib is a CYP3A4 substrate, consistent with in vitro data.
Example 6 - Contraindication with coadministration of sotorasib with CYP34A substrates
[0347] 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.
[0348] 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 7 - Contraindication with coadministration of sotorasib and P-gp substrates
[0349] 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. [0350] Digoxin median time to maximal plasma concentration (tmax) and mean terminal half-life (ti/2) were similar following coadministration of digoxin with sotorasib compared to those of digoxin alone. Geometric mean digoxin AUCint (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.
[0351] Results indicated that coadministration of digoxin with a single dose of sotorasib increased digoxin AUCint and Cmax by approximately 21% and 91%, respectively, compared with digoxin alone.
[0352] 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.
[0353] 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.
[0354] References:
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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 afatinib 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 720 mg sotorasib to the patient
4. The method of claim 1, comprising administering 480 mg sotorasib to the patient.
5. The method of claim 1, comprising administering 240 mg sotorasib to the patient.
6. The method of claim 1, comprising administering 120 mg sotorasib to the patient.
7. The method of any one of claims 1-6, comprising administering sotorasib to the patient once daily.
8. The method of any one of claims 1-6, comprising administering sotorasib to the patient twice daily.
9. The method of any one of claims 1-6, comprising administering afatinib to the patient once daily.
10. The method of any one of claims 1-9, comprising administering 40 mg afatinib to the patient.
11 . The method of any one of claims 1-9, comprising administering 30 mg afatinib to the patient.
12. The method of any one of claims 1-9, comprising administering 20 mg afatinib to the patient.
13. The method of any one of claims 1 and 7-9, comprising administering to the patient (a) 960 mg sotorasib daily; and (b) 40 mg afatinib daily.
14. The method of any one of claims 1 and 7-9, comprising administering to the patient (a) 960 mg sotorasib daily; and (b) 30 mg afatinib daily.
15. The method of any one of claims 1 and 7-9, comprising administering to the patient (a) 960 mg sotorasib daily; and (b) 20 mg afatinib daily.
16. The method of any one of claims 1 and 7-9, comprising administering to the patient (a) 240 mg sotorasib daily; and (b) 30 mg afatinib daily.
17. The method of any one of claims 1 and 7-9, comprising administering to the patient (a) 240 mg sotorasib daily; and (b) 20 mg afatinib daily.
18. The method of any one of claims 1 and 7-9, comprising administering to the patient (a) 120 mg sotorasib daily; and (b) 30 mg afatinib daily.
19. The method of any one of claims 1 and 7-9, comprising administering to the patient (a) 120 mg sotorasib daily; and (b) 20 mg afatinib daily.
52
20. The method of any one of claims 1-19, further comprising administering an anti-diarrheal agent to the patient.
21 ., The method of claim 20, wherein the anti-diarrheal agent is loperamide or atropine/diphenoxylate.
22. The method of any one of claims 1-21, comprising administering the sotorasib and afatinib for a treatment period of at least 21 days, at least 3 months, at least 6 months, or at least 1 year.
23. The method of any one of claims1-21, wherein the sotorasib and afatinib are administered to the patient under fasted conditions.
24. The method of any one of claims 1-23, wherein sotorasib is administered before afatinib.
25. The method of any one of claims 1-24, wherein the cancer is a solid tumor.
26. The method of any one of claims 1-25, 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 tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
27. The method of any one of claims 1-25, wherein the cancer is non-small cell lung cancer (NSCLC).
28. The method of any one of claims 1-27, 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.
29. The method of any one of claims 1-27, 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.
30. The method of any one of claims 1-29, wherein the patient has previously undergone therapy with a KRASG12C inhibitor.
31 . The method of any one of claims 1-30, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2.
32. The method of any one of claims 1-31, wherein the patient does not have spinal compression or an active brain metastases from a non-brain tumor.
33. The method of any one of claims 1-32, wherein the patient does not have interstitial lung disease or active, non-infectious pneumonitis.
53
34. The method of any one of claims 1-33, wherein the patient did not have a myocardial infarction 6 months before beginning treatment.
35. The method of any one of claims 1-34, wherein the patient was not administered an anti-tumor therapy less than 28 days before beginning treatment.
36. The method of any one of claims 1-35, wherein the patient was not administered a tyrosine kinase inhibitor monotherapy less than 14 days before beginning treatment.
37. The method of any one of claims 1-36, wherein the patient was not administered sotorasib monotherapy less than 14 days before beginning treatment.
38. The method of any one of claims 1-37, wherein the patient exhibits at least a stable disease (SD) after 1 , 3, or 6 months of sotorasib and afatinib therapy, as measured by RECIST 1.1 protocol.
39. The method of any one of claims 1-37, wherein the patient exhibits at least a partial response (PR) after 1 , 3, or 6 months of sotorasib and afatinib therapy, as measured by RECIST 1.1 protocol.
40. The method of any one of claims 1-37, wherein the patient exhibits a progression free survival (PFS) of at least 3 months.
41 . The method of any one of claims 1-40, wherein the patient is not suffering from a hepatitis B infection, or a hepatitis C infection.
42. The method of any one of claims 1-41, wherein the patient is in further need of treatment with an acid-reducing agent.
43. The method of claim 42, wherein the acid-reducing agent is a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), or a locally acting antacid.
44. The method of claim 42 or claim 43, 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.
45. The method of claim 43 or claim 44, wherein the locally acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide.
46. The method of any one of claims 1-45, wherein the patient is in further need of treatment with a proton pump inhibitor (PPI) or H2 receptor antagonist (H2RA).
47. The method of claim 46, wherein the patient is not administered a PPI or a H2RA in combination with sotorasib.
48. The method of any one of claims 43, 46, or 47, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole.
49. The method of any one of claims 43, 46, or 47, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine.
54
50. The method of any one of claims 1-49, wherein the patient is in further need of treatment with a CYP3A4 inducer.
51 . The method of claim 48, wherein the patient is not administered a CYP3A4 inducer in combination with sotorasib.
52. The method of claim 50 or 51, wherein the CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoid, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, or troglitazone.
53. The method of claim 50 or claim 51 , wherein the patient is not administered a strong CYP3A4 inducer in combination with sotorasib.
54. The method of claim 53, wherein the strong CYP3A4 inducer is phenytoin or rifampin.
55. The method of any one of claims 1-54, wherein the patient is in further need of treatment with a CYP3A4 substrate.
56. The method of claim 55, wherein the patient is not administered a CYP3A4 substrate in combination with sotorasib.
57. The method of claim 55 or 56, 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, venetodax, venlafaxine, verapamil, vilazodone, vincristine, vorapaxar, voriconazole, zaleplon, or ziprasidone.
55
58. The method of any one of claims 1-57, wherein the patient is in further need of treatment with a P-glycoprotein (P-gp) substrate.
59. The method of claim 58, wherein the patient is not administered a P-gp substrate in combination with sotorasib.
60. The method of claim 58 or claim 59, wherein the P-gp substrate is dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine.
61 . The method of any one of claims 1-60, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of 1-49%.
62. The method of any one of claims 1-61, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of less than 1 %.
63. The method of any one of claims 1-62, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of 50-100%.
64. The method of any one of claims 1-63, wherein the cancer further comprises a STK11 mutation.
65. The method of any one of claims 1-64, wherein the cancer further comprises a KEAP1 mutation.
66. The method of claim 64 or claim 65, wherein the mutation is a loss-of-function mutation.
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