Use of KRAS G12C inhibitors in the treatment of cancer

Abstract

The present disclosure relates to the use of compounds of formula I in treating cancer, such as non-small cell lung cancer, in subjects with certain characteristics. KRAS such as compound TIFF2024502446000070.tif34170 (AMG 510, sotorasib) G12C Uses relating to inhibitors are provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 135,449, filed January 8, 2021, and U.S. Provisional Patent Application No. 63 / 189,625, filed May 17, 2021, each of which is incorporated by reference in its entirety herein.

[0002] The present disclosure relates to the use of KRAS inhibitors, such as compounds of formula I (AMG 510, sotorasib), in treating cancer, such as non-small cell lung cancer, in subjects with certain characteristics. G12C Uses relating to inhibitors are provided. [Background technology]

[0003] Lung cancer is the leading cause of cancer deaths, with more than 80% of all lung cancer cases classified as non-small cell lung cancer (NSCLC). Worldwide, lung cancer (small cell and non-small cell) is the most common cancer occurring in both men and women, with an estimated 2.09 million cases in 2018 (World Health Organization Statistics, 2018). In 2018, more than 250,000, 470,039 and 1,225,000 new cases of lung cancer were reported in North America, Europe and Asia, respectively. The estimated number of deaths attributable to lung cancer in 2018 was 173,278 in North America, 387,913 in Europe and 1,068,862 in Asia (Globocan-Lung Cancer, 2018). Advanced NSCLC (stages IIIB and IV) is a serious and life-threatening disease with a 5-year survival rate of 5.2% (Surveillance, Epidemiology, and End Results [SEER], 2019).

[0004] Oncogenic RAS and KRAS G12C mutations Several proto-oncogene mutations have been implicated in the development of NSCLC. Among these, mutations in the RAS family of proto-oncogenes are the most prevalent. The RAS family of proto-oncogenes consists of three closely related genes that encode guanosine triphosphatases (GTPases) involved in the regulation of cell proliferation and survival (Simanshu et al., 2017; Barbacid, 1987). Different tumor types are associated with mutations in specific isoforms of RAS, with Kirsten rat sarcoma viral oncogene homolog (KRAS) being the most frequently mutated isoform in the majority of cancers (Prior et al., 2012).

[0005] An estimated 80% of KRAS mutations occur at codon 12. The KRAS G12C mutation at codon 12 is a single guanine to thymine substitution that results in a glycine to cysteine ​​substitution at amino acid position 12. This structural change in the protein results in a defect in the association of guanosine triphosphatase-activating protein (GAP), thereby reducing the hydrolysis of guanosine triphosphate (GTP) by the KRAS protein. The resulting accumulation of active, GTP-bound KRAS triggers proliferation and survival signaling in tumor cells (Jones et al., 2017). KRAS G12C mutations are present in approximately 13% of lung adenocarcinomas and have been identified as a putative oncogenic driver in this tumor type (AACR Project GENIE Consortium, 2017; Biernacka et al., 2016; Fernandez-Medarde and Santos, 2011).

[0006] Although the role of KRAS mutations in human cancers, including NSCLC, has been known for decades, inhibitors that specifically target the KRAS G12C mutation have not been successfully developed until recently (McCormick, 2019).

[0007] Existing treatments and unmet medical needs The treatment of advanced NSCLC has clearly improved since the discovery of immunotherapy (checkpoint inhibitors) and targeted therapy for various oncogenic mutations. The National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) treatment guidelines call for testing of all subjects with NSCLC for oncogenic driver mutations (Ettinger et al., 2019; Planchard et al., 2018). However, there are currently no approved anticancer therapies for the treatment of subjects with NSCLC that specifically target tumors harboring the KRAS G12C mutation (Roman et al., 2018; McCormick, 2016). Furthermore, oncogenic KRAS mutations rarely occur concomitantly with other oncogenic mutations, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), B-raf (BRAF); ROS proto-oncogene 1 (ROS1) or neurotrophic tyrosine kinase (NTRK) (Scheffler et al., 2019; Martorell et al., 2017; Gainor et al., 2013). Thus, most subjects with oncogenic KRAS mutations, including KRAS G12C mutations, are not candidates for the recently approved targeted therapies and are consequently typically treated as subjects without targetable mutations (i.e., with chemotherapy, immunotherapy or antiangiogenic agents) (Planchard et al., 2018; Van Cutsem et al., 2014).

[0008] Unmet medical needs Checkpoint inhibitors have emerged as novel frontline therapies, and chemotherapy with or without antiangiogenic agents is the standard of care in the second-line and beyond for subjects without curative mutations (Ettinger et al., 2019; Planchard et al., 2018). Given the low response rates to chemotherapy regimens and poor survival outcomes for subjects with NSCLC in the second-line and beyond, novel biomarker-driven anticancer therapies are needed in this subject population.

