CN117940132A

CN117940132A - ERK1/2 and KRAS G12C inhibitor combination therapies

Info

Publication number: CN117940132A
Application number: CN202280057477.6A
Authority: CN
Inventors: 罗伯特·菲尔德·舒梅克; 艾琳·丹尼斯·卢; 林卫; 张京川; 乔安妮·吴
Original assignee: Yirui Shikang Pharmaceutical Research And Development Co
Current assignee: Yirui Shikang Pharmaceutical Research And Development Co
Priority date: 2021-06-24
Filing date: 2022-06-23
Publication date: 2024-04-26

Abstract

The present disclosure relates generally to the use of ERK1/2 inhibitors in combination with KRAS G12C inhibitors for the treatment of cancer, in particular solid tumors.

Description

ERK1/2 and KRAS G12C inhibitor combination therapies

Cross reference

The present application claims the benefit of U.S. provisional application Ser. No. 63/214,767, U.S. provisional application Ser. No. 63/277,548, U.S. provisional application Ser. No. 63/283,034, U.S. provisional application Ser. No. 63/321,609, and U.S. provisional application Ser. No. 63/321,609, U.S. Ser. No. 4/034, and U.S. Ser. No. 2022, 3/18, filed on 6/24, 2021, 11/9, 2021, and incorporated herein by reference in their entirety.

Background

ERK1 and ERK2 (collectively, "ERK 1/2") are related protein-serine/threonine kinases that are involved in the Ras-Raf-MEK-ERK signal transduction pathway, and the like, sometimes referred to as the mitogen-activated protein kinase (MAPK) pathway. This pathway is thought to play an important role in regulating many basic cellular processes including one or more of cell proliferation, survival, adhesion, cyclical progression, migration, differentiation, metabolism and transcription. Activation of the MAPK pathway has been reported in many tumor types, including lung, colon, pancreas, kidney, and ovary. Thus, substances that can reduce activation may be of interest for possible treatments.

Disclosure of Invention

MEK appears to activate ERK1/2 through phosphorylation of both threonine and tyrosine residues (i.e., at Tyr204/187 and Thr 202/185). Once activated, ERK1/2 catalyzes the phosphorylation of serine/threonine residues of over 100 substrates, and activates both cytoplasmic and nuclear proteins associated with cell growth, proliferation, survival, angiogenesis, and differentiation (all markers of the cancer phenotype). Thus, it may be beneficial to target ERK1 and ERK 2 to develop and use ERK1/2 inhibitors as a way to inhibit tumor growth.

In addition, ERK inhibitors may have utility in combination with other kinase (e.g., MAPK) inhibitors. Recently, researchers have reported that small molecule inhibitors have a synergistic effect on the dual inhibition of MEK and ERK and act to overcome acquired resistance to MEK inhibitors. See Hatzivassiliou et al, ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition, mol. Cancer Ther.2012,11,1143-1154.

In addition to ERK 1/2, the RAS-MAPK signaling pathway also includes the RAS protein family. This family includes three related gtpases (KRAS, NRAS and HRAS) that play a role in the signal transduction pathway. In particular, KRAS is known to have a number of mutations indicative of oncogenic status. KRAS mutants, such as mutations occurring at amino acid residue 12 (i.e., G12X), are generally known to cause cancer. For example, G12C mutations occur in about 13% of NSCLC patients and 1% to 3% of colorectal cancer and solid tumor patients.

The present embodiments disclosed herein relate generally to compositions and methods related to combination therapies that utilize an ERK1/2 inhibitor in combination with a KRAS-G12C inhibitor to treat cancer while providing an unexpected degree of synergy.

Disclosed herein is a method of treating cancer in a subject in need thereof, comprising: administering to a subject in need thereof a therapeutically effective amount of (i) compound 1: Or a pharmaceutically acceptable salt thereof; and

(Ii) KRAS G12C inhibitors.

In some embodiments, the KRAS G12C inhibitor is adaglazecloth (adagrasib), ARS-3248, BBP-454, BI1701963, GDC-6036, sotoracicmide (sotorasib), or tipifanib (tipifarnib).

In some embodiments, the KRAS G12C inhibitor is sotorubin.

In some embodiments, the sotoracicada is administered in an amount of about 960 mg/day.

In some embodiments, the KRAS G12C inhibitor is adaglazeb.

In some embodiments, adaglazeb is administered in an amount of about 1200 mg/day.

Also disclosed herein is a method of treating cancer in a subject in need thereof, comprising: administering to a subject in need thereof a therapeutically effective amount of (i) compound 1: Or a pharmaceutically acceptable salt thereof; and

(Ii) Sotoracicb.

(Ii) Adaglazeb.

In some embodiments, the pharmaceutically acceptable salt of compound 1 is mandelate.

In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer.

In some embodiments, the cancer is a BRAF-driven cancer, HRAS-driven cancer, or NRAS-driven cancer.

In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK.

In some embodiments, the cancer has at least one mutation in the RAS. In some embodiments, the cancer has at least one mutation in RAF. In some embodiments, the cancer has at least one mutation in MEK.

In some embodiments, the cancer has a G12C KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a G12S KRAS mutation. In some embodiments, the cancer has a G12V KRAS mutation. In some embodiments, the cancer has a G13D KRAS mutation. In some embodiments, the cancer has a Q16H KRAS mutation. In some embodiments, the cancer has a Q16KKRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation.

In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer is a pan-carcinoma that does not receive MAPKm/MAPKi.

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of: increased EGFR gene copy, EGFR gene amplification, chromosome 7 polyhedra, L858R, exon 19 deletion/insertion, L861, Q, G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, vvi and Vii), A289D, A289T, A289 858A, G598V, T790M and C797S.

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

In some embodiments, the cancer is a solid tumor.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is an EGFR mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12C mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12D mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12S mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12V mutant NSCLC. In some embodiments, the NSCLC is a KRAS G13D mutant NSCLC. In some embodiments, the NSCLC is a KRAS Q61H mutant NSCLC. In some embodiments, the NSCLC is a KRAS Q61K mutant NSCLC. In some embodiments, the NSCLC is an NRAS Q61R mutant NSCLC. In some embodiments, the cancer is NSCLC that does not receive MAPKm/MAPKi. In some embodiments, the cancer is BRAFi treated V600 NSCLC. In some embodiments, the cancer is KRAS treated G12C NSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS-treated G12SNSCLC. In some embodiments, the cancer is KRAS treated G12V NSCLC. In some embodiments, the cancer is KRAS treated G13D NSCLC. In some embodiments, the cancer is KRAS treated Q61H NSCLC. In some embodiments, the cancer is KRAS treated Q61K NSCLC. In some embodiments, the cancer is NRAS treated Q61R NSCLC.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is pancreatic cancer that does not receive MAPKm/MAPKi.

In some embodiments, the cancer is melanoma.

In some embodiments, the melanoma is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer is BRAFi treated V600 melanoma.

In some embodiments, the cancer is a salivary gland tumor.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is a BRAF V600E CRC. In some embodiments, the CRC is a KRAS mutant CRC. In some embodiments, the CRC is a KRAS G12C mutant CRC. In some embodiments, the CRC is a KRAS G12D mutant CRC. In some embodiments, the CRC is a KRAS G12S mutant CRC. In some embodiments, the CRC is a KRAS G12V mutant CRC. In some embodiments, the CRC is a KRAS G13D mutant CRC. In some embodiments, the CRC is a KRAS Q61H mutant CRC. In some embodiments, the CRC is a KRAS Q61K mutant CRC. In some embodiments, the CRC is an NRAS mutant CRC. In some embodiments, the CRC is an NRAS Q61R mutant CRC.

