Therapeutic compositions, combinations, and methods of use

Abstract

This disclosure relates to methods of treating KRAS G12C mutant non-small cell lung cancer (NSCLC) by administering a triple combination therapy including defactinib, avutometinib, and sotorasib in a subject such as humans.

Description

Attorney Docket VSM-099WOTHERAPEUTIC COMPOSITIONS, COMBINATIONS, AND METHODS OF USE Background

[0001] Convincing evidence suggests that Focal Adhesion Kinase (FAK), a cytoplasmic nonreceptor tyrosine kinase, plays an essential role in cell survival, proliferation, migration, invasion, and adhesion (Clark and Brugge 1995, Science 268: 233-239) and its aberrant expression and / or activation is associated with an increase in the metastatic potential of tumors (Owens et al. 1995, Cancer Research 55: 2752-2755). FAK activation has been reported in response to chemotherapy and target therapies, including RAF and MEK inhibitors among others (Hirata et al. 2015; Chen et al. 2018). Selective inhibitors of FAK are useful in the treatment of abnormal cell growth, in particular, cancer, in mammals.

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a GTPase and member of the RAS oncogene family. KRAS serves as a molecular switch cycling between inactive (GDP- bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases and downstream effectors to regulate cellular processes, including proliferation (Alamgeer et al., 2013, Current Opin. Pharmcol. 13: 394-401). KRAS gene mutations are common in cancer. For example, KRAS mutations are observed in about 30% of patients with lung adenocarcinoma, and approximately 13% of these patients have a KRAS G12C mutation (Kodaz et al., 2017, EJMO 1: 1-7). Selective inhibitors of KRAS G12C are useful for the treatment of cancer.

[0003] Components of the RAS / RAF / MEK / ERK (MAPK) signal transduction pathway also present opportunities for the treatment of cancer. MEK proteins are the primary downstream targets of RAF, and they belong to a family of dual-specificity kinases, having both serine / threonine and tyrosine kinase activity. Selective inhibitors of certain components of the RAS / RAF / MEK / ERK signal transduction pathway, such as RAS, RAF, MEK and ERK (including dual RAF / MEK inhibitors) are useful in the treatment of abnormal cell growth, in particular, cancer, in mammals.

[0004] Due to the severity and breadth of diseases and disorders associated with abnormal cell growth (e.g., cancer), there is a need for effective therapeutic means and methods for treatment. The compounds, compound combinations, compositions, and methods of treatment described herein are directed toward this end.Brief Description of the Drawings

[0005] FIG. 1 is a waterfall plot depicting patient best overall response in two groups of patients. One group had not previously received any KRAS G12C inhibitory therapy (“KRAS1IPTS / 200232471.2Attorney Docket VSM-099WOG12Ci naive”). The other group previously experienced disease progression upon treatment with a KRAS G12C inhibitor (“KRAS G12Ci progressor”). Both groups were administered the combination of sotorasib, defactinib, and avutometinib (“triple”). The response is measured as a % change in tumor volume.

[0006] FIG. 2 is a spider plot depicting patient response to treatment with the triplet as a function of time over a 9 month period in both the KRAS G12Ci-naive and KRAS G12Ci- progressor groups.

[0007] FIG 3. shows a comparison of progression free survival, in months, to triplet treatment between the KRAS G12Ci-naive and KRAS G12Ci -progressor patient groups.Summary

[0008] In some embodiments, the disclosure relates to a method for treating cancer wherein a subject is treated with a triple combination therapy comprising a FAK inhibitor, a dual RAF / MEK inhibitor, and a KRAS G12C inhibitor. In some embodiments, the FAK inhibitor is defactinib, or a pharmaceutically acceptable salt thereof, the dual RAF / MEK inhibitor is avutometinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is sotorasib, or a pharmaceutically acceptable salt thereof. In some embodiments, the FAK inhibitor is defactinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the dual RAF / MEK inhibitor is avutometinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS G12C inhibitor is sotorasib, or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is RAS mutant lung cancer. In some embodiments, the RAS mutant lung cancer is KRAS mutant lung cancer. In some embodiments, the KRAS mutant lung cancer is KRAS G12C mutant lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0010] In some aspects, the defactinib is dosed twice daily. In other aspects, the defactinib is dosed once daily. In some aspects, the avutometinib is dosed twice a week. In some aspects, the sotorasib is dosed once daily. In some embodiments, the avutometinib and the defactinib are dosed for at least three weeks of a four- week cycle. In some embodiments, the avutometinib and the defactinib are independently dosed cyclically for three weeks on, and then one week off. In some embodiments, both of the avutometinib and the defactinib are simultaneously dosed cyclically for three weeks on and then one week off. In some embodiments the sotorasib is dosed continuously for the four-week cycle.2IPTS / 200232471.2Attorney Docket VSM-099WO

[0011] In some aspects, the defactinib is dosed at about 100 mg to about 500 mg. In some embodiments, the defactinib is dosed at about 100 mg to about 400 mg. In further embodiments, the defactinib is dosed at about 200 mg to about 400 mg. In other embodiments, the defactinib is dosed at about 200 mg.

[0012] In some aspects, the avutometinib is dosed at about 0.5 mg to about 10 mg. In some embodiments, the avutometinib is dosed at about 1.6 mg to about 4 mg. In some embodiments, the avutometinib is dosed at about 2.4 mg to about 4 mg. In further embodiments, the avutometinib is dosed at about 4 mg. In other embodiments, the avutometinib is dosed at about 3.2 mg. In other embodiments, the avutometinib is dosed at about 2.4 mg. In other embodiments, the avutometinib is dosed at about 1.6 mg.

[0013] In some aspects, the sotorasib is dosed at about 240 mg to about 960 mg. In further embodiments, the sotorasib is dosed at about 240 mg. In further embodiments, the sotorasib is dosed at about 480 mg. In other embodiments, the sotorasib is dosed at about 960 mg.