[0009] Standard treatment outcomes for subjects with advanced / metastatic NSCLC in second-line or later therapy (who are not candidates for recently approved targeted therapies) who have received doublet first-line platinum-containing chemotherapy (typically cisplatin / pemetrexed) have shown objective response rates (ORR; objective response = complete response + partial response) of 5.5% to 13% with chemotherapy (typically with taxanes) and 9.7% to 22.5% with chemotherapy + vascular endothelial growth factor receptor (VEGFR) inhibitors (Gridelli et al., 2018; Rittmeyer et al., 2017; Herbst et al., 2016; Borghaei et al., 2015; Herbst et al., 2007). These studies also showed progression-free survival (PFS) and overall survival (OS) of 2.8 to 4.2 months and 6 to 11.4 months, respectively, for chemotherapy alone, and 4.8 to 5.4 months and 9.9 to 12.6 months, respectively, for chemotherapy with VEGFR inhibitors. In the second-line or later therapy setting, patients unselected for KRAS mutations showed a median PFS of 4.0 months when treated with anti-PD-1 therapy. Median OS was 12.7 months (Herbst et al, 2016).

[0010] Furthermore, KRAS G12C mutations were observed in the presence of high STK11 and KEAP1 mutation levels. STK11 mutations are frequently observed in NSCLC and even more frequently in KRAS-mutated NSCLC. This co-mutation pattern is associated with poorer OS and resistance to immune checkpoint inhibitors (Scheffler et al., 2019; Ricciuti et al., 2020; Pavan et al., 2020; Tamiya et al., 2020; An et al., 2020; Uba et al., 2020). Similarly, KEAP1 deletion has been associated with chemotherapy resistance in preclinical models of NSCLC, and KEAP1 mutations have been associated with poorer OS in NSCLC, while subjects with NSCLC harboring KEAP1 mutations are less sensitive to platinum-based therapy ( Jeong et al., 2020 ; Tian et al., 2016 ; Solis et al., 2010 ; Arbour et al., 2018 ; Goeman et al., 2019 ).

[0011] Furthermore, while the development of checkpoint inhibitors has changed the treatment strategy for advanced cancers such as NSCLC, the majority of subjects do not respond to treatment. Programmed death-ligand 1 (PD-L1) has emerged as an early biomarker to be tested in immunotherapy clinical trials. While PD-L1 testing has not provided a biomarker with broad scope of application, it has demonstrated value for certain tumor types such as NSCLC and remains a common immune-based biomarker in current practice (Davis et al., 2019). Indeed, the US Food and Drug Administration (FDA), for example, has linked approval of pembrolizumab for use as a single agent in certain NSCLC settings to a PD-L1 tumor proportion score (TPS) of 1% or greater as determined by an FDA-approved test (Pembrolizumab Prescribing Information, November 2020 Update, https: / / www.merck.com / product / usa / pi_circulars / k / keytruda / keytruda_pi.pdf; accessed January 2020).

Prior technical literature

Non-licensed literature

[0012] [Non-licensed document 1] World Health Organization Statistics, 2018 [Non-licensed document 2] Globocan-Lung Cancer,2018 [Non-licensed document 3] Surveillance,Epidemiology,and End Results[SEER],2019

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[0013] These survival and treatment challenges make current therapies inadequate and improve treatment methods for previously treated and untreated subjects with cancer are desirable. [Means for solving the problem]

[0014] Provided herein is a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof. In one embodiment, the subject has a PD-L1 tumor fraction score of less than 50%. In one embodiment, the subject is positive for a mutation in STK11, such as a loss-of-function mutation in STK11. In one embodiment, the subject is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1. In one embodiment, the subject does not have brain metastases. In one embodiment, the subject does not have bone metastases.

[0015] Further provided herein are methods for identifying subjects susceptible to the methods of treatment disclosed herein. Also provided herein are methods for determining treatment for subjects with certain characteristics as disclosed herein. [Brief description of the drawings]

[0016] [Figure 1]Objective response rates (ORR, %, non-responders / responders) for different programmed death-ligand 1 (PD-L1) expression level groups by tumor proportion score (TPS) (<1%, 1-49%, and ≥50%) are shown in the patient population evaluable for efficacy according to the central review committee (N=124) with available biomarker data (N=86) (data cutoff December 1, 2020). [Diagram 2] Objective response rate (ORR, %, non-responders / responders) by coexisting STK11 / KEAP1 mutation in the population evaluable for efficacy (N=124) according to the central review committee (data cutoff December 1, 2020) with available biomarker data (N=104). WT=wild type. MUT=mutant. [Diagram 3] Objective response rate (ORR, %, non-responders / responders) is shown by TP53 / STK11 / KEAP1 (data cutoff March 15, 2021). [Figure 4] Objective response rate (ORR, %) is shown by PD-L1 expression level group for each TPS (<1%, 1-49%, and ≥50%) superimposed by coexisting STK11 mutations (data cutoff March 15, 2021). Wt = wild type. Mut = mutant. [Diagram 5] The objective response rate (ORR, %) is shown by PD-L1 expression level group for each TPS (<1%, 1-49%, and ≥50%) superimposed by coexisting KEAP1 mutations (data cutoff March 15, 2021). Wt = wild type. Mut = mutant. [Figure 6] Objective response rate (ORR, %) is shown by PD-L1 expression level group for each TPS (<1%, 1-49%, and ≥50%) superimposed by coexisting TP53 mutations (data cutoff March 15, 2021). Wt = wild type. Mut = mutant. [Figure 7] Progression-free survival (PFS) is shown by STK11 status (data cutoff March 15, 2021). WT = wild type. Mut = mutant. [Figure 8]Progression-free survival (PFS) is shown by KEAP1 status (data cutoff March 15, 2021). WT = wild type. Mut = mutant. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] First aspect: PD-L1 protein expression As embodiment 1, provided herein is a method of treating non-small cell lung cancer in a subject in need thereof, comprising: (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) assaying a sample obtained from the subject for a PD-L1 tumor proportion score; and (B) administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and has a PD-L1 tumor fraction score of less than 50%.