In some embodiments, the cancer is esophageal cancer.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day to about 300 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 25 mg/day to 150 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily (QD). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered three times per day (TID).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice weekly.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 150mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 50mg, about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, or about 250mg, twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 50mg, about 100mg, about 125mg, or about 150mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 125mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least a 28 day period.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, 15, and 22 of a 28 day cycle.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered on day 1, day 8, day 15 of the 28 day cycle.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, the method further comprises administering an additional MAPK pathway inhibitor.

In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAF1 inhibitor, MEK2 inhibitor, c-Mycv, CDK4/6, inhibitor CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor.

In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor.

In some embodiments, the additional MAPK pathway inhibitor is a BRAF inhibitor.

In some embodiments, the additional MAPK pathway inhibitor is an EGFR inhibitor.

In some embodiments, the additional MAPK pathway inhibitor is a CDK4/6 inhibitor.

In some embodiments, the additional MAPK pathway inhibitor is a FLT3 inhibitor.

In some embodiments, the additional MAPK pathway inhibitor is adalimib, afatinib (afatinib), ASTX029, bimetanib (binimetinib), cetuximab (cetuximab), cobimanib (cobimeinib), dabigafenib (dabrafenib), dacatinib (dacomitinib), kang Naifei ni (encorafenib), erlotinib (erlotinib), gefitinib (gefitinib), gefitinib (gilteritinib), lapatinib (lapatinib), LTT462, LY3214996, cetuximab (necitumumab), lenatinib (neratinib), nimotuzumab (nimotuzumab), octuzumab (osimertinib), palbociclib (palbociclib), panitumumab (panitumab), semitenib (selumetinib), sotoltinib, trimatinib (trametinib), iritinib (ulixertinib) and vanadulthood (vandetanib).

In some embodiments, the additional MAPK pathway inhibitor is cetuximab.

In some embodiments, the additional MAPK pathway inhibitor is dabrafenib.

In some embodiments, the additional MAPK pathway inhibitor is Kang Naifei ni.

In some embodiments, the additional MAPK pathway inhibitor is gefitinib.

In some embodiments, the additional MAPK pathway inhibitor is palbociclib.

In some embodiments, the additional MAPK pathway inhibitor is panitumumab.

Incorporation by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

FIG. 1A shows cell viability assay data for Compound 1 and Soto-Racebub in NCI-H2122-GFP cells.

FIG. 1B shows cell viability assay data for Compound 1 and Soto-Racebub in HCC1171-GFP cells.

Fig. 1C shows cell viability assay data for compound 1 and sotoracicb in LU65 cells.

FIG. 1D shows cell viability assay data for Compound 1 and Soto-Racebub in NCI-H23-GFP cells.

FIG. 1E shows cell viability assay data for Compound 1 and Soto-Racebub in HCC44-GFP cells.

FIG. 1F shows cell viability assay data for Compound 1 and Soto-trabecular in MIA PaCa-2-GFP cells.

Figure 1G shows cell viability assay data for compound 1 and sotoracicb in NCI-H2030 cells.

Fig. 1H shows cell viability assay data for compound 1 and sotorubin in LU99 cells.

Figure 1I shows cell viability assay data for compound 1 and sotorubin in LIM2099 cells.

Figure 1J shows cell viability assay data for compound 1 and sotorubin in SW837 cells.

FIG. 2A shows cell viability assay data for Compound 1 and adaglazeb in NCI-H2122-GFP cells.

FIG. 2B shows cell viability assay data for Compound 1 and adaglazeb in HCC1171-GFP cells.

Fig. 2C shows cell viability assay data for compound 1 and adaglazeb in LU65 cells.

FIG. 2D shows cell viability assay data for Compound 1 and adaglazeb in NCI-H23-GFP cells.

Fig. 2E shows cell viability assay data for compound 1 and adaglazeb in HCC44-GFP cells.

FIG. 2F shows cell viability assay data for Compound 1 and adaglazeb in MIA PaCa-2-GFP cells.

Figure 2G shows cell viability assay data for compound 1 and adaglazeb in NCI-H2030 cells.

Fig. 2H shows cell viability assay data for compound 1 and adaglazeb in LU99 cells.

Figure 2I shows cell viability assay data for compound 1 and adaglazeb in LIM2099 cells.

Figure 2J shows cell viability assay data for compound 1 and adaglazeb in SW837 cells.

Figure 3 shows that compound 1 and sotoprazole exhibit in vivo combined benefits based on an exemplary tumor growth curve (PDX = patient-derived xenograft) in KRASG12C mutant CRC PDX model CO-04-0307.

Figure 4 shows that compound 1 and sotoprazole exhibit in vivo combined benefits based on exemplary tumor growth curves in KRAS ^G12C mutant CRC PDX model CO-04-0310.

Figure 5 shows that compound 1 and sotoprazole demonstrate in vivo combined benefits based on exemplary tumor growth curves in KRASG12C mutant NSCLC PDX model LU-01-0046.

Detailed Description

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., formula), it is intended to include all combinations and subcombinations of the ranges and specific embodiments therein. When referring to a number or range of values, the term "about" means that the number or range of values referred to is an approximation within experimental variability (or within statistical experimental error), and thus in some cases the number or range of values will vary from 1% to 15% of the number or range of values. The term "comprising" (and related terms such as "having" or "including") is not intended to exclude "consisting of" or "consisting essentially of" any of the other embodiments, e.g., embodiments of any of the compositions of matter, compositions, methods, or processes described herein, etc.

As used in the specification and the appended claims, the following terms have the meanings indicated below, unless otherwise indicated.

As used herein, the term "therapeutic agent" refers to an agent for treating, combating, ameliorating, preventing or ameliorating an undesired condition or disease in a patient. In some embodiments, a therapeutic agent such as compound 1 is involved in the treatment and/or amelioration of cancer.

When used in combination with a therapeutic agent, "administering" refers to the systemic or local administration of the therapeutic agent directly into or onto the target tissue, or to the patient, whereby the therapeutic agent positively affects the tissue to which it is targeted. Thus, as used herein, the term "administering" when used in conjunction with the compositions described herein can include, but is not limited to, providing the composition into or onto a target tissue; the composition is provided systemically to the patient, for example, by oral administration, whereby the therapeutic agent reaches the target tissue or cells. "administration" of the composition may be accomplished by injection, topical administration, and oral administration, or by other methods alone or in combination with other known techniques.

The term "animal" as used herein includes, but is not limited to, human and non-human vertebrates, such as wild, domestic and farm animals. As used herein, the terms "patient," "subject," and "individual" are intended to include living organisms in which certain conditions as described herein may occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In some cases, the person is an adult. In some cases, the person is a child. In other cases, the person is less than 12 years old. In some cases, the person is an elderly person. In other cases, the age of the person is 60 years or older. Other examples of subjects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cattle. The experimental animal may be an animal model of a disorder, such as a transgenic mouse with hypertensive pathology.

By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term "pharmaceutical composition" shall mean a composition comprising at least one active ingredient, whereby the composition is suitable for studying specific effective results in mammals (e.g. but not limited to humans). Those of ordinary skill in the art will understand and appreciate techniques suitable for determining whether an active ingredient has a desired effective result based on the needs of the skilled artisan.

As used herein, "therapeutically effective amount" or "effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, subject, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) prevention of disease; for example, preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who has not yet experienced or displayed the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., arresting further development of the pathology and/or symptom), and (3) ameliorating the disease; for example, a disease, condition, or disorder (i.e., reversing pathology and/or symptoms) is ameliorated in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder.

The term "treatment" as used herein refers in some embodiments to therapeutic treatment, and in other embodiments to prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reducing the extent of a condition, disorder or disease; stabilization (i.e., not worsening) of the condition, disorder or disease state; delay onset of or slow progression of the condition, disorder or disease; improving a condition, disorder or disease state; and either detectable or undetectable remission (whether partial or complete) of a condition, disorder or disease, or enhancement or amelioration of a condition, disorder or disease. Treatment involves eliciting a clinically significant response without undue levels of side effects. Treatment also includes prolonging survival compared to the expected survival without treatment. The prophylactic benefit of treatment includes preventing the condition, slowing the progression of the condition, stabilizing the condition, or reducing the likelihood of the condition developing. As used herein, in some embodiments, "treating" includes prophylaxis.