[0014] In some embodiments, the defactinib is dosed at about 200 mg twice daily, the avutometinib is dosed at about 4 mg twice a week, and the sotorasib is dosed at about 960 mg once daily. In some embodiments, the defactinib is dosed at about 200 mg twice daily, the avutometinib is dosed at about 3.2 mg twice a week, and the sotorasib is dosed at about 960 mg daily. In some embodiments, the defactinib is dosed at 200 mg twice daily, the avutometinib is dosed at 2.4 mg twice a week, and the sotorasib is dosed at 960 mg daily. In some embodiments, the defactinib is dosed at 200 mg twice daily, the avutometinib is dosed at 1.6 mg twice a week, and the sotorasib is dosed at 960 mg daily.Detailed Description of the Invention

[0015] Described herein, are methods for treating abnormal cell growth, e.g., cancer, (e.g., lung cancer or NSCLC) in a subject with a KRAS G12C mutation, the method comprising administering to a subject a FAK inhibitor, a dual RAF / MEK inhibitor, and a KRAS G12C inhibitor, wherein the FAK inhibitor is defactinib, or a pharmaceutically acceptable salt thereof, the dual RAF / MEK inhibitor is avutometinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is sotorasib, or a pharmaceutically acceptable salt thereof.Methods of Treatment and Administration

[0016] The methods described herein relate to treating a subject (e.g., a human subject) suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer3IPTS / 200232471.2Attorney Docket VSM-099WO(e.g., a cancer described herein)) with a triple combination comprising a FAK inhibitor, a dual RAF / MEK inhibitor, and a KRAS G12C inhibitor, wherein the FAK inhibitor is defactinib, or a pharmaceutically acceptable salt thereof, the dual RAF / MEK inhibitor is avutometinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is sotorasib, or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the delivery of one or more treatments is still occurring when the delivery of the second and / or third begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent” delivery”. In other embodiments, the delivery of one or more treatments ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the third treatment is more effective, e.g., an equivalent effect is seen with less of the third treatment, or the third treatment reduces symptoms to a greater extent, than would be seen if the third treatment were administered in the absence of the first and second treatments, or the analogous situation is seen with the first or second treatments. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder, is greater than what would be observed with one or more treatments delivered in the absence of an additional treatment. The effect of the three treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first and second treatments delivered are still detectable when the third is delivered.

[0018] In some embodiments, the method comprises administration of defactinib and sotorasib before administration of avutometinib. In some embodiments, the method comprises administration of defactinib after administration of avutometinib and sotorasib. In some embodiments, the method comprises administration of defactinib and sotorasib concurrently with administration of avutometinib. In some embodiments, the method comprises administration of avutometinib concurrently with defactinib and sotorasib. In some embodiments, defactinib, avutometinib, and sotorasib may each be in the form of a pharmaceutically acceptable salt.

[0019] In some embodiments, the defactinib, avutometinib, and sotorasib are administered on a four-week cycle wherein the avutometinib and defactinib are administered concurrently with sotorasib and concurrently with each other. In another embodiment, the defactinib, avutometinib, and sotorasib are administered on a four-week cycle wherein the avutometinib and defactinib are administered concurrently with sotorasib and the avutometinib is4IPTS / 200232471.2Attorney Docket VSM-099WO administered either before or after the defactinib. In some embodiments, defactinib, avutometinib, and sotorasib may each be in the form of a pharmaceutically acceptable salt.

[0020] In some embodiments, the 4-week cycle is repeated two times (8 weeks) to 45 times (approximately 3 years and 5 months). For example, and more specifically, it is repeated 8 times (32 weeks) to 18 times (72 weeks). Even if the number of cycles to be repeated has previously been determined, the number of cycles may be changed based on the judgment of the physician depending on, for example, the condition of the subject. Moreover, administration may even be stopped during the cycle based on the judgment of the physician depending on, for example, the condition of the subject.

[0021] Methods of the present disclosure contemplate single as well as multiple administrations of a therapeutically effective amount of a triple combination of defactinib, avutometinib, and sotorasib. Combinations, e.g., a combination as described herein, e.g., a triple combination of defactinib, avutometinib, and sotorasib, can be administered at regular intervals, depending on the nature, severity, and extent of the subject’s condition. In some embodiments, a triple combination as described herein, e.g., defactinib, avutometinib, and sotorasib, is administered in a single dose. In some embodiments, a triple combination as described herein, e.g., a triple combination of defactinib, avutometinib, and sotorasib, is administered in multiple doses. In some embodiments, a therapeutically effective amount of a triple combination as described herein, e.g., defactinib, avutometinib, and sotorasib may be administered orally and periodically at regular intervals (e.g. , 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times every 1, 2, 3, 4, 5, or 6 days, or every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9 months or longer).

[0022] In some embodiments, a therapeutically effective amount of a triple combination as described herein, e.g., defactinib that may be administered orally and periodically (e.g., twice daily), with avutometinib that may be administered orally and periodically (e.g., twice a week (e.g., with two and three days between the two administrations per week)), and with sotorasib that may be administered orally and periodically (e.g. once daily). In some embodiments, a therapeutically effective amount of a triple combination as described herein, e.g., defactinib that may be administered orally and periodically (e.g. , once daily), with avutometinib that may be administered orally and periodically (e.g., twice a week), and with sotorasib that may be administered orally and periodically (e.g., once daily). In some embodiments, a therapeutically effective amount of a triple combination as described herein, e.g., defactinib that may be administered orally and periodically (e.g., twice daily) with avutometinib that may be administered orally and periodically (e.g., three times a week) and sotorasib that may be 5IPTS / 200232471.2Attorney Docket VSM-099WO administered orally and periodically (e.g., once daily). In some embodiments, defactinib, avutometinib, and sotorasib may each be in the form of a pharmaceutically acceptable salt.

[0023] In some embodiments, a combination as described herein, defactinib is administered orally and periodically (e.g., twice daily) in combination with avutometinib, that is administered orally and at a predetermined interval (e.g., twice a week), for three weeks, followed by one week off (or an interval of no administration of either defactinib or avutometinib, then repeated cyclically (e.g., three weeks on, one week off, three weeks on, one week off, etc.)) and sotorasib that is administered orally and periodically (e.g., once daily) for at least four weeks.

[0024] Exemplary courses of treatment for a 28-day cycle of the triple combination therapy are represented as follows:Exemplary Dosing Schedules 1-36IPTS / 200232471.2Attorney Docket VSM-099WOExemplary Schedule 1, 2 = Exemplary Schedule 2, and 3 = Exemplary Schedule 3.

[0025] The timing of one week off for defactinib, or a pharmaceutically acceptable salt thereof, and the timing of one week off for avutometinib, or a pharmaceutically acceptable salt thereof, can be simultaneous or different. In a preferred embodiment, timing of one week off for defactinib, or a pharmaceutically acceptable salt thereof, and timing of one week off for avutometinib, or a pharmaceutically acceptable salt thereof, is simultaneous (e.g., the same week). In other embodiments, timing of one week off for defactinib, or a pharmaceutically acceptable salt thereof, and timing of one week off for avutometinib, or a pharmaceutically acceptable salt thereof, is different (e.g., different weeks).