[0018] As embodiment 2, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject has a PD-L1 tumor proportion score of less than 50%.

[0019] As embodiment 3, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation, and the subject comprises cells having a PD-L1 tumor fraction score of less than 50%.

[0020] As embodiment 4, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation, and the non-small cell lung cancer comprises cells having a PD-L1 tumor proportion score of less than 50%.

[0021] As embodiment 5, the present disclosure relates to a method for treating a subject with non-small cell lung cancer, comprising administering to said subject a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) assaying a sample obtained from the subject for a PD-L1 Tumor Proportion Score, wherein the subject is identified as susceptible to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof when the sample is positive for a KRAS G12C mutation and the sample has a PD-L1 Tumor Proportion Score of less than 50%.

[0022] As embodiment 6, provided herein is a method of determining a treatment for a subject having non-small cell lung cancer, comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) assaying a sample obtained from the subject for a PD-L1 Tumor Proportion Score, wherein when the sample is positive for the KRAS G12C mutation and the sample has a PD-L1 Tumor Proportion Score of less than 50%, the treatment determined for the subject is a PD-L1 Tumor Proportion Score determined according to Formula I. [ka] or a pharma- ceutically acceptable salt thereof to a subject.

[0023] As embodiment 7, provided herein is a method according to any one of embodiments 1 to 6, wherein the PD-L1 tumor proportion score is greater than or equal to 1% and less than 50%.

[0024] As embodiment 8, provided herein is a method according to any one of embodiments 1 to 6, wherein the PD-L1 tumor proportion score is less than 1%.

[0025] As embodiment 9, provided herein is a method according to any one of embodiments 1 to 8, wherein the PD-L1 tumor proportion score is determined using an immunohistochemistry (IHC) test.

[0026] As embodiment 10, the present specification provides a method according to embodiment 9, wherein the test is a PD-L1 IHC 22C3 pharmDx test.

[0027] Second aspect: coexisting STK11 and KEAP1 mutations As embodiment 11, provided herein is a method of treating non-small cell lung cancer in a subject in need thereof, comprising: (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) assaying a sample obtained from the subject for a mutation in STK11, such as a loss-of-function mutation in STK11; and (B) administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and positive for a mutation in STK11, such as a loss-of-function mutation in STK11.

[0028] As embodiment 12, the present specification provides a method according to embodiment 11, wherein step (A) further comprises (iii) assaying a sample obtained from the subject for a mutation in KEAP1, such as a loss-of-function mutation of KEAP1, and in step (B), the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for a mutation in STK11, such as a loss-of-function mutation of STK11, and positive for a mutation in KEAP1, such as a loss-of-function mutation of KEAP1.

[0029] As embodiment 13, the present specification provides a method according to embodiment 11, wherein step (A) further comprises (iii) assaying a sample obtained from the subject for wild-type KEAP1, and in step (B), the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for a mutation in STK11, such as a loss-of-function mutation in STK11, and positive for wild-type KEAP1.

[0030] As embodiment 14, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject is positive for a mutation in STK11, such as a loss-of-function mutation in STK11.

[0031] As embodiment 15, there is provided herein the method of embodiment 14, wherein the subject is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0032] As embodiment 16, there is provided herein the method of embodiment 14, wherein the subject is positive for the wild type of KEAP1.

[0033] As embodiment 17, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject contains cells that are positive for a KRAS G12C mutation and positive for a mutation in STK11, such as a loss-of-function mutation in STK11.

[0034] As embodiment 18, there is provided herein the method of embodiment 17, wherein the subject further comprises cells that are positive for the wild type of KEAP1.

[0035] As embodiment 19, there is provided herein the method of embodiment 17, wherein the subject further comprises cells that are positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0036] As embodiment 20, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation and positive for a mutation in STK11, such as a loss-of-function mutation in STK11.

[0037] As embodiment 21, there is provided herein the method of embodiment 20, wherein the cancer further comprises cells that are positive for the wild type of KEAP1.

[0038] As embodiment 22, there is provided herein the method of embodiment 20, wherein the cancer further comprises cells that are positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0039] As embodiment 23, the present disclosure relates to a method for treating a subject with non-small cell lung cancer, comprising administering to said subject a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) assaying a sample obtained from the subject for a mutation in STK11, such as a loss-of-function mutation of STK11, wherein when the sample is positive for the KRAS G12C mutation and the sample is positive for a mutation in STK11, such as a loss-of-function mutation of STK11, the subject is identified as being susceptible to treatment with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0040] As embodiment 24, the present specification provides a method according to embodiment 23, further comprising (iii) assaying a sample obtained from the subject for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, wherein the subject is identified as susceptible to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof when the sample is positive for a KRAS G12C mutation, the sample is positive for a mutation in STK11, such as a loss-of-function mutation in STK11, and the sample is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0041] As embodiment 25, the present specification provides a method according to embodiment 23, further comprising: (iii) assaying a sample obtained from the subject for wild-type KEAP1, wherein the subject is identified as susceptible to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof when the sample is positive for a KRAS G12C mutation, the sample is positive for a mutation in STK11, such as a loss-of-function mutation in STK11, and the sample is positive for wild-type KEAP1.