The term "substantially identical" as used herein means that the powder X-ray diffraction pattern or differential scanning calorimetry pattern is different from those depicted herein, but falls within the limits of experimental error when considered by one of ordinary skill in the art.

Compound 1

Disclosed herein are (S) -N- (2-amino-1- (3-chloro-5-fluorophenyl) ethyl) -1- (5-methyl-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -1H-imidazole-4-carboxamide: Or a pharmaceutically acceptable salt thereof.

In some embodiments, the salt of compound 1 is a mandelate salt. In some embodiments, the salt of compound 1 is a benzenesulfonate salt. In some embodiments, the salt of compound 1 is the hydrochloride salt. In some embodiments, the salt of compound 1 is p-toluenesulfonate.

In some embodiments, the salt of compound 1 is a benzenesulfonate salt.

KRAS G12C inhibitors

KRAS is a key regulator of signaling pathways responsible for cell proliferation, differentiation and survival. KRAS is the most frequently mutated oncogene in human cancers, and mutations in KRAS can lead to sustained cell proliferation and cancer progression. The G12C mutation is a single point mutation with a glycine to cysteine substitution at codon 12. This substitution favors the activation state of KRAS, amplifying the signaling pathways leading to tumorigenesis.

In some embodiments, the KRAS G12C inhibitor is adaglazeb, ARS-3248, BBP-454, BI1701963, GDC-6036, sotoracicb, or tipifarnib.

In some embodiments, the KRAS G12C inhibitor is adaglazeb. In some embodiments, the KRAS G12C inhibitor is sotorubin.

Soto-la sibutra

Soto-la sibutraUnder the trade name/>And/>The next market, marketed by Amgen, is an anticancer drug for the treatment of non-small cell lung cancer (NSCLC). It targets a specific mutation G12C in the protein K-Ras encoded by the gene KRAS, which is responsible for various forms of cancer. Sotorubin is an inhibitor of the RAS gtpase family.

Sotoprazole is the first approved targeted therapy for tumors with any KRAS mutation that accounts for about 25% of mutations in non-small cell lung cancer. KRAS G12C mutations occur in about 13% of non-small cell lung cancer patients.

At month 5 of 2021, the FDA approved sotoracicb for the treatment of KRAS G12C mutated NSCLC.

Aldaglazeb (MRTX-849)Is an experimental cancer drug developed by Mirati Therapeutics. It acts as a covalent binding inhibitor of a mutant form of protein KRAS known as G12C, which is typically present in various forms of cancer and acts as a growth factor. It has shown promising results in preclinical testing and is currently in clinical trials.

Combination of two or more kinds of materials

Disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of (i) compound 1: Or a pharmaceutically acceptable salt thereof; and

(Ii) KRAS G12C inhibitors.

(Ii) Sotoracicb.

(Ii) Adaglazeb.

Further combination of

In some embodiments, the method comprises administering an additional MAPK pathway inhibitor. Without being bound by theory, inhibition of MAPK signaling in cancer cells may lead to down-regulation of PD-L1 expression and increase the likelihood that cancer cells will be detected by the immune system. Such a third MAPK pathway inhibitor may be based on other mutations in the protein in the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor inhibits a protein in the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor inhibits a protein other than the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAF1 inhibitor, MEK2 inhibitor, c-Mycv, CDK4/6, inhibitor CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor. Exemplary MAPK pathway inhibitors include, but are not limited to, adaglazeb, afatinib, ASTX029, bimatinib, cetuximab, cobratinib, dabrafenib, dactyltinib, kang Naifei, erlotinib, gefitinib, ji Ruiti, lapatinib, LTT462, LY3214996, rituximab, lenatinib, nimodib, octreotide, palbociclib, panitumumab, sematinib, sotoracicb, trimetinib, ulitinib, and vande.

In some embodiments, the additional MAPK pathway inhibitor is adaglazeb. In some embodiments, the additional MAPK pathway inhibitor is afatinib. In some embodiments, the additional MAPK pathway inhibitor is bimetanib. In some embodiments, the additional MAPK pathway inhibitor is cetuximab. In some embodiments, the additional MAPK pathway inhibitor is cobicitinib. In some embodiments, the additional MAPK pathway inhibitor is dabrafenib. In some embodiments, the additional MAPK pathway inhibitor is dactinib. In some embodiments, the additional MAPK pathway inhibitor is Kang Naifei ni. In some embodiments, the additional MAPK pathway inhibitor is erlotinib. In some embodiments, the additional MAPK pathway inhibitor is gefitinib. In some embodiments, the additional MAPK pathway inhibitor is gefitinib. In some embodiments, the additional MAPK pathway inhibitor is lapatinib. In some embodiments, the additional MAPK pathway inhibitor is LTT462. In some embodiments, the additional MAPK pathway inhibitor is LY3214996. In some embodiments, the additional MAPK pathway inhibitor is rituximab. In some embodiments, the additional MAPK pathway inhibitor is lenatinib. In some embodiments, the additional MAPK pathway inhibitor is nituzumab. In some embodiments, the additional MAPK pathway inhibitor is octreotide. In some embodiments, the additional MAPK pathway inhibitor is palbociclib. In some embodiments, the additional MAPK pathway inhibitor is panitumumab. In some embodiments, the additional MAPK pathway inhibitor is semantenib. In some embodiments, the additional MAPK pathway inhibitor is sotorubin. In some embodiments, the additional MAPK pathway inhibitor is trametinib. In some embodiments, the additional MAPK pathway inhibitor is ulitinib. In some embodiments, the additional MAPK pathway inhibitor is vandetanib.

Cancer of the human body

Disclosed herein are methods of treating cancer using the combinations disclosed herein.

"Cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including, but not limited to, leukemia, lymphoma, myeloma, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer (such as pancreatic adenocarcinoma, PDAC), medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, hodgkin's disease, and non-hodgkin's lymphoma. Exemplary cancers that may be treated with the compounds or methods provided herein include blood cancer, thyroid cancer, cancer of the endocrine system, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, stomach cancer, and uterine cancer. Further examples include thyroid cancer, cholangiocarcinoma, pancreatic adenocarcinoma, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, malignant insulinoma (MALIGNANT PANCREATIC insulanoma), malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumor, medullary thyroid cancer (medullary thyroid cancer), medullary thyroid cancer (medullary thyroid carcinoma), melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma or prostate cancer.

In some embodiments, the cancer has a class 1B-Raf mutation.

In some embodiments, the cancer has at least one of EGFR, KRAS, BRAF (e.g., BRAF class III) and/or NF1 (e.g., loss of function) mutations.

In some embodiments, the mutant B-Raf comprises a V600 mutation. In some embodiments, the mutant of B-Raf comprises the mutation V600E. In some embodiments, the mutation is V600K. In some embodiments, the mutation is V600D. In some embodiments, the mutation is V600L. In some embodiments, the mutation is V600R. In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer has a G12C KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a G12R KRAS mutation. In some embodiments, the cancer has a G12S KRAS mutation. In some embodiments, the cancer has a G12V KRAS mutation. In some embodiments, the cancer has a G12W KRAS mutation. In some embodiments, the cancer has a G13DKRAS mutation. In some embodiments, the cancer has an H95D KRAS mutation. In some embodiments, the cancer has an H95Q KRAS mutation. In some embodiments, the cancer has an H95R KRAS mutation. In some embodiments, the cancer has a Q61H KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a Q61K KRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation. In some embodiments, the cancer has an R68S KRAS mutation.