[0026] In some embodiments, the defactinib is administered orally twice a day. In some embodiments, the defactinib is administered orally once a day. In some embodiments, the defactinib is administered in a dose of about 100 mg to about 600 mg. In some embodiments, the defactinib is administered in a dose of about 100 mg to about 500 mg. In some embodiments, the defactinib is administered in a dose of about 100 mg to about 400 mg. In some embodiments, the defactinib is administered in a dose of about 200 mg to about 400 mg. In some embodiments, the defactinib is administered in a dose of about 200 mg. In some embodiments, the defactinib is administered in a dose of about 400 mg. It should be appreciated that the defactinib may be administered in a dose at any of the periodic time periods described herein. For example, the defactinib may be administered in a dose of about 200 mg twice daily. The defactinib may be administered in a dose of about 400 mg twice daily. In some embodiments, defactinib may be in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt of defactinib is a hydrochloride salt of defactinib.

[0027] In some embodiments, the avutometinib is administered orally once a week. In other embodiments, the avutometinib is administered orally twice a week. In other embodiments, the avutometinib is administered orally three times a week. In other embodiments, the 7IPTS / 200232471.2Attorney Docket VSM-099WO avutometinib is administered orally four times a week. In other embodiments, the avutometinib is administered orally five times a week. In other embodiments, the avutometinib is administered orally once a day. In other embodiments, the avutometinib is administered orally twice a day. In some embodiments, the avutometinib is dosed at about 0.5 mg to about 10 mg. In some In some embodiments, the avutometinib is dosed at about 1.6 mg to about 4 mg. In some embodiments, the avutometinib is dosed at about 2.4 mg to about 4 mg. In further embodiments, the avutometinib is dosed at about 4 mg. In other embodiments, the avutometinib is dosed at about 3.2 mg. In other embodiments, the avutometinib is dosed at about 2.4 mg. In other embodiments, the avutometinib is dosed at about 1.6 mg. It should be appreciated that the avutometinib may be administered in a dose at any of the periodic time periods described herein. For example, the avutometinib may be administered in a dose of about 1.6 mg twice a week, in a dose of about 2.4 mg twice a week, in a dose of about 3.2 mg twice a week, or at a dose of about 4 mg twice a week. In some embodiments, avutometinib may be in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt of avutometinib is a potassium salt of avutometinib.

[0028] In some embodiments, the sotorasib is administered orally once a day. In some embodiments, the sotorasib is administered in a dose of about 240 mg to about 960 mg. In some embodiments, the sotorasib is administered in a dose of about 240 mg, about 480 mg, or about 960 mg. In other embodiments, the sotorasib is dosed at 960 mg. In some embodiments, sotorasib may be in the form of a pharmaceutically acceptable salt. In some embodiments, sotorasib is a free-base of sotorasib.

[0029] In some embodiments, the defactinib is administered within 30 minutes of a meal, the avutometinib is administered with or without food, and the sotorasib is administered with or without food.

[0030] The period during which the avutometinib is used in combination with the defactinib may be determined based on the judgment of the physician depending on, for example, the condition of the subject. Also, administration of one of, two of, or all three of the avutometinib, the defactinib, or the sotorasib may be stopped based on the judgment of the physician depending on, for example, the condition of the subject.Cancer

[0031] In some embodiments, the methods of the present disclosure may be useful in the treatment of cancer, including, for example, solid tumors, soft tissue tumors, and metastases thereof. In some embodiments, the methods of the present disclosure may be useful in the8IPTS / 200232471.2Attorney Docket VSM-099WO treatment of cancer in which the RAS-RAF-MEK-ERK pathway is activated. The disclosed methods are also useful in treating non-solid cancers. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems.

[0032] The cancer can be a primary tumor, i.e., located at the anatomical site of tumor growth initiation. The cancer can also be metastatic, i.e., appearing at least a second anatomical site other than the anatomical site of tumor growth initiation. The cancer can be a recurrent cancer, i.e. , cancer that returns following treatment, and after a period of time in which the cancer was undetectable. The recurrent cancer can be anatomically located locally to the original tumor, e.g., anatomically near the original tumor; regionally to the original tumor, e.g., in a lymph node located near the original tumor; or distantly to the original tumor, e.g., anatomically in a region remote from the original tumor.

[0033] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is refractory (e.g., resistant) after standard therapy.

[0034] The cancer can also have a RAS mutation, meaning that the cancer is caused by a mutation of a RAS gene (HRAS, NR AS, or KRAS). The cancer could also have a KRAS mutation, meaning that the cancer is caused by a mutation of the KRAS gene (e.g., a KRAS G12C mutation). The cancer could have a KRAS G12 mutation (e.g., a KRAS G12C mutation). In some embodiments, the KRAS G12C mutation is a KRAS G12C mutation. In some embodiments, the cancer is a KRAS G12C mutant cancer. In some embodiments, the cancer is lung cancer caused by a mutation of a RAS gene (e.g. , a KRAS G12C mutation). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC) caused by a mutation of a RAS gene (e.g., a KRAS G12C mutation). In some embodiments, the non-small cell lung cancer (NSCLC) is caused by a KRAS mutation (e.g., a KRAS G12C mutation). In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC (e.g., KRAS G12C mutant NSCLC), e.g., metastatic lung cancer). In some embodiments, the non-small cell lung cancer (NSCLC) is KRAS G12C mutant non-small cell lung cancer.

[0035] Examples of genes mutated in the cancer also include EGFR, FGFR, ALK, ROS1, PI3K, NF-1, BRAF, HRAS, KRAS and NRAS. In one embodiment, the cancer is a KRAS mutant (e.g., a KRAS G12C mutant) cancer. In another embodiment, the cancer is a KRAS mutant (e.g., a KRAS G12C mutant) solid cancer (e.g., lung cancer (e.g., non-small-cell lung cancer)).9IPTS / 200232471.2Attorney Docket VSM-099WO

[0036] Methods described herein can reduce, ameliorate or altogether eliminate the disorder, and / or its associated symptoms, to keep it from becoming worse, to slow the rate of progression, or to minimize the rate of recurrence of the disorder once it has been initially eliminated (i.e., to avoid a relapse). A suitable dose and therapeutic regimen may vary depending upon the specific compounds and / or pharmaceutical compositions used and the mode of delivery of the compounds and / or pharmaceutical compositions. In some embodiments, the method increases the average length of survival, increases the average length of progression-free survival, and / or reduces the rate of recurrence, of subjects treated with the combinations described herein in a statistically significant manner.Compounds