[0042] As embodiment 26, provided herein is a method of determining a treatment for a subject having non-small cell lung cancer, comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) assaying a sample obtained from the subject for a mutation in STK11, such as a loss-of-function mutation in STK11, wherein when the sample is positive for the KRAS G12C mutation and the sample is positive for a mutation in STK11, such as a loss-of-function mutation in STK11, the treatment determined for the subject is a nucleotide sequence represented by Formula I. [ka] or a pharma- ceutically acceptable salt thereof to a subject.

[0043] As embodiment 27, the present specification provides a method according to embodiment 26, further comprising: (iii) assaying a sample obtained from the subject for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, wherein when the sample is positive for a KRAS G12C mutation, the sample is positive for a mutation in STK11, such as a loss-of-function mutation in STK11, and the sample is positive for a loss-of-function mutation in KEAP1, the treatment determined for the subject comprises administering to the subject a compound of formula I or a pharma- ceutical acceptable salt thereof.

[0044] As embodiment 28, the present specification provides a method according to embodiment 26, further comprising: (iii) assaying a sample obtained from the subject for wild-type KEAP1, wherein when the sample is positive for a KRAS G12C mutation, the sample is positive for a mutation in STK11, such as a loss-of-function mutation in STK11, and the sample is positive for wild-type KEAP1, the treatment determined for the subject comprises administering to the subject a compound of formula I or a pharma- ceutical acceptable salt thereof.

[0045] As embodiment 29, provided herein is a method of treating non-small cell lung cancer in a subject in need thereof, comprising: (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation, and (ii) assaying a sample obtained from the subject for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1; and (B) administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0046] As embodiment 30, the present specification provides a method according to embodiment 29, wherein step (A) further comprises (iii) assaying a sample obtained from the subject for a mutation in STK11, such as a loss-of-function mutation of STK11, and in step (B), the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for a mutation in KEAP1, such as a loss-of-function mutation of KEAP1, and positive for a mutation in STK11, such as a loss-of-function mutation of STK11.

[0047] As embodiment 31, the present specification provides a method according to embodiment 29, wherein step (A) further comprises (iii) assaying a sample obtained from the subject for wild-type KEAP1, and in step (B), the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, and positive for wild-type STK11.

[0048] As embodiment 32, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0049] As embodiment 33, there is provided herein the method of embodiment 32, wherein the subject is positive for a mutation in STK11, such as a loss-of-function mutation in STK11.

[0050] As embodiment 34, there is provided herein the method of embodiment 32, wherein the subject is positive for wild-type STK11.

[0051] As embodiment 35, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, wherein the subject contains cells that are positive for a KRAS G12C mutation and positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0052] As embodiment 36, there is provided herein the method of embodiment 35, wherein the subject further comprises cells that are positive for the wild type of STK11.

[0053] As embodiment 37, there is provided herein the method of embodiment 35, wherein the subject further comprises cells that are positive for a mutation in STK11, such as a loss-of-function mutation in STK11.

[0054] As embodiment 38, the present specification provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer is positive for a KRAS G12C mutation and includes cells positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0055] As embodiment 39, there is provided herein the method of embodiment 38, wherein the cancer further comprises cells that are positive for the wild type of STK11.

[0056] As embodiment 40, there is provided herein the method of embodiment 38, wherein the cancer further comprises cells positive for a mutation in STK11, such as a loss-of-function mutation in STK11.

[0057] As embodiment 41, the present disclosure relates to a method for treating a subject with non-small cell lung cancer, comprising administering to said subject a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) assaying a sample obtained from the subject for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, wherein when the sample is positive for the KRAS G12C mutation and the sample is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, the subject is identified as being susceptible to treatment with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0058] As embodiment 42, the present specification provides a method according to embodiment 41, further comprising: (iii) assaying a sample obtained from the subject for a mutation in STK11, such as a loss-of-function mutation in STK11, wherein the subject is identified as susceptible to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof when the sample is positive for a KRAS G12C mutation, the sample is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, and the sample is positive for a mutation in STK11, such as a loss-of-function mutation in STK11.

[0059] As embodiment 43, the present specification provides a method according to embodiment 41, further comprising: (iii) assaying a sample obtained from the subject for wild-type STK11, wherein the subject is identified as susceptible to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof when the sample is positive for a KRAS G12C mutation, the sample is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, and the sample is positive for wild-type STK11.

[0060] As embodiment 44, provided herein is a method of determining a treatment for a subject having non-small cell lung cancer, comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) assaying a sample obtained from the subject for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, wherein when the sample is positive for a KRAS G12C mutation and the sample is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, the treatment determined for the subject is a nucleotide sequence represented by Formula I. [ka] or a pharma- ceutically acceptable salt thereof to a subject.