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of: increased EGFR gene copy, EGFR gene amplification, chromosome 7 multimerity, L858R, exon 19 deletion/insertion, L861Q, G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, vvi and Vii), A289D, A289T, A289V, G289A, G598V, T790M and C797S. In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced or metastatic solid tumor.

In some embodiments, the cancer is colorectal cancer (CRC), pancreatic Ductal Adenocarcinoma (PDAC), cholangiocarcinoma, appendiceal carcinoma, gastric cancer, esophageal cancer, non-small cell lung cancer (NSCLC), head and neck cancer, ovarian cancer, uterine cancer, acute Myelogenous Leukemia (AML), or melanoma.

In some embodiments, the cancer is gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is anal cancer, cholangiocarcinoma, colon cancer, rectal cancer, esophageal cancer, gallbladder cancer, liver cancer, pancreatic cancer, small intestine cancer, or stomach cancer.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is an EGFR mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12C mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12D mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12S mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12V mutant NSCLC. In some embodiments, the NSCLC is a KRAS G13D mutant NSCLC. In some embodiments, the NSCLC is a KRAS Q61H mutant NSCLC. In some embodiments, the NSCLC is a KRAS Q61K mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12R mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12W mutant NSCLC. In some embodiments, the NSCLC is KRAS H95D mutant NSCLC. In some embodiments, the NSCLC is a KRAS H95Q mutant NSCLC. In some embodiments, the NSCLC is a KRAS H95R mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12D mutant NSCLC. In some embodiments, the NSCLC is KRAS R68S mutant NSCLC.

In some embodiments, the NSCLC is an NRAS Q61R mutant NSCLC. In some embodiments, the cancer is NSCLC that does not receive MAPKm/MAPKi. In some embodiments, the cancer is BRAFi treated V600 NSCLC. In some embodiments, the cancer is KRAS treated G12C NSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS treated G12S NSCLC. In some embodiments, the cancer is KRAS treated G12V NSCLC. In some embodiments, the cancer is KRAS-treated G13DNSCLC. In some embodiments, the cancer is KRAS treated Q61H NSCLC. In some embodiments, the cancer is KRAS treated Q61K NSCLC. In some embodiments, the cancer is NRAS treated Q61R NSCLC. In some embodiments, the cancer is KRAS treated G12R NSCLC. In some embodiments, the cancer is KRAS treated G12W NSCLC. In some embodiments, the cancer is KRAS treated H95D NSCLC. In some embodiments, the cancer is KRAS treated H95Q NSCLC. In some embodiments, the cancer is KRAS-treated H95RNSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS treated R68S NSCLC.

In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic cancer that does not receive MAPKm/MAPKi. In some embodiments, the cancer is Pancreatic Ductal Adenocarcinoma (PDAC). In some embodiments, the PDAC cancer has a G12V mutation.

In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is a BRAF V600E or V600K mutant tumor. In some embodiments, the cancer is BRAFi treated V600 melanoma.

In some embodiments, the cancer is a salivary gland tumor.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is a BRAF V600E CRC. In some embodiments, the CRC is a KRAS mutant CRC.

In some embodiments, the CRC is a KRAS G12C mutant CRC. In some embodiments, the CRC is a KRAS G12D mutant CRC. In some embodiments, the CRC is a KRAS G12S mutant CRC. In some embodiments, the CRC is a KRAS G12V mutant CRC. In some embodiments, the CRC is a KRAS G13D mutant CRC. In some embodiments, the CRC is a KRAS Q61H mutant CRC. In some embodiments, the CRC is a KRAS Q61K mutant CRC. In some embodiments, the CRC is an NRAS mutant CRC. In some embodiments, the CRC is an NRAS Q61R mutant CRC.

In some embodiments, the cancer is esophageal cancer.

In some embodiments, the cancer has one or more acquired mutations. In some embodiments, the acquired mutation results from first line therapy. In some embodiments, the first line treatment is a KRAS inhibitor. In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is adaglazeb. In some embodiments, the KRAS G12C inhibitor is sotorubin. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is NSCLC.

In some embodiments, the acquired mutation is an acquired KRAS mutation. In some embodiments, the acquired mutation is KRAS G12C. In some embodiments, the acquired mutation is KRAS G12D. In some embodiments, the acquired mutation is KRAS G12R. In some embodiments, the acquired mutation is KRAS G12V. In some embodiments, the acquired mutation is KRAS G12W. In some embodiments, the acquired mutation is KRAS G13D. In some embodiments, the acquired mutation is KRAS H95D. In some embodiments, the acquired mutation is KRAS H95D. In some embodiments, the acquired mutation is KRAS H95Q. In some embodiments, the acquired mutation is KRAS H95R. In some embodiments, the acquired mutation is KRAS Q61H. In some embodiments, the acquired mutation is KRAS R68S.

In some embodiments, the acquired mutation is an acquired MAPK pathway mutation. In some embodiments, the acquired MAPK pathway mutation is MAP2K 1K 57N. In some embodiments, the acquired MAPK pathway mutation is MAP2K 1K 57T. In some embodiments, the acquired MAPK pathway mutation is CCDC6-RET. In some embodiments, the acquired MAPK pathway mutation is RITIP L. In some embodiments, the acquired MAPK pathway mutation is PTEN G209V. In some embodiments, the acquired MAPK pathway mutation is BRAF V600E. In some embodiments, the acquired MAPK pathway mutation is MAP2K1 199_k104del. In some embodiments, the acquired MAPK pathway mutation is MAP2K 1K 57N. In some embodiments, the acquired MAPK pathway mutation is EML4-ALK. In some embodiments, the acquired MAPK pathway mutation is EGFR a289A. In some embodiments, the acquired MAPK pathway mutation is FGFR3-TACC3. In some embodiments, the acquired MAPK pathway mutation is AKAP9-BRAF. In some embodiments, the acquired MAPK pathway mutation is RAF1-CCDC176. In some embodiments, the acquired MAPK pathway mutation is RAF1-TRAK1. In some embodiments, the acquired MAPK pathway mutation is NRAS Q61K. In some embodiments, the acquired MAPK pathway mutation is MAP2 k1e102_1103 DEL. In some embodiments, the acquired MAPK pathway mutation is NRF1-BRAF.

In some embodiments, the acquired mutation is a KRAS G12C reactivation mutation. In some embodiments, the KRAS G12C reactivation mutation is RKRAS G C gene amplification. In some embodiments, the KRAS G12C reactivation mutation is NF 1R 22637 (LoF).

In some embodiments, the acquired mutation is a non-G12C activating KRAS mutation. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12D. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12R. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12V. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12W. In some embodiments, the non-G12C activating KRAS mutation is KRAS G13D. In some embodiments, the non-G12C activating KRAS mutation is KRAS Q61H. In some embodiments, the non-G12C activating KRAS mutation is KRAS Q61K.

In some embodiments, the acquired mutation is a sterically hindered KRAS G12C mutation. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS R68S. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS H95D. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS H95Q. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS H95R. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS Y96C.

In some embodiments, the acquired mutation is an RTK activating mutation. In some embodiments, the RTK activating mutation is EGFR a289V. In some embodiments, the RTK activating mutation is RET M918T. In some embodiments, the RTK activating mutation is MET gene amplification. In some embodiments, the RTK activating mutation is EML-ALK. In some embodiments, the RTK activating mutation is CCDC6-RET. In some embodiments, the RTK activating mutation is FGFR3-TACC3.

In some embodiments, the acquired mutation is a downstream RAS/MAPK activation mutation. In some embodiments, the downstream RAS/MAPK activation mutation is BRAF V600E. In some embodiments, the downstream RAS/MAPK activation mutation is MAP2K I99_k104del. In some embodiments, the downstream RAS/MAPK activation mutation is MAP2k1i99_k104del. In some embodiments, the downstream RAS/MAPK activation mutation is MAP2 k1e102_i103del. In some embodiments, the downstream RAS/MAPK activation mutation is a RAF fusion.