[0037] The methods described herein comprise, among other things, administering a triple combination of a FAK inhibitor, adual RAF / MEK inhibitor, and a KRAS G12C inhibitor to a subject having cancer (e.g. , KRAS G12C mutant non-small cell lung cancer), wherein the FAK inhibitor is defactinib, or a pharmaceutically acceptable salt thereof, and the dual RAF / MEK inhibitor is avutometinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is sotorasib, or a pharmaceutically acceptable salt thereof.Defactinib

[0038] Defactinib (also identified as FAKZYNJA™,VS-6063, or PF-0455878) is a FAK inhibitor. Included herein are methods of using defactinib, or a pharmaceutically acceptable salt thereof (e.g., defactinib hydrochloride). Defactinib and related compounds are also disclosed in, e.g., U.S. Pat. No. 7,928,109. In some embodiments, defactinib can form a pharmaceutically acceptable salt (e.g., defactinib hydrochloride). Defactinib (free base) is represented by the following structure:

[0039] Defactinib hydrochloride is represented by the following structure:10IPTS / 200232471.2Attorney Docket VSM-099WOAvutometinib

[0040] Avutometinib (also identified as AVMAPKI™, RO5126766, or CH5126766) is a dualRAF / MEK inhibitor. Included herein are methods of using avutometinib, or a pharmaceutically acceptable salt thereof. Avutometinib (free base) is represented by the following structure:

[0041] In some embodiments, the avutometinib or pharmaceutically acceptable salt thereof to be used in the present disclosure is a potassium salt of avutometinib. The potassium salt of avutometinib is, for example, a salt represented by the following formula:

[0042] For example, avutometinib, and pharmaceutically acceptable salts thereof, are disclosed in WO 2007 / 091736 and WO 2009 / 014100 and can be prepared according to the method described in those publications.Sotorasib

[0043] Sotorasib (also identified as LUMAKRAS® or AMG 510) is an inhibitor of KRAS G12C, a tumor-restricted, mutant-oncogenic form of the RAS GTPase, KRAS. Included herein are methods of using sotorasib, or a pharmaceutically acceptable salt thereof. Sotorasib (free base) is represented by the following structure:11IPTS / 200232471.2Attorney Docket VSM-099WOFirst-Line Therapy

[0044] In some embodiments, described herein is a method of treating a human subject having cancer, wherein the subject has failed (e.g., relapsed from, insensitive to, received no or little benefit from) first-line treatment (e.g. , first-line therapy for cancer). The present disclosure also describes a method of treating a human subject having cancer, wherein the methods of the disclosure are administered with an additional agent. In some embodiments, the additional agent is a first-line therapy for cancer.

[0045] First-line therapy is typically the first treatment given for a disease (e.g., cancer as described herein). It is often part of a standard set of treatments, such as surgery followed by chemotherapy and radiation. When used by itself, first-line therapy is generally the one accepted as the best treatment. If it does not cure the disease or it causes severe side effects, other treatment(s) may be added or used instead. First-line therapy is also called induction therapy, primary therapy, and primary treatment.Second-Line Therapy

[0046] In some embodiments, described herein is a method of treating a human subject having cancer, wherein the subject has failed (e.g., relapsed from, insensitive to, received no or little benefit from) second-line or more treatment (e.g., second-line therapy for cancer, or third-line therapy for cancer). The present disclosure also describes a method of treating a human subject having cancer, wherein the methods of the disclosure are administered with an additional agent. In some embodiments, the additional agent is a first- or second-line therapy for cancer. Second- line therapy generally refers to treatment that is given when initial treatment (e.g., first-line therapy) does not achieve a desired result, e.g., it does not work, is not efficacious; stops working. Second-line therapy is typically considered or given when a subject does not respond or develops a resistance to initial treatment (e.g., first-line therapy). For example, second-line therapy is typically considered or given to a subject with relapsed or refractory disease.12IPTS / 200232471.2Attorney Docket VSM-099WOAdministration and Dosage

[0047] Exemplary pharmaceutical compositions include compressed tablets (e.g., directly compressed tablets), e.g., comprising a FAK inhibitor (e.g., defactinib); or a KRAS G12C inhibitor (e.g., sotorasib). Exemplary pharmaceutical compositions include capsules, e.g., comprising a dual RAF / MEK inhibitor (e.g., avutometinib). In some embodiments, the FAK inhibitor is in the form of a tablet, the dual RAF / MEK inhibitor is in the form of a capsule, and the KRAS G12C inhibitor is in the form of a tablet.

[0048] Tablets or capsules are also provided comprising the active or therapeutic ingredient (e.g., compound as described herein (e.g., a FAK inhibitor (e.g., defactinib), a dual RAF / MEK inhibitor (e.g., avutometinib), and a KRAS G12C inhibitor (e.g., sotorasib)). In addition to the active or therapeutic ingredients, tablets or capsules may contain a number of inert materials such as carriers. Oral dosage forms for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which can be used pharmaceutically.

[0049] Excipients can impart good powder flow and compression characteristics to the material being compressed. Examples of excipients are described, for example, in the Handbook of Pharmaceutical Excipients (5thedition), Edited by Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen; Publisher: Pharmaceutical Press.

[0050] For oral administration, the active ingredients, e.g., the compound as described herein (e.g., a FAK inhibitor (e.g., defactinib); a dual RAF / MEK inhibitor (e.g., avutometinib); a KRAS G12C inhibitor (e.g., sotorasib)), can be formulated readily by combining the active ingredients with pharmaceutically acceptable carriers well known in the art. Such carriers enable the active ingredients of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in water or nonaqueous media, and the like, for oral ingestion by a subject. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain, for example, tablets. Suitable excipients such as diluents, binders or disintegrants may be desirable. Also, a FAK inhibitor (e.g., defactinib), a dual RAF / MEK inhibitor (e.g., avutometinib), and a KRAS G12C inhibitor (e.g., sotorasib) can be formulated separately according to the method described above.

[0051] The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be 13IPTS / 200232471.2Attorney Docket VSM-099WO chosen by the individual physician in view of the patient’s condition. (See, e.g., Fingl, et al., 1975, in “The Pharmacological Basis of Therapeutics”). Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject’ s disposition to the disease, condition or symptoms, and the judgment of the treating physician. A course of therapy can comprise one or more separate administrations of a compound as described herein (e.g., defactinib, or a pharmaceutically acceptable salt thereof, and / or avutometinib, or a pharmaceutically acceptable salt thereof, and / or sotorasib, or a pharmaceutically acceptable salt thereof).