[0061] As embodiment 45, the present specification provides a method according to embodiment 44, further comprising: (iii) assaying a sample obtained from the subject for a mutation in STK11, such as a loss-of-function mutation in STK11; and when the sample is positive for a KRAS G12C mutation, the sample is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, and the sample is positive for a mutation in STK11, such as a loss-of-function mutation in STK11, the treatment determined for the subject comprises administering to the subject a compound of formula I or a pharma- ceutical acceptable salt thereof.

[0062] As embodiment 46, there is provided herein a method according to embodiment 44, further comprising: (iii) assaying a sample obtained from the subject for wild-type STK11, wherein when the sample is positive for a KRAS G12C mutation, the sample is positive for a mutation in KEAP1, such as a loss-of-function mutation in KEAP1, and the sample is positive for wild-type STK11, the treatment determined for the subject comprises administering to the subject a compound of formula I or a pharma- ceutical acceptable salt thereof.

[0063] Third aspect: Absence of brain metastases As embodiment 47, provided herein is a method of treating non-small cell lung cancer in a subject in need thereof, comprising: (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation, and (ii) determining whether the subject has brain metastases; and (B) administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and wherein the subject does not have brain metastases.

[0064] As embodiment 48, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject does not have brain metastases.

[0065] As embodiment 49, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation, and the subject does not have brain metastases.

[0066] As embodiment 50, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation, and the subject does not have brain metastases.

[0067] As embodiment 51, the present disclosure relates to a method for treating a subject with non-small cell lung cancer, comprising administering to said subject a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) determining whether the subject has brain metastases, wherein when the sample is positive for a KRAS G12C mutation and the subject does not have brain metastases, the subject is identified as being susceptible to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0068] As embodiment 52, provided herein is a method of determining a treatment for a subject having non-small cell lung cancer, comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) determining whether the subject has brain metastases, wherein when the sample is positive for a KRAS G12C mutation and the subject does not have brain metastases, the treatment determined for the subject is a KRAS G12C mutation represented by Formula I. [ka] or a pharma- ceutically acceptable salt thereof to a subject.

[0069] Fourth aspect: Absence of bone metastases As embodiment 53, provided herein is a method of treating non-small cell lung cancer in a subject in need thereof, comprising: (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation, and (ii) determining whether the subject has bone metastasis; and (B) administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation, the subject not having bone metastases.

[0070] As embodiment 54, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject does not have bone metastases.

[0071] As embodiment 55, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation, and the subject does not have bone metastases.

[0072] As embodiment 56, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation, and the subject does not have bone metastases.

[0073] As embodiment 57, the present disclosure relates to a method for treating a subject with non-small cell lung cancer, comprising administering to said subject a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) determining whether the subject has bone metastases, wherein when the sample is positive for a KRAS G12C mutation and the subject does not have bone metastases, the subject is identified as being susceptible to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0074] As embodiment 58, provided herein is a method of determining a treatment for a subject having non-small cell lung cancer, comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) determining whether the subject has bone metastases, wherein when the sample is positive for a KRAS G12C mutation and the subject does not have bone metastases, the treatment determined for the subject is a KRAS G12C mutation represented by Formula I. [ka] or a pharma- ceutically acceptable salt thereof to a subject.

[0075] As embodiment 59, provided herein is a method according to any one of embodiments 5, 23, 41, 51, and 57, wherein the treatment comprises administering to the subject a total daily dose of 960 mg of the compound of formula I or a pharma- ceutically acceptable salt thereof.

[0076] As embodiment 60, provided herein is a method according to any one of embodiments 6, 26, 44, and 58, wherein the treatment comprises administering to the subject a total daily dose of 960 mg of the compound of formula I or a pharma- ceutically acceptable salt thereof.

[0077] Fifth aspect: Absence of prior platinum-based chemotherapy As embodiment 61, provided herein is a method of treating non-small cell lung cancer in a subject in need thereof, comprising: (A) (i) assaying a sample obtained from the subject for KRAS G12C mutation, and (ii) determining whether the subject has received prior systemic platinum-based chemotherapy; and (B) administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation, the subject having not received prior platinum-based chemotherapy.

[0078] As embodiment 62, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject has not received prior systemic platinum-based chemotherapy.

[0079] As embodiment 63, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation, and the subject has not received prior systemic platinum-based chemotherapy.

[0080] As embodiment 64, the present disclosure provides a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation, and the subject has not received prior systemic platinum-based chemotherapy.

[0081] As embodiment 65, the present specification provides a method for treating a subject with non-small cell lung cancer, comprising administering to a subject a compound of formula I [ka] or a pharmaceutical acceptable salt thereof, the method comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) determining whether the subject has received prior systemic platinum-based chemotherapy, wherein when the sample is positive for a KRAS G12C mutation and the subject has not received prior systemic platinum-based chemotherapy, the subject is identified as being susceptible to treatment with a compound of Formula I or a pharmaceutical acceptable salt thereof.