In some embodiments, the acquired mutation is a parallel pathway activation mutation. In some embodiments, the parallel pathway activation mutation is PIK3CA H1047R. In some embodiments, the parallel pathway activation mutation is PIK3R 1S 361fs. In some embodiments, the parallel pathway activation mutation is PTEN N48K. In some embodiments, the parallel pathway activation mutation is PTEN G209V. In some embodiments, the parallel pathway activation mutation is RIT1P128L.

Administration of drugs

In one aspect, the compositions described herein are used to treat diseases and conditions described herein. Furthermore, a method for treating any disease or condition described herein in a subject in need of such treatment comprises administering to the subject a therapeutically effective amount of the composition.

The dosage of the compositions described herein may be determined by any suitable method. The Maximum Tolerated Dose (MTD) and the Maximum Response Dose (MRD) of compound 1 or a pharmaceutically acceptable salt thereof can be determined by established animal and human protocols and examples described herein. For example, toxicity and therapeutic efficacy of compound 1 or a pharmaceutically acceptable salt thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals including, but not limited to, for determining LD ₅₀ (the dose lethal to 50% of the population) and ED ₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio between LD ₅₀ and ED ₅₀. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably within a circulating concentration range, including ED ₅₀ with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration employed. Additional relative doses expressed as a percentage of the maximum response or maximum tolerated dose are readily obtained via the protocol.

In some embodiments, the amount of a given formulation comprising compound 1 or a pharmaceutically acceptable salt thereof corresponding to such amount varies depending on factors such as the molecular weight of the particular salt or form, the disease condition and severity thereof, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, and the like, but may be determined according to the particular circumstances surrounding the case, including, for example, the particular agent administered, the type of liquid formulation, the condition being treated, and the subject or host being treated.

In some embodiments, the amount of compound 1, or a pharmaceutically acceptable salt thereof, as described herein is relative to the free base equivalent of compound 1.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 100mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 50mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 150mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 100mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 150mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 175mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 175mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 175mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 225mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 225mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 300mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 250mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 300mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 250mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 300mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 250mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg, once per week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg, once per week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200mg, once per week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250mg, once a day, one day a week.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 30mg, 40mg, 50mg, about 60mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 175mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 225mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, or about 300 mg.

In some embodiments, each of the above amounts may be administered QD, QW, BID, BID-QD or BID-QW.

Application of

Compound 1 or a pharmaceutically acceptable salt thereof and a combination partner (partner) described herein are administered at the dosages described herein or at other dosage levels and compositions determined and considered by the medical practitioner. In certain embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a patient already suffering from a disease in an amount sufficient to cure the disease or at least partially prevent or ameliorate symptoms. The amount effective for this use will depend on the age of the patient, the severity of the disease, the previous treatment, the health of the patient, the weight and response to the composition, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, up-dosing clinical trials.

In prophylactic applications, the compositions described herein are administered to a patient susceptible to or otherwise at risk of a particular disease (e.g., cancer). Such an amount is defined as a "prophylactically effective amount or dose". In this use, the precise amount will also depend on the age, health, weight, etc. of the patient. When used in a patient, the effective amount for such use will depend on the risk or susceptibility to developing the particular disease, the previous treatment, the patient's health and response to the composition, and the discretion of the treating physician.

In certain embodiments, wherein the condition of the patient is not improved, the compositions described herein are administered chronically (i.e., for an extended period of time, including throughout the life of the patient) at the discretion of the physician, in order to improve or otherwise control or limit the symptoms of the patient's disease. In other embodiments, the administration of the composition is continued until a complete or partial response to the disease.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and a combination partner described herein, are administered once daily. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and a combination partner described herein, are administered twice daily. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and a combination partner described herein, are administered three times daily.

In some embodiments, the sotoracicada is administered once a day. In some embodiments, the sotoracicada is administered twice daily. In some embodiments, the sotoracicada is administered three times per day.

In some embodiments, the adaglazeb is administered once daily. In some embodiments, adaglazeb is administered twice daily. In some embodiments, adaglazeb is administered three times daily.

In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fasted state. Fasted state refers to a subject that is not fed or fasted for a period of time. Typical fasted periods include no feeding for at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, and at least 16 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fasted state for at least 8 hours. In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fasted state for at least 10 hours. In still other embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fasted state for at least 12 hours. In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject who has fasted overnight.

In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fed state. Fed state refers to a subject that has been fed or has been fed. In certain embodiments, the composition is administered to a subject in a fed state at 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certain instances, compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state 30 minutes after a meal. In other cases, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fed state 1 hour after a meal. In a further embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject in combination with food.

The length of the treatment period depends on the treatment administered. In some embodiments, the length of the treatment period ranges from 2 to 6 weeks. In some embodiments, the length of the treatment period ranges from 3 to 6 weeks. In some embodiments, the length of the treatment period ranges from 3 to 4 weeks. In some embodiments, the length of the treatment period is 3 weeks (or 21 days). In some embodiments, the length of the treatment period is 4 weeks (28 days). In some embodiments, the length of the treatment period is 5 weeks (35 days). In some embodiments, the length of the treatment period is 56 days. In some embodiments, the treatment period lasts for 1, 2, 3, 4, or 5 weeks. In some embodiments, the treatment period lasts for 3 weeks. In some embodiments, the treatment period lasts for 4 weeks. In some embodiments, the treatment period lasts for 5 weeks. The number of therapeutic doses scheduled in each cycle also varies depending on the drug administered.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered at a 28 day period. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in a plurality of 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least one 28-day cycle. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least two 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least three 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least four 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least five 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least six 28-day cycles.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-7 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-21 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-28 of each 28-day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 1 of a 28 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 8 of the 28 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 15 of a 28 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 22 of the 28 day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is not administered twice a day on day 22 of the 28 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily on days 1, 8 and 15 of a 28 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is not administered on days 2-7, 9-14, 16-21, 23-28 of the 28 day cycle.

In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in a 35 day period. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in a plurality of 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered at least one 35 day period. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least two 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least three 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least four 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least five 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least six 35 day cycles.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-7 of each 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-21 of each 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-28 of each 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-35 of each 35 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 1 of a 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 8 of the 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 15 of a 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 22 of the 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 29 of the 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is not administered twice a day on day 29 of the 35 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily on days 1, 8, 15 and 22 of a 35 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is not administered on days 2-7, 9-14, 16-21, 23-28, and 30-35 of the 28 day cycle.

Examples

Example 1: in vitro vitality assay (Compound 1+Soto Racebuxine)

Cells were seeded in 96-well plates (Corning # 3903) at a density of 1,000 (NCI-H2122-GFP, LU65, NCI-H23-GFP, MIA PaCa-2-GFP, LU99, LIM 2099) or 5,000 (HCC 1171-GFP, HCC44, NCI-H2030, SW 837) cells per well. Cells were allowed to adhere overnight and compounds were added in matrix format using a HP Tecan D300e digital dispenser (Switzerland). From bottom to top of the plate (rows B-H) at 1:3 dilution series (8 point dose response) compound 1 was added and from right to left (columns 2-11) at 1:2 dilution series (11 point dose response) to add sotorubin. Final DMSO concentrations were normalized across the plate. Cell viability was assessed 5 days after treatment using Promega CellTiter-Glo 3D cell viability assay reagent (#g9683) according to the manufacturer's protocol. Luminescence was assessed using SpectraMax M3e (Molecular Devices, san Jose, CA) and combined benefits were assessed using the BLISS model in Combenefit software (CANCER RESEARCH UK Cambridge Institute).