[0052] Oral dosage forms may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.

[0053] The dosing regimen used in the present disclosure makes it possible to administer the avutometinib in combination with the defactinib and the sotorasib for prolonged periods while minimizing side effects and maintaining the drug’s efficacy. In addition, the dosing regimen and the combination make it possible to treat or prevent cell proliferative disorders, particularly cancer, while minimizing the burden on patients.Definitions

[0054] As used herein, the articles “a” and “an” refer to one or to more than one (e.g., at least one) of the grammatical object of the article.

[0055] ‘ ‘About” and “approximately,” as used herein, refer to an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.14IPTS / 200232471.2Attorney Docket VSM-099WO

[0056] As used herein, an amount of a compound effective to treat a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), “effective amount” or “effective course” refers to an amount of the compound which is effective, upon single or multiple dose administration(s) to a subject, in treating a subject, or in curing, alleviating, relieving or improving a subject with a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)) beyond that expected in the absence of such treatment (e.g., placebo treatment).

[0057] The term “pharmaceutically acceptable”, as used herein, refers to a compound or carrier (e.g., excipient) that may be administered to a subject, together with a compound described herein (e.g., defactinib, or a pharmaceutically acceptable salt thereof, and / or avutometinib, or a pharmaceutically acceptable salt thereof, and / or sotorasib, or a pharmaceutically acceptable salt), and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[0058] The term, “pharmaceutically acceptable salts”, as used herein, refers to derivatives of a compound described herein (e.g., defactinib, or a pharmaceutically acceptable salt thereof, and / or avutometinib, or a pharmaceutically acceptable salt thereof, and / or sotorasib, or a pharmaceutically acceptable salt thereof), wherein the compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the disclosure include the conventional non-toxic salts of a compound described herein, formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the disclosure can be synthesized from a compound described herein (e.g., defactinib, or a pharmaceutically acceptable salt thereof, and / or avutometinib, or a pharmaceutically acceptable salt thereof, or sotorasib, or a pharmaceutically acceptable salt thereof), which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0059] Lists of suitable salts are found in Remington ’s Pharmaceutical Sciences, 17thed. , Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. Examples of pharmaceutically acceptable salts also include: inorganic acid salts such as hydrochlorides, 15IPTS / 200232471.2Attorney Docket VSM-099WO hydrobromides, hydroiodides, sulfates and phosphates; sulfonates such as methanesulfonates, benzenesulfonates and toluenesulfonates; carboxylates such as formates, acetates, oxalates, maleates, fumarates, citrates, malates, succinates, malonates, gluconates, mandelates, benzoates, salicylates, fluoroacetates, trifluoroacetates, tartrates, propionates and glutarates; alkali metal salts such as lithium salts, sodium salts, potassium salts, cesium salts and rubidium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts.

[0060] The term, “oral dosage form,” as used herein, refers to a composition or medium used to administer an agent, e.g., a therapeutic agent, e.g., a compound as described herein, to a subject. Typically, an oral dosage form is administered via the mouth, however, “oral dosage form” is intended to cover any substance which is administered to a subject and is absorbed across a membrane, e.g., a mucosal membrane, of the gastrointestinal tract, including, e.g., the mouth, esophagus, stomach, small intestine, large intestine, and colon. For example, “oral dosage form” covers a solution which is administered through a feeding tube into the stomach.

[0061] The term, “treat” or “treatment”, as used herein, refers to the application or administration of a compound, alone or in combination with, an additional agent to a subject, e.g., a subject who has a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)) or is suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), a symptom of a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), or a predisposition toward a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)).

[0062] The phrase, “in combination with,” and the terms “co-administration,” “coadministering,” or “co-providing,” as used herein in the context of the administration of a compound described herein or a therapy described herein, means that two (or more) different compounds or therapies are delivered to the subject during the course of the subject’s affliction with the disease or disorder (e.g., a cancer), e.g., two (or more) different compounds or therapies are delivered to the subject after the subject has been diagnosed with the disease or disorder (e.g., a disease or disorder as described herein, e.g., cancer) and before the disease or disorder has been cured or eliminated or treatment has ceased for other reasons. Combinations16IPTS / 200232471.2Attorney Docket VSM-099WO can achieve synergistic results, i.e., greater than additive results, e.g., at least 20, 50, 70, or 100% greater than additive.

[0063] As used herein, the phrase “synergistic effect” refers to a greater than additive effect (e.g., therapeutic effect) of two or more compounds or compositions. An exemplary synergistic effect includes administration of an amount of a FAK inhibitor (e.g., defactinib) used (e.g., administered) in combination with an amount of a dual RAF / MEK inhibitor (e.g., avutometinib) and a KRAS G12C inhibitor (e.g., sotorasib) that results in a therapeutic effect that is greater than the additive therapeutic effect of each inhibitor used alone.

[0064] “Course of therapy,” as referred to herein, comprises one or more separate administrations of a therapeutic agent. A course of therapy can comprise one or more cycles of a therapeutic agent.

[0065] A “cycle,” as used herein in the context of a cycle of administration of a drug, refers to a period of time for which a drug is administered to a patient. In one embodiment, one cycle is equal to four weeks.

[0066] Numerous ranges, e.g., ranges for the amount of a drug administered per day, are provided herein. In some embodiments, the range includes both endpoints. In other embodiments, the range excludes one or both endpoints. By way of example, the range can exclude the lower endpoint. Thus, in such an embodiment, a range of 100 to 400 mg / day, excluding the lower endpoint, would cover an amount greater than 100 that is less than or equal to 400 mg / day.

[0067] As used herein, the term “subject” is intended to include human and non-human animals. In some embodiments, the subject is a human. Exemplary human subjects include a human subject having a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)) or is suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)). The term “non-human animals” of the disclosure includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc..

[0068] The phrase “twice a week” means that the avutometinib is administered two times during a one-week period. Administration may be performed twice on the same day, or once a day on different days (which may be consecutive), but it is preferably performed on different days. More preferably, administration is performed on the 1st and 4th days or the 2nd and 5th days of the period, for example, so that the avutometinib is administered at dose intervals as uniform as possible, i.e., at dose intervals of 3 to 4 days. The one-week period may start on a17IPTS / 200232471.2Attorney Docket VSM-099WOMonday, for example, or it may start on a Tuesday, for example. When two administrations are performed on different days, each may be performed at any time of day, but they are preferably performed at the same time of day (for example, after breakfast).