[0082] As embodiment 66, provided herein is a method of determining a treatment for a subject having non-small cell lung cancer, comprising: (i) assaying a sample obtained from the subject for a KRAS G12C mutation; and (ii) determining whether the subject has received prior systemic platinum-based chemotherapy; wherein when the sample is positive for a KRAS G12C mutation and the subject has not received prior systemic platinum-based chemotherapy, the treatment determined for the subject is a cytotoxic T cell inhibitor represented by Formula I. [ka] or a pharma- ceutically acceptable salt thereof to a subject.

[0083] As embodiment 67, there is provided herein a method according to embodiment 65, wherein the treatment comprises administering to the subject a total daily dose of 960 mg of the compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0084] As embodiment 68, there is provided herein a method according to embodiment 66, wherein the treatment comprises administering to the subject a total daily dose of 960 mg of the compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0085] Additional Embodiments of the Disclosure As embodiment 69, provided herein is a method according to any one of embodiments 61 to 68, wherein the subject has received at least one prior anti-cancer systemic therapy.

[0086] As embodiment 70, provided herein is a method according to any one of embodiments 1 to 60, wherein the subject has received at least one prior anti-cancer systemic therapy.

[0087] As embodiment 71, provided herein is a method according to any one of embodiments 1 to 70, wherein the subject has received 1, 2, or 3 prior systemic therapies.

[0088] As embodiment 72, provided herein is a method according to any one of embodiments 1 to 70, wherein the subject has received one prior anti-cancer systemic therapy.

[0089] As embodiment 73, provided herein is a method according to any one of embodiments 1 to 70, wherein the subject has received two prior anti-cancer systemic therapies.

[0090] As embodiment 74, provided herein is a method according to embodiments 1 to 70, wherein the subject has received three prior anti-cancer systemic therapies.

[0091] As embodiment 75, provided herein is a method according to embodiment 69 or embodiment 70, wherein the one prior anti-cancer systemic therapy is an anti-PD1 or anti-PD-L1 immunotherapy.

[0092] As embodiment 76, provided herein is a method according to embodiment 70, wherein the one prior anticancer systemic therapy is a platinum-based chemotherapy.

[0093] As embodiment 77, provided herein is a method according to any one of embodiments 1 to 76, wherein the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0094] As embodiment 78, provided herein is a method according to any one of embodiments 1 to 77, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 0.

[0095] As embodiment 79, provided herein is a method according to any one of embodiments 1 to 78, wherein the subject is 18 years of age or older.

[0096] As embodiment 80, provided herein is a method according to any one of embodiments 1 to 79, wherein the compound is administered as a free base.

[0097] As embodiment 81, provided herein is a method according to embodiment 80, wherein the compound is administered as a crystalline form of the free base.

[0098] As embodiment 82, provided herein is the method according to embodiment 81, wherein the crystalline form is an anhydrous crystalline form.

[0099] As embodiment 83, provided herein is the method according to embodiment 82, wherein the anhydrous crystalline form is Type I anhydrous crystalline.

[0100] As embodiment 84, provided herein is a method according to any one of embodiments 1 to 83, wherein the compound is administered as a pharmaceutical composition comprising the compound and a pharma- ceutically acceptable excipient.

[0101] As embodiment 85, there is provided herein the method according to embodiment 84, wherein the pharmaceutical composition is a solid dosage form.

[0102] As embodiment 86, there is provided herein the method according to embodiment 84 or embodiment 85, wherein the pharmaceutical composition is for oral administration.

[0103] As embodiment 87, provided herein is a method according to any one of embodiments 84 to 86, wherein the pharmaceutical composition is a tablet.

[0104] As embodiment 88, provided herein is a method according to embodiment 87, wherein the tablet comprises a fraction of the total daily dose of the compound of formula I.

[0105] As embodiment 89, provided herein is a method according to any one of embodiments 1 to 87, wherein the total daily dose of the compound is administered once a day.

[0106] As embodiment 90, provided herein is a method according to any one of embodiments 1 to 87, wherein the total daily dose of the compound is administered over two separate administrations of 480 mg doses each.

[0107] As embodiment 91, provided herein is a method according to any one of embodiments 1 to 90, wherein the treatment results in the induction or increase of tumor regression in the subject.

[0108] As embodiment 92, provided herein is a method according to any one of embodiments 1 to 90, wherein treating results in a reduction in tumor or cancer growth in the subject.

[0109] As embodiment 93, provided herein is a method according to any one of embodiments 1 to 90, wherein the treatment results in the induction or increase of cancer cell death in the subject.

[0110] For the avoidance of doubt, it is noted that the present disclosure also includes embodiments that encompass one or more embodiments of one or more aspects combined. For example, embodiments that encompass (i) an embodiment of the first aspect of the present disclosure, or (ii) an embodiment of the second aspect of the present disclosure are also provided herein. More specifically, the present disclosure also encompasses embodiments that recite (i) the features of embodiment 8, or (ii) the features of embodiment 14, or both. For example, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I. [ka] or a pharma- ceutical acceptable salt thereof, wherein (i) the subject has a PD-L1 tumor fraction score of less than 1%, or (ii) the subject is positive for a mutation in STK11, such as a loss-of-function mutation in STK11; or both. The features of the embodiments recited in the sections entitled "Additional embodiments of the present disclosure" and "Additional subpopulations" apply equally to any embodiment, including one or more embodiments of one or more aspects combined.