In the 3D cell viability assay, NCI-H2122-GFP cells (FIG. 1A), HCC1171-GFP cells (FIG. 1B), LU65 cells (FIG. 1C), NCI-H23-GFP cells (FIG. 1D), HCC44-GFP cells (FIG. 1E), MIA PaCa-2-GFP cells (FIG. 1F), NCI-H2030 cells (FIG. 1G), LU99 cells (FIG. 1H), LIM2099 cells (FIG. 1I) and SW837 cells (FIG. 1J) were treated with a dilution matrix of compound 1 and sotoracicb. Cell viability, expressed as percent of viable cells relative to vehicle-treated controls, is shown in the matrix.

Compound 1 and sotoracicada showed combined activity in the KRAS G12C cell model.

Example 2: in vitro vitality assay (Compound 1+adaglazeb)

Cells were seeded in 96-well plates (Corning # 3903) at a density of 1,000 (NCI-H2122-GFP, LU65, NCI-H23-GFP, MIA PaCa-2-GFP, LU99, LIM 2099) or 5,000 (HCC 1171-GFP, HCC44, NCI-H2030, SW 837) cells per well. Cells were allowed to adhere overnight and compounds were added in matrix format using a HP Tecan D300e digital dispenser (Switzerland). From bottom to top of the plate (rows B-H) at 1:3 dilution series (8 point dose response) compound 1 was added and from right to left (columns 2-11) at 1: dilution series 2 (11 point dose response) add adaglazeb. Final DMSO concentrations were normalized across the plate. Cell viability was assessed 5 days after treatment using Promega CellTiter-Glo 3D cell viability assay reagent (#g9683) according to the manufacturer's protocol. Luminescence was assessed using SpectraMax M3e (Molecular Devices, san Jose, CA) and combined benefits were assessed using the BLISS model in Combenefit software (CANCER RESEARCH UK Cambridge Institute).

In the 3D cell viability assay, NCI-H2122-GFP cells (FIG. 1A), HCC1171-GFP cells (FIG. 1B), LU65 cells (FIG. 1C), NCI-H23-GFP cells (FIG. 1D), HCC44-GFP cells (FIG. 1E), MIA PaCa-2-GFP cells (FIG. 1F), NCI-H2030 cells (FIG. 1G), LU99 cells (FIG. 1H), LIM2099 cells (FIG. 1I) and SW837 cells (FIG. 1J) were treated with a dilution matrix of compound 1 and adaglazeb. Cell viability, expressed as percent of viable cells relative to vehicle-treated controls, is shown in the matrix.

Compound 1 and adaglazeb showed combined activity in the KRAS G12C cell model.

Example 3: phase 1b/2 study of agents targeting mitogen-activated protein kinase pathways in patients with advanced non-small cell lung cancer

The study will include: 1) The safety and tolerability of increasing doses of compound 1 in combination with other cancer therapies was assessed in study participants with advanced non-small cell lung cancer (NSCLC); 2) Determining the Maximum Tolerated Dose (MTD) and/or Recommended Dose (RD) of compound 1 to be administered in combination with other cancer therapies; 3) Assessing the anti-tumor activity of compound 1 in combination with other cancer therapies; and 4) assessing the Pharmacokinetic (PK) profile of Compound 1 when administered in combination with other cancer therapies.

Phase 1b/2 studies would involve assessing the safety, tolerability and antitumor activity of compound 1 in combination with other cancer therapies in study participants with advanced NSCLC. The study will include a dose escalation group in which compound 1 and sotorubin are administered to study participants with advanced NSCLC harboring a Kirsten rat sarcoma G12C mutation (KRAS G12 Cm). Compound 1 will be administered orally in combination with sotoracicb at multiple QW dose levels of 150mg to 250mg (inclusive) or multiple BID-QW dose levels of 75mg to 125mg (inclusive) to study participants with KRAS G12Cm NSCLC, with doses being continuously escalated until toxicity is unacceptable, disease progression or withdrawal consent. In study participants with advanced EGFRm or KRAS G12Cm NSCLC, dose expansion will follow and compound 1 orally administered with RD identified from the respective dose escalating group will be evaluated.

Dosing regimen

The following inclusion and exclusion criteria will apply to the study:

Inclusion criteria

The age is more than or equal to 18 years old.

Willing and able to give written informed consent.

NSCLC with histological or cytologically confirmed presence of EGFR mutations sensitive to EGFR inhibitors or presence of KRAS G12C mutations.

Measurable disease according to the solid tumor response assessment criteria (Response Evaluation CRITERIA IN Solid Tumors, RECIST) v 1.1.

Sufficient bone marrow and organ function.

Eastern tumor collaboration group (Eastern Cooperative Oncology Group, ECOG) performance status of united states with 0 or 1:

Stage 0: is fully active and is capable of performing all pre-disease manifestations without limitation;

Stage 1: strenuous physical activity is limited, but ambulatory, and light or sedentary work can be performed, such as light household work, office work.

Is willing to adhere to all scheme required accesses, evaluations and procedures.

Can swallow oral medicine.

Exclusion criteria

Concurrent with any systemic anti-cancer therapy for NSCLC, including any approved or studied agents.

For participants with KRAS G12Cm NSCLC: treatment with SHP2, ERK or KRAS G12C inhibitors was previously used (depending on which group was considered recruited).

Palliative radiation treatment was performed within 7 days of recruitment.

An unacceptable history of toxicity to sotoraciclovir treatment.

Major surgery was performed within 28 days of recruitment.

At the time of recruitment, the unresolved toxicity from previous systemic therapies was greater than NCI adverse event generic term standard (Common Terminology Criteria for ADVERSE EVENTS, CTCAE) grade 1, except for toxicities that were not considered safety risk (e.g., alopecia, vitiligo, and grade 2 neuropathy due to previous chemotherapy).

There is a history of another malignancy less than or equal to 5 years prior to the first administration, except for patients with no disease >2 years after treatment with curative intent or with carcinoma in situ.

Symptomatic and unstable brain metastases, or spinal cord compression, except for patients who have completed definitive therapy (surgery or radiation therapy), do not use steroids, and have a stable neurological status for at least 2 weeks after completion of definitive therapy and use of steroids.

Clinically active Interstitial Lung Disease (ILD), drug-induced ILD or radiation pneumonitis or a history thereof requiring steroid treatment.

Cardiovascular function is impaired or clinically significant cardiovascular disease.

Retinal Pigment Epithelial Detachment (RPED), central serous retinopathy, retinal Vein Occlusion (RVO) or a history or current evidence of RPED or RVO-inducing factors.

Any evidence of severe or uncontrolled systemic disease or any other significant clinical condition or laboratory-discovered evidence that renders the patient unsuitable for participation in the study.

Pregnant women or lactating women.

According to the local label, the sotoracib is forbidden.

Example 4: in vivo KRAS ^G12C mutant CRC PDX model CO-04-0307 assay vehicle/control Propylene Glycol (PG) in deionized water was prepared and stored at ambient conditions throughout 28 days of administration in mice.

Compound 1 was prepared weekly in a vehicle of 0.5% Methylcellulose (MC) and 0.1% tween 80 solution and stored under ambient conditions. The combination agent sotoracicmide was prepared weekly in a vehicle of 50% polyethylene glycol 400+50% propylene glycol w/w and stored at 2-8 ℃.

Female Balb/c nude mice were 6-8 weeks old at the time of implantation. Mice were housed in a Special Pathogen Free (SPF) environment of an animal feeding facility and were adapted to their new environment for at least 3 days before any experiments were initiated according to the IACUC protocol.

A CO-04-0307PDX model was established at WuXi AppTec for preclinical efficacy studies. The PDX model was derived from 82 year old chinese female CRC patients. The KRASG12C mutation in the PDX model CO-04-0307 was confirmed by whole exome sequencing and PCR sequencing. The skin of the mice was cleaned on the right abdomen with an appropriate surgical scrub and alcohol. Tumor fragments (15-30 mm ³) harvested from the PDX model (FP 5) were subcutaneously implanted into the right abdomen of mice using an 18g trocar. 300 mice were implanted in this study. Animals were monitored daily for health and tumor growth. Tumor volumes were measured twice a week by calipers when tumors were palpable and measurable. When tumor volumes reached an average of 155mm ³ (range 96-259mm ³) on day 22 post-subcutaneous implantation, tumor-bearing mice were randomly divided into different groups of 8 mice each. Randomization date is expressed as day 0 of treatment.