[0069] Additional disclosure can be found is provisional US Patent Application No 63 / 733,886, which is incorporated herein by reference in its entirety.Embodiments

[0070] 1. A method for treating non-small cell lung cancer in a human subject in need thereof, the method comprising:(A) orally administering a therapeutically effective amount of avutometinib, or a pharmaceutically acceptable salt thereof, twice weekly;(B) orally administering a therapeutically effective amount of defactinib, or a pharmaceutically acceptable salt thereof, twice daily; and(C) orally administering a therapeutically effective amount of sotorasib, or a pharmaceutically acceptable salt thereof, once daily; wherein avutometinib is administered for 3 weeks and then not administered for1 week thereafter; and wherein defactinib is administered for 3 weeks and then not administered for 1 week thereafter.

[0071] 2. The method of embodiment 1, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 0.5 mg to 10 mg per administration.

[0072] 3. The method of embodiment 1 or 2, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 2.4 mg per administration.

[0073] 4. The method of embodiment 1 or 2, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 3.2 mg per administration.

[0074] 5. The method of embodiment 1 or 2, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 4 mg per administration.

[0075] 6. The method of any one of embodiments 1 to 5, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is a potassium salt of avutometinib.

[0076] 7. The method of any one of embodiments 1 to 6, wherein defactinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg to 500 mg per administration.18IPTS / 200232471.2Attorney Docket VSM-099WO

[0077] 8. The method of any one of embodiments 1 to 7, wherein defactinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg per administration.

[0078] 9. The method of any one of embodiments 1 to 7, wherein defactinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 400 mg per administration.

[0079] 10. The method of any one of embodiments 1-0. wherein defactinib, or a pharmaceutically acceptable salt thereof, is a hydrochloride salt of defactinib.

[0080] 11. The method of any one of embodiments 1 to 10, wherein defactinib, or a pharmaceutically acceptable salt thereof, is administered within 30 minutes following a meal.

[0081] 12. The method of any one of embodiments 1 to 11, wherein sotorasib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 240 mg to 960 mg per administration.

[0082] 13. The method of any one of embodiments 1 to 12, wherein sotorasib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 960 mg per administration.

[0083] 14. The method of any one of embodiments 1 to 12, wherein sotorasib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 480 mg per administration.

[0084] 15. The method of any one of embodiments 1 to 12, wherein sotorasib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 240 mg per administration.

[0085] 16. The method of any one of embodiment 1 to 15, wherein the sotorasib is continually administered throughout a four-week cycle.

[0086] 17. The method of any one of embodiments 1 to 16, wherein the subject has not been previously treated with a KRAS G12C inhibitor.

[0087] 18. The method of any one of embodiments 1 to 16, wherein the subject has experienced disease progression while having treatment with a KRAS G12C inhibitor.

[0088] 19. The method of any one of embodiments 1 to 18, wherein the subject has been identified as having a KRAS G12C mutation.19IPTS / 200232471.2Attorney Docket VSM-099WOExamplesExample 1

[0089] A Phase 1 / 2, multicenter, open-label, dose evaluation / dose expansion study was conducted to evaluate the efficacy and safety of the combination of avutometinib and sotorasib with or without defactinib in patients with KRAS G12C mutant NSCLC who have not been previously treated with a KRAS G12C inhibitor (KRAS G12Ci-naive) or have experienced disease progression while undergoing therapy with a KRAS G12C inhibitor (KRAS G12Ci- progressor) (RAMP 203; NCT05074810).

[0090] The study was conducted in two parts: Part A (dose evaluation) and Part B (dose expansion). Up to 3 dose levels were evaluated in Part A for avutometinib and sotorasib to determine the RP2D (Recommended Phase 2 Dose) for Part B. Up to 2 dose levels were evaluated in Part A for avutometinib in combination with sotorasib and defactinib to determine the Alternative RP2D (Alt-RP2D, or Alternative Recommended Phase 2 Dose) for Part B. Part B assessed the efficacy of the RP2D and / or the Alternative RP2D identified from Part A and was conducted in 2 cohorts: patients who are G12C inhibitor treatment naive (Cohort 1), and patients who had experienced disease progression during G12C inhibitor therapy (Cohort 2).Part A Dose Evaluation for Avutometinib and Sotorasib:

[0091] Part A included patients with KRAS G12C mutant NSCLC regardless of their prior G12C inhibitor therapy status (Cohort 1 and Cohort 2). Dose evaluation and DLT (doselimiting toxicities) assessment were conducted using a 3+3 design to select the RP2D for expansion in Part B, as shown below.Dose Levels for Part A Dose EvaluationAbbreviations: BIW = twice weekly; N= number; po = orally; QD = once dailyPart A Dose Evaluation for Avutometinib, Sotorasib, and Defactinib:

[0092] Part A included patients with KRAS G12C mutant NSCLC regardless of their priorG12C inhibitor therapy exposure (Cohort 1 and Cohort 2). Dose evaluation and DLT20IPTS / 200232471.2Attorney Docket VSM-099WO assessment were conducted using a 3+3 design to select the Alt-RP2D for expansion in Part B, as shown below.Dose Levels for Part A Dose EvaluationAbbreviations: BID = twice daily; BIW = twice weekly; N= number; po = orally; QD = once daily

[0093] Study dose evaluation began with dose level 1 (avutometinib and sotorasib) and lb (avutometinib, sotorasib, and defactinib). Treatment with avutometinib was administered for 3 weeks followed by a 1-week rest period in each 4-week (28 day) cycle. Sotorasib was administered each day of the 4-week (28 day) cycle. Treatment with defactinib was administered for 3 weeks followed by a 1-week rest period in each 4-week (28 day) cycle.Part B Dose Expansion:

[0094] Part B consisted of 4 cohorts of patients with KRAS G12C mutant NSCLC, enrolled independently in a 2-stage manner:Cohort 1: Patients who are G12C inhibitor treatment naive and treated with the RP2D and or the Alt-RP2D identified in Part A.Cohort 2: Patients who experienced disease progression on prior G12C inhibitor monotherapy and treated with the RP2D and or Alt-RP2D identified in Part A.