[0111] An alternative set of embodiments of the present disclosure As an alternative embodiment 1, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject has a PD-L1 tumor proportion score of less than 50%.

[0112] As alternative embodiment 2, there is provided herein a method according to alternative embodiment 1, wherein the PD-L1 tumor proportion score is greater than or equal to 1% and less than 50%.

[0113] As alternative embodiment 3, there is provided herein a method according to alternative embodiment 1, wherein the PD-L1 tumor proportion score is less than 1%.

[0114] As an alternative embodiment 4, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject is positive for a loss-of-function mutation in STK11.

[0115] As an alternative embodiment 5, there is provided herein the method of alternative embodiment 4, wherein the subject is positive for a loss-of-function mutation in KEAP1.

[0116] As an alternative embodiment 6, there is provided herein the method of alternative embodiment 4, wherein the subject is positive for the wild type of KEAP1.

[0117] As an alternative embodiment 7, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, wherein (i) the subject has a PD-L1 tumor fraction score of less than 50%, or (ii) the subject is positive for a loss-of-function mutation in STK11.

[0118] As an alternative embodiment 8, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, wherein (i) the subject has a PD-L1 tumor fraction score of less than 50%, and (ii) the subject is positive for a loss-of-function mutation in STK11.

[0119] As an alternative embodiment 9, the present disclosure provides a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, wherein (i) the subject has a PD-L1 tumor fraction score of less than 50%, (ii) the subject is positive for a loss-of-function mutation in STK11, or (iii) the subject has a PD-L1 tumor fraction score of less than 50% and the subject is positive for a loss-of-function mutation in STK11.

[0120] As alternative embodiment 10, there is provided herein a method according to any one of alternative embodiments 7-9, wherein the PD-L1 tumor proportion score is greater than or equal to 1% and less than 50%.

[0121] As an alternative embodiment 11, provided herein is a method according to any one of alternative embodiments 7-9, wherein the PD-L1 tumor proportion score is less than 1%.

[0122] As an alternative embodiment 12, there is provided herein a method according to any one of alternative embodiments 7-11, wherein the subject is positive for a loss-of-function mutation in KEAP1.

[0123] As an alternative embodiment 13, there is provided herein the method of any one of alternative embodiments 7-11, wherein the subject is positive for the wild type of KEAP1.

[0124] As an alternative embodiment 14, provided herein is a method according to any one of alternative embodiments 1-13, wherein the subject has not received prior anti-cancer systemic therapy.

[0125] As an alternative embodiment 15, provided herein is a method according to any one of alternative embodiments 1-13, wherein the subject has received at least one prior anti-cancer systemic therapy.

[0126] As alternative embodiment 16, provided herein is a method according to any one of alternative embodiments 1-13, wherein the subject has received one prior anti-cancer systemic therapy.

[0127] As alternative embodiment 17, provided herein is a method according to any one of alternative embodiments 1-13, wherein the subject has received two prior anti-cancer systemic therapies.

[0128] As alternative embodiment 18, provided herein is a method according to alternative embodiments 1-13, wherein the subject has received three prior anti-cancer systemic therapies.

[0129] As alternative embodiment 19, provided herein is a method according to alternative embodiment 15 or alternative embodiment 16, wherein the one prior anti-cancer systemic therapy is an anti-PD1 or anti-PD-L1 immunotherapy.

[0130] As alternative embodiment 20, provided herein is a method according to alternative embodiment 15 or alternative embodiment 16, wherein the one prior anti-cancer systemic therapy is a platinum-based chemotherapy.

[0131] As alternative embodiment 21, provided herein is a method according to any one of alternative embodiments 1-20, wherein the non-small cell lung cancer is stage IV non-small cell lung cancer.

[0132] As alternative embodiment 22, provided herein is a method according to any one of alternative embodiments 1-20, wherein the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0133] As alternative embodiment 23, there is provided herein a method according to any one of alternative embodiments 1-22, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 0.

[0134] As alternative embodiment 24, provided herein is a method according to any one of alternative embodiments 1-23, wherein the subject is 18 years of age or older.

[0135] As an alternative embodiment 25, provided herein is a method according to any one of embodiments 1 to 24, wherein the compound is administered as a free base.

[0136] As an alternative embodiment 26, provided herein is a method according to any one of alternative embodiments 1-25, wherein the compound is administered as a pharmaceutical composition comprising the compound and a pharma- ceutically acceptable excipient.

[0137] As alternative embodiment 27, there is provided herein a method according to alternative embodiment 26, wherein the pharmaceutical composition is a solid dosage form.

[0138] As alternative embodiment 28, provided herein is a method according to alternative embodiment 26 or alternative embodiment 27, wherein the pharmaceutical composition is for oral administration.

[0139] As alternative embodiment 29, provided herein is a method according to any one of alternative embodiments 26-28, wherein the pharmaceutical composition is a tablet.

[0140] As alternative embodiment 30, provided herein is a method according to any one of alternative embodiments 1-29, wherein the total daily dose of the compound is administered once a day.