Treatment of

Treatment was started the following day after randomization. The day of treatment initiation is indicated as day 1 of treatment. Mice were dosed by oral administration of vehicle control solutions or monotherapy treatments of compound 1 or 100mg/kg QD of sotoracicada. The other group received 30 mg/kg/dose of combination therapy of Compound 1 of BID or 100mg/kg QD of sotoraciclovir. BID is administered at 8 hour intervals. In addition to conventional food and water supply, dietGel (Ready) was added to the cages in which at least two mice in the treatment group began to show >10% BWL on any measurement day76A,Ready Biotechnology (ShenZhen) co., ltd.). DietGel was provided during the remaining study after DietGel addition. According to this practice, mice in the monotherapy treatment group and mice in the combination treatment group were served DietGel food at 30 mg/kg/dose of compound 1BID starting on day 7 of treatment. The study was terminated on day 28 of treatment as defined in the study protocol.

As shown in fig. 3, compound 1 and sotoracicmide showed combined benefits in vivo in the KRAS ^G12C mutant CRC PDX model.

Example 5: in vivo KRAS ^G12C mutant CRC PDX model CO-04-0310 vehicle/control Propylene Glycol (PG) in deionized water was prepared and stored at ambient conditions throughout 28 days of dosing in mice.

Test article compound 1 was prepared weekly in a vehicle of 0.5% Methylcellulose (MC) and 0.1% tween 80 solution and stored under ambient conditions. The combination agent sotoracicmide was prepared weekly in a vehicle of 50% polyethylene glycol 400+50% propylene glycol w/w and stored at 2-8 ℃.

Female Balb/c nude mice were 6-8 weeks old at the time of implantation. Mice were housed in a special pathogen-free environment of an animal feeding facility and allowed to adapt to their new environment for at least 3 days before any experiments were initiated according to the IACUC protocol.

A CO-04-0310PDX model was established at WuXi AppTec for preclinical efficacy studies. The PDX model was derived from 82 year old chinese female CRC patients. The KRAS ^G12C mutation in PDX model CO-04-0310 was confirmed by whole-exome sequencing and PCR sequencing. The skin of the mice was cleaned on the right abdomen with an appropriate surgical scrub and alcohol. Tumor fragments (15-30 mm ³) harvested from the PDX model (FP 5) were subcutaneously implanted into the right abdomen of mice using an 18g trocar. 300 mice were implanted in this study. Animals were monitored daily for health and tumor growth. Tumor volumes were measured twice a week by calipers when tumors were palpable and measurable. When tumor volumes reached an average of 157mm ³ (range 95-240mm ³) on day 18 post-subcutaneous implantation, tumor-bearing mice were randomly divided into different groups of 8 mice each. Randomization date is expressed as day 0 of treatment.

Treatment of

Treatment was started the following day after randomization. The day of treatment initiation is indicated as day 1 of treatment. Mice were dosed by oral administration of vehicle control solutions or monotherapy treatments of compound 1 or 100mg/kg QD of sotoracicada. The other group received 30 mg/kg/dose of combination therapy of Compound 1 of BID or 100mg/kg QD of sotoraciclovir. BID is administered at 8 hour intervals. In the combination group, sotorubin was administered first and compound 1 was administered 1 hour later. In addition to conventional food and water supply, dietGel (Ready) was added to the cages in which at least two mice in the treatment group began to show >10% BWL on any measurement day76A,Ready Biotechnology (ShenZhen) co., ltd.). DietGel was provided during the remaining study after DietGel addition. According to this practice, mice in the monotherapy treatment group of 30 mg/kg/dose of compound 1BID were supplied DietGel with food starting on day 14 of treatment. The study was terminated on day 28 of treatment as defined in the study protocol.

As shown in fig. 4, compound 1 and sotoracicmide showed combined benefits in vivo in the KRAS ^G12C mutant CRC PDX model.

Example 6: in vivo KRAS G12C mutant NSCLC PDX model LU-01-0046 assay

Vehicle/control Propylene Glycol (PG) in deionized water was prepared and stored at ambient conditions throughout the 28 day dosing process in mice.

The LU-01-0046PDX model was built at WuXi AppTec for preclinical efficacy studies. The PDX model was derived from a 74 year old chinese male NSCLC patient. The KRASG12C mutation in PDX model LU-01-0046 was confirmed by whole exome sequencing and PCR sequencing. The skin of the mice was cleaned on the right abdomen with an appropriate surgical scrub and alcohol. Tumor fragments (15-30 mm ³) harvested from the PDX model (FP 5) were subcutaneously implanted into the right abdomen of mice using an 18g trocar. 300 mice were implanted in this study. Animals were monitored daily for health and tumor growth. Tumor volumes were measured twice a week by calipers when tumors were palpable and measurable. When the tumor volume reached an average of 191mm ³ (range 84-321mm ³) on day 21 after subcutaneous implantation, tumor-bearing mice were randomly divided into different groups of 8 mice each. Randomization date is expressed as day 0 of treatment.

Treatment of

Treatment was started the following day after randomization. The day of treatment initiation is indicated as day 1 of treatment. Mice were dosed by oral administration of vehicle control solutions or monotherapy treatments of compound 1 or 100mg/kg QD of sotoracicada. The other group received 30 mg/kg/dose of combination therapy of Compound 1 of BID or 100mg/kg QD of sotoraciclovir. BID is administered at 8 hour intervals. In the combination group, sotorubin was administered first and compound 1 was administered 1 hour later.

As shown in fig. 5, compound 1 and sotoracicmide showed combined benefits in vivo in KRAS ^G12C mutant NSCLC PDX model.

Claims

1. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(I) Compound 1: Or a pharmaceutically acceptable salt thereof; and

(Ii) KRAS G12C inhibitors.

2. The method of claim 1, wherein the KRAS G12C inhibitor is adaglazeb, ARS-3248, BBP-454, BI1701963, GDC-6036, sotoracicb, or tipifarnib.

3. The method of claim 1 or 2, wherein the KRAS G12C inhibitor is sotoraciclovir.

4. The method of claim 2 or 3, wherein the sotoracicada is administered in an amount of about 960 mg/day.

5. The method of claim 1 or 2, wherein the KRAS G12C inhibitor is adaglazeb.

6. The method of claim 2 or 5, wherein adaglazeb is administered in an amount of about 1200 mg/day.

7. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(I) Compound 1: Or a pharmaceutically acceptable salt thereof; and

(Ii) Sotoracicb.

8. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(I) Compound 1: Or a pharmaceutically acceptable salt thereof; and

(Ii) Adaglazeb.

9. The method of any one of claims 1-8, wherein the pharmaceutically acceptable salt of compound 1 is mandelate.

10. The method of any one of claims 1-8, wherein the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer.

11. The method according to any one of claims 1-8, wherein the cancer is a BRAF-driven cancer, HRAS-driven cancer, or NRAS-driven cancer.

12. The method of any one of claims 1-8, wherein the cancer comprises at least one cancer cell driven by deregulated ERK.