[0095] Among six KRAS G12C inhibitor treatment naive patients treated with the triplet combination, four patients were evaluated for response according to RECIST 1.1 (Eisenhauer 2009). Among twelve KRAS G12C inhibitor pretreated patients treated with the triplet combination, eleven were evaluated for response according to RECIST 1.1.Inclusion and Exclusion Criteria:Inclusion Criteria

[0096] Patients were eligible for inclusion in the study if they met the following criteria:1. Male or female patients > 18 years of age.2. Histologic or cytologic evidence of NSCLC without histological evidence of a small cell or neuroendocrine components that are either metastatic (Stage 4) or locally advanced (Stage 3B-C) and unresectable (IASLC 8th edition).21IPTS / 200232471.2Attorney Docket VSM-099WO3. Patients must have a known KRAS G12C mutation determined using a validated test prior to enrollment.4. The patient must have received, in any setting, anti-programmed cell death protein 1 or anti-programmed death-ligand 1 immunotherapy (unless not indicated) AND / OR platinum-based combination chemotherapy; AND targeted therapy for actionable oncogenic driver mutations (ie, EGFR, ALK, and ROS1) excluding KRAS G12C.5. The patient must have received appropriate treatment with at least 1 prior systemic regimen, but no more than 2 prior systemic regimens, for Stage 3B-C or 4 NSCLC.6. The patient may have previously received adjuvant chemotherapy for early-stage disease.7. For prior G12C inhibitor use: a. Part A (avutometinib and sotorasib); Either prior G12C inhibitor exposure or no exposure is allowed. If prior G12C inhibitor use, must have had a best response to prior G12C inhibitor of confirmed response (CR or PR) by RECIST 1.1 or SD for >4 cycles, b. Part A (avutometinib and sotorasib and defactinib); Either prior G12C inhibitor exposure or no exposure is allowed. If prior G12C inhibitor use, must have had a best response to prior G12C inhibitor of confirmed response (CR or PR) by RECIST 1.1 or SD for >4 cycles. c. Part B, Cohort 1: No prior therapy with G12C inhibitor. d. Part B, Cohort 2: Must have received prior G12C inhibitor for at least 12 weeks.8. Measurable disease according to RECIST 1.1.9. An Eastern Cooperative Group (ECOG) performance status < 1.10. Must have adequate organ function defined by the following laboratory parameters: a. Adequate hematologic function including: hemoglobin (Hb) > 9.0 g / dL; platelets > 100,000 / mm3; and absolute neutrophil count (ANC) > 1500 / mm3. If a red blood cell transfusion has been administered the Hb must remain stable and >9 g / dL for at least 1 week prior to first dose of study therapy. b. Adequate hepatic function: (i) total bilirubin < 1.5 x upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg / dL (51 pmol / L) upon discussion with Medical Monitor; (ii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN (or< 5 x ULN in patients with liver metastases). c. Adequate renal function with creatinine clearance rate of > 50 mL / min as calculated by the Cockcroft-Gault formula or serum creatinine of < 1.5 ULN.22IPTS / 200232471.2Attorney Docket VSM-099WO d. International normalized ratio (INR) < 1.5 and partial thromboplastin time (PTT)< 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation. e. Albumin >3.0 g / dL (451 pmol / L). f. Creatine phosphokinase (CPK) < 2.5 x ULN. g. Adequate cardiac function with left ventricular ejection fraction > 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.11. Baseline corrected QT interval (QTc) interval < 470 ms for females and < 450 ms for males (average of triplicate readings) (CTCAE Grade 1) using Fredericia’s QT correction formula. NOTE: This criterion does not apply to patients with a right or left bundle branch block.12. Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v5.0. Exceptions include alopecia and peripheral neuropathy Grade < 2. Patients with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the Sponsor.13. Male and female patients with reproductive potential agree to use a highly effective method of contraceptive during the trial and for 3 months following the last dose of study intervention for male patients, and 1 month following the last dose of study intervention for female patients.Exclusion Criteria

[0097] Patients were excluded from the study if they meet any of the following criteria:1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy except sotorasib or another KRAS G12C inhibitor for Part A or Cohort 2 in Part B which must be discontinued at least 6 days prior to Day 1 of study therapy.2. History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.3. Major surgery within 4 weeks, minor surgery within 2 weeks (excluding placement of vascular access), or palliative radiotherapy within 1 week of the first dose of study therapy.4. Treatment with warfarin. Patients on warfarin for deep vein thrombosis / pulmonary embolism can be converted to low-molecular- weight heparin or direct oral anticoagulants.5. History of treatment with a direct and specific inhibitor of MEK.6. History of treatment with a KRAS G12C inhibitor in order to be enrolled in the cohort23IPTS / 200232471.2Attorney Docket VSM-099WO evaluating the combination in those patients who are G12C inhibitor treatment naive (Cohort 1).7. Use of proton pump inhibitors (PPIs) within 3 days and H2 receptor antagonists within 1 day prior to Study Day 1 and during time on study.8. Exposure to medicines (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interaction with study interventions within 14 days prior to the first dose of study intervention and during the course of therapy, including: a. Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions with sotorasib (CYP3A4 inducer only), avutometinib and defactinib. b. Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions with defactinib. This exclusion only applies to patients treated with defactinib. c. Strong P-glycoprotein (P-gp) inhibitors or inducers or sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy. d. Exposure to strong Breast Cancer Resistance Protein (BCRP) inhibitors or inducers within 14 days prior to the first dose and during the course of therapy.9. Part A-and Part B: Leptomeningeal metastases-or active CNS metastases are excluded. However, subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 are eligible if they meet all of the following criteria: a. residual neurological symptoms grade < 2; b. on stable doses of corticosteroids, if applicable; and c. follow-up MRI shows no new lesions appearing.10. Weight loss >10% within 4 weeks prior to first dose of study therapy.11. Known severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection (clinical symptoms) < 28 days prior to first dose of study therapy.12. Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and / or requires therapy.13. Active skin disorder that has required systemic therapy within the past 1 year.14. History of rhabdomyolysis.15. History of interstitial lung disease (ILD).16. Concurrent ocular disorders: a. Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled24IPTS / 200232471.2Attorney Docket VSM-099WO diabetes. b. Patient with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO. c. Patients with active or chronic visually significant corneal disorders, other active ocular conditions requiring ongoing therapy, or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy.17. Concurrent congestive heart failure, prior history of class III / IV cardiac disease (New York Heart Association), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or severe obstructive pulmonary disease.18. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.19. Patients with a history of hypersensitivity to any of the active (avutometinib, sotorasib or defactinib as applicable) or inactive (croscarmellose sodium, hydroxypropyl methylcellulose, lactose monohydrate, mannitol, magnesium stearate, microcrystalline cellulose) ingredients of the investigational products.20. Female patients who are pregnant or breastfeeding.21. Any other medical condition (eg, cardiac, gastrointestinal, pulmonary, psychiatric, neurological, genetic, etc.) that in the opinion of the investigator would place the patient at unacceptably high risk for toxicity.

[0098] Patients that were previously treated with sotorasib and were dose reduced due to toxicity.Study Interventions:

[0099] Avutometinib was administered twice weekly for 3 weeks followed by a 1-week rest period in each 4-week (28 day) cycle.• Avutometinib was administered at 1.6 mg, 2.4 mg, 3.2 mg, or 4.0 mg orally twice a week (e.g., on Monday / Thursday, Tuesday / Friday, or Wednesday / Saturday). Avutometinib can be dosed with or without food. On pharmacokinetic study days (“PK days,” e.g., C1D1, C1D15, and C2D1), avutometinib was dosed in clinic at least 2 hours after a meal.

[0100] Defactinib was administered twice daily for 3 weeks followed by a 1-week rest period in each 4-week (28 day) cycle.25IPTS / 200232471.2Attorney Docket VSM-099WO• Defactinib was administered at 200 mg orally twice daily within 30 minutes following a meal. Treatment was for 3 weeks, followed by a 1-week rest period, in each 4-week (28 day) cycle.

[0101] Sotorasib was administered each day of the 4-week (28 day) cycle.• Sotorasib was administered at 240 mg, 480 mg, or 960 mg orally (PO) once a day with or without food. On pharmacokinetic study days (“PK days,” e.g., C1D1, C1D15, and C2D1), sotorasib was dosed in clinic at least 2 hours after a meal.Assessment:

[0102] Assessment of disease response and progression status in patients was evaluated by imaging scans, for example computed tomography (CT) or magnetic resonance imaging (MRI) scans. Imaging may occur at fixed calendar intervals (i.e. , first post-treatment scan after 8 weeks [± 5 days], then every 8 weeks [± 5 days], regardless of any changes to visit or cycle schedules). Imaging as carried out for about 9 months total, as exemplified in FIG. 2.Results:

[0103] Initial results demonstrated anti-tumor activity upon treatment with the triple combination of avutometinib, sotorasib, and defactinib. Results showed that three of the four KRAS G12Ci-naive patients treated with defactinib + avutometinib + sotorasib demonstrated tumor reductions of at least 20% at the first scan (1 stable disease and 2 partial responses). Results also showed that six of eleven KRAS G12Ci-progressor patients treated with defactinib + avutometinib + sotorasib demonstrated tumor reductions of at least 20% at two or more scans (4 stable disease and 2 partial response). These results are further exemplified in FIG. 1.

[0104] Among six KRAS G12Ci-naive patients treated at dose level lb (3.2 mg avutometinib BIW, 960 mg sotorasib QD, and 200 mg defactinib BID), four were treatment evaluable. One patient experienced stable disease while two patients had a partial response of at least 30% reduction in tumor volume (50% ORR), as shown in FIG. 1. Among 12 KRAS G12Ci-progressor patients treated at dose level lb (3.2 mg avutometinib BIW, 960 mg sotorasib QD, and 200 mg defactinib BID), eleven were treatment evaluable. Eight patients experienced stable disease while two patients had a partial response of at least 30% reduction in tumor volume (18% ORR), as shown in FIG. 1.

[0105] Among the four evaluable G12Ci-naive patients treated with the triplet combination, median progression free survival (PFS) could not be determined. Among the eleven evaluable G12Ci-progressor patients treated with the triplet combination, the median PFS was 3.6 months (FIG. 3),26IPTS / 200232471.2Attorney Docket VSM-099WO

[0106] Among the 18 patients treated with the triplet combination, no dose limiting toxicities (DLTs) were observed . The most common treatment related adverse events included nausea (55.6%), diarrhea (44.4%), and fatigue (38.9%).27IPTS / 200232471.2

Claims

Attorney Docket VSM-099WOCLAIMS1. A method for treating non-small cell lung cancer in a human subject in need thereof, the method comprising:(A) orally administering a therapeutically effective amount of avutometinib, or a pharmaceutically acceptable salt thereof, twice weekly;(B) orally administering a therapeutically effective amount of defactinib, or a pharmaceutically acceptable salt thereof, twice daily; and(C) orally administering a therapeutically effective amount of sotorasib, or a pharmaceutically acceptable salt thereof, once daily; wherein avutometinib is administered for 3 weeks and then not administered for 1 week thereafter; and wherein defactinib is administered for 3 weeks and then not administered for 1 week thereafter.

2. The method of claim 1, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 0.5 mg to 10 mg per administration.

3. The method of claim 1 or 2, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 1.6 mg per administration.

4. The method of claim 1 or 2, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 2.4 mg per administration.

5. The method of claim 1 or 2, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 3.2 mg per administration.

6. The method of claim 1 or 2, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 4 mg per administration.

7. The method of any one of claims 1 to 6, wherein avutometinib, or a pharmaceutically acceptable salt thereof, is a potassium salt of avutometinib.28IPTS / 200232471.2Attorney Docket VSM-099WO8. The method of any one of claims 1 to 7, wherein defactinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg to 500 mg per administration.

9. The method of any one of claims 1 to 8, wherein defactinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg per administration.

10. The method of any one of claims 1 to 8, wherein defactinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 400 mg per administration.

11. The method of any one of claims 1 to 10, wherein defactinib, or a pharmaceutically acceptable salt thereof, is a hydrochloride salt of defactinib.

12. The method of any one of claims 1 to 11, wherein defactinib, or a pharmaceutically acceptable salt thereof, is administered within 30 minutes following a meal.

13. The method of any one of claims 1 to 12, wherein sotorasib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 240 mg to 960 mg per administration.

14. The method of any one of claims 1 to 13, wherein sotorasib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 960 mg per administration.

15. The method of any one of claims 1 to 13, wherein sotorasib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 480 mg per administration.

16. The method of any one of claims 1 to 13, wherein sotorasib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 240 mg per administration.

17. The method of any one of claims 1 to 16, wherein sotorasib is a free-base of sotorasib.

18. The method of any one of claims 1 to 17, wherein the sotorasib is continuously administered daily throughout a four- week cycle.

19. The method of any one of claims 1 to 18, wherein the subject has not been previously treated with a KRAS G12C inhibitor.29IPTS / 200232471.2Attorney Docket VSM-099WO20. The method of any one of claims 1 to 18, wherein the subject has experienced disease progression while having treatment with a KRAS G12C inhibitor.

21. The method of any one of claims 1 to 20, wherein the subject has been identified as having a KRAS G12C mutation.30IPTS / 200232471.2

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