13. The method of any one of claims 1-8, wherein the cancer has at least one mutation in the RAS.

14. The method of any one of claims 1-8, wherein the cancer has at least one mutation in RAF.

15. The method of any one of claims 1-8, wherein the cancer has at least one mutation in MEK.

16. The method of any one of claims 1-8, wherein the cancer has a G12C KRAS mutation.

17. The method of any one of claims 1-8, wherein the cancer has a G12D KRAS mutation.

18. The method of any one of claims 1-8, wherein the cancer has a G12S KRAS mutation.

19. The method of any one of claims 1-8, wherein the cancer has a G12V KRAS mutation.

20. The method of any one of claims 1-8, wherein the cancer has a G13D KRAS mutation.

21. The method of any one of claims 1-8, wherein the cancer has a Q16H KRAS mutation.

22. The method of any one of claims 1-8, wherein the cancer has a Q16K KRAS mutation.

23. The method of any one of claims 1-8, wherein the cancer has a Q61R NRAS mutation.

24. The method according to any one of claims 1-8, wherein the cancer is a BRAF V600E or V600K mutant tumor.

25. The method of any one of claims 1-8, wherein the cancer is a pan-carcinoma that does not receive MAPKm/MAPKi.

26. The method of any one of claims 1-8, wherein the cancer comprises one or more EGFR mutations selected from the group consisting of: increased EGFR gene copy, EGFR gene amplification, chromosome 7 polyhedra, L858R, exon 19 deletion/insertion, L861, Q, G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, vvi and Vii), A289D, A289T, A289 858A, G598V, T790M and C797S.

27. The method of any one of claims 1-8, wherein the cancer comprises one or more EGFR mutations selected from L858R, exon 19 deletion, and T790M.

28. The method of any one of claims 1-27, wherein the cancer is a solid tumor.

29. The method of any one of claims 1-28, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

30. The method of any one of claims 1-28, wherein the cancer is non-small cell lung cancer (NSCLC).

31. The method of claim 30, wherein the NSCLC is an EGFR mutant NSCLC.

32. The method of claim 30, wherein the NSCLC is KRAS G12C mutant NSCLC.

33. The method of claim 30, wherein the NSCLC is KRAS G12D mutant NSCLC.

34. The method of claim 30, wherein the NSCLC is KRAS G12S mutant NSCLC.

35. The method of claim 30, wherein the NSCLC is KRAS G12V mutant NSCLC.

36. The method of claim 30, wherein the NSCLC is KRAS G13D mutant NSCLC.

37. The method of claim 30, wherein the NSCLC is KRAS Q61H mutant NSCLC.

38. The method of claim 30, wherein the NSCLC is KRAS Q61K mutant NSCLC.

39. The method of claim 30, wherein the NSCLC is NRAS Q61R mutant NSCLC.

40. The method of claim 30, wherein the cancer is NSCLC that did not receive MAPKm/MAPKi.

41. The method of claim 30, wherein the cancer is BRAFi treated V600 NSCLC.

42. The method of claim 30, wherein the cancer is KRAS treated G12C NSCLC.

43. The method of claim 30, wherein the cancer is KRAS-treated G12D NSCLC.

44. The method of claim 30, wherein the cancer is KRAS-treated G12S NSCLC.

45. The method of claim 30, wherein the cancer is KRAS treated G12V NSCLC.

46. The method of claim 30, wherein the cancer is KRAS treated G13D NSCLC.

47. The method of claim 30, wherein the cancer is KRAS treated Q61H NSCLC.

48. The method of claim 30, wherein the cancer is KRAS treated Q61K NSCLC.

49. The method of claim 30, wherein the cancer is NRAS treated Q61R NSCLC.

50. The method of any one of claims 1-28, wherein the cancer is pancreatic cancer.

51. The method of claim 50, wherein the cancer is pancreatic cancer that does not receive MAPKm/MAPKi.

52. The method of any one of claims 1-28, wherein the cancer is melanoma.

53. The method according to claim 52, wherein the melanoma is BRAF V600E or V600K mutant tumor.

54. The method of claim 52, wherein the cancer is BRAFi treated V600 melanoma.

55. The method of any one of claims 1-28, wherein the cancer is a salivary gland tumor.

56. The method of any one of claims 1-28, wherein the cancer is thyroid cancer.

57. The method of any one of claims 1-28, wherein the cancer is colorectal cancer (CRC).

58. The method of claim 57, wherein the CRC is BRAF V600ECRC.

59. The method of claim 57, wherein the CRC is a KRAS mutant CRC.

60. The method of claim 59, wherein the CRC is a KRAS G12C mutant CRC.

61. The method of claim 59, wherein the CRC is a KRAS G12D mutant CRC.

62. The method of claim 59, wherein the CRC is a KRAS G12S mutant CRC.

63. The method of claim 59, wherein the CRC is a KRAS G12V mutant CRC.

64. The method of claim 59, wherein the CRC is a KRAS G13D mutant CRC.

65. The method of claim 59, wherein the CRC is a KRAS Q61H mutant CRC.

66. The method of claim 59, wherein the CRC is a KRAS Q61K mutant CRC.

67. The method of claim 57, wherein the CRC is an NRAS mutant CRC.

68. The method of claim 67, wherein the CRC is an NRAS Q61R mutant CRC.

69. The method of any one of claims 1-28, wherein the cancer is esophageal cancer.

70. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day to about 300 mg/day.

71. The method of any one of claims 1-70, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 25 mg/day to 150 mg/day.

72. The method of any one of claims 1-71, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

73. The method of any one of claims 1-72, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

74. The method of any one of claims 1-71, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250 mg/day.

75. The method of any one of claims 1-74, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered once daily (QD).

76. The method of any one of claims 1-74, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID).

77. The method of any one of claims 1-74, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered three times per day (TID).

78. The method of any one of claims 1-77, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered weekly.

79. The method of any one of claims 1-77, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered twice weekly.

80. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 300mg twice daily, one day per week (BID-QW).

81. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 250mg twice daily, one day per week (BID-QW).

82. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 150mg twice daily, one day per week (BID-QW).

83. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 50mg, about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, or about 250mg twice daily, one day per week (BID-QW).

84. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 50mg, about 100mg, about 125mg, or about 150mg twice daily, one day per week (BID-QW).

85. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 125mg twice daily, one day per week (BID-QW).

86. The method of any one of claims 1-85, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day period.

87. The method of any one of claims 1-86, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, 15, and 22 of a 28-day cycle.

88. The method of any one of claims 1-86, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered on day 1, day 8, day 15 of a 28 day cycle.

89. The method of any one of claims 1-88, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

90. The method of any one of claims 1-89, wherein the method further comprises administering an additional MAPK pathway inhibitor.

91. The method of claim 90, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAF1 inhibitor, MEK2 inhibitor, c-Mycv, CDK4/6, inhibitor CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor.

92. The method of claim 90, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor.

93. The method of claim 90, wherein the additional MAPK pathway inhibitor is a BRAF inhibitor.

94. The method of claim 90, wherein the additional MAPK pathway inhibitor is an EGFR inhibitor.

95. The method of claim 90, wherein the additional MAPK pathway inhibitor is CDK4/6.

96. The method of claim 90, wherein the additional MAPK pathway inhibitor is a FLT3 inhibitor.

97. The method of claim 90, wherein the additional MAPK pathway inhibitor is adaglazeb, afatinib, ASTX029, bimatinib, cetuximab, cobratinib, dabrafenib, dacatinib, kang Naifei ni, erlotinib, gefitinib, ji Ruiti ni, lapatinib, LTT462, LY3214996, rituximab, lenatinib, nimotuzumab, octyitinib, palbociclib, panitumumab, sematinib, sotolsibirib, trimetinib, ulitinib, and vandetanib.

98. The method of claim 90, wherein the additional MAPK pathway inhibitor is cetuximab.

99. The method of claim 90, wherein the additional MAPK pathway inhibitor is dabrafenib.

100. The method of claim 90, wherein the additional MAPK pathway inhibitor is Kang Naifei ni.

101. The method of claim 90, wherein the additional MAPK pathway inhibitor is gefitinib.

102. The method of claim 90, wherein the additional MAPK pathway inhibitor is palbociclib.

103. The method of claim 90, wherein the additional MAPK pathway inhibitor is panitumumab.