[0141] Alternative embodiments 1-29 may also be combined with one or more of the embodiments listed in the sections entitled "Additional Embodiments of the Disclosure" and "Additional Subpopulations."

[0142] definition The following definitions are provided to facilitate understanding of the scope of the present disclosure.

[0143] The term "anti-PD1 or PD-L1 immunotherapy" as used herein refers to treatment that includes the administration of programmed death receptor-1 (PD1) blocking antibodies, such as pembrolizumab, or programmed death ligand-1 (PD-L1) blocking antibodies, such as atezolizumab.

[0144] The term "compound of formula I" as used herein refers to the compounds described herein below in the section entitled "Compound of formula I and Phase I clinical trial results". The compound of formula I (AMG 510, sotorasib, 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one) is disclosed in U.S. Pat. No. 10,519,146 (Example 41 (col. 411-415) and Example 41-1 (col. 469)), which Examples are specifically incorporated herein by reference in their entirety. U.S. Pat. No. 10,519,146 is incorporated herein by reference in its entirety.

[0145] The term "Type I anhydrous crystals" as used herein refers to Type I anhydrous crystals of the compound of formula I as described in U.S. Patent Application Publication No. 2020 / 00369662A1, which is specifically incorporated herein by reference in its entirety, in particular paragraphs

[0226] to

[0240] and

[0346] to

[0351] (Example 2). U.S. Patent Application Publication No. 2020 / 00369662A1 is specifically incorporated herein by reference in its entirety.

[0146] In one embodiment, the compound of formula I is characterized by a powder X-ray diffraction pattern comprising peaks at 9.0, 12.0, 12.6, and 19.0±0.2 degrees two-theta as measured by powder X-ray diffraction using an x-ray wavelength of 1.54 Å. In another embodiment, the compound of formula I is characterized by a powder X-ray diffraction pattern comprising at least 3, 4, 5, 6, or 7 peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta as measured by powder X-ray diffraction using an x-ray wavelength of 1.54 Å. In yet another embodiment, the compound of formula I is characterized by a powder X-ray diffraction pattern comprising peaks at 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9 and 25.0±0.2 degrees 2-theta as measured by powder x-ray diffraction using an x-ray wavelength of 1.54 Å. In one embodiment, the compound of formula I is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 293° C. In one embodiment, the compound of formula I is characterized by a thermogravimetry thermogram comprising a weight loss of about 0.2% when heated from about 25° C. to about 275° C. In one embodiment, the compound of formula I comprises at least 3, 4, 5, 6, or 7 peaks selected from peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. 13 In another embodiment, the compound of formula I comprises peaks at approximately 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. 13In one embodiment, the compound of formula I comprises peaks at approximately -49, -60, -79, -90, -109, -120, -138, -150, -168, and -179 ppm. 19 Characterized by F solid-state NMR. The analytical characterizations herein above were carried out as described in U.S. Patent Application Publication No. 2020 / 00369662A1 (see, for example, paragraphs

[0322] to

[0328] ).

[0147] The term "loss-of-function mutation" as used herein refers to a mutation (e.g., substitution, deletion, truncation, or frameshift mutation) that results in the expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological or enzymatic activity), or that results in the expression of only a fragment of a protein that no longer exhibits wild-type activity, or that does not result in the expression of a wild-type protein. For example, a loss-of-function mutation affecting the STK11 gene in a cell can result in the expression of a reduced STK11 protein, the expression of only a fragment of the STK11 protein, or the expression of an STK11 protein that exhibits reduced or no enzymatic activity in a cancerous cell (e.g., no serine / threonine kinase enzymatic activity). Similarly, a loss-of-function mutation affecting the KEAP1 gene in a cell can result in the expression of a reduced KEAP1 protein, the expression of only a fragment of the KEAP1 protein, or the expression of a KEAP1 protein that exhibits reduced or no activity in a cell (e.g., unable to interact with or activate erythroid transcription factor 2-related transcription factor 2 (NRF2)).

[0148] As used herein, the term "pharmaceutical acceptable salt" refers to a salt of a compound of formula I that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also the Revised Edition (2011).

[0149] The term "platinum-based chemotherapy" as used herein refers to chemotherapy treatments that include the administration of a compound that contains platinum. For example, the compound used in platinum-based chemotherapy is cisplatin or carboplatin. In certain embodiments, cisplatin or carboplatin is used in combination with one or more compounds selected from paclitaxel (Taxol), albumin-bound paclitaxel (nab-paclitaxel, Abraxane), docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), etoposide (VP-16) and pemetrexed (Alimta). Other platinum-based chemotherapy includes, but is not limited to, oxaliplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin, prolindac and aroplatin.

[0150] As used herein, the term "pharmaceutical acceptable excipient" refers to a wide range of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations.Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adhesive agents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, and preservatives.

[0151] The term "subject," as used herein, refers to a human subject.

[0152] Methods for detecting KRAS, STK11, KEAP1 and TP53 mutation status Determining whether a tumor or cancer contains a KRAS G12C, STK11, KEAP1 or TP53 mutation can be made, for example, by evaluating the nucleotide sequence encoding the KRAS, STK11, KEAP1 or TP53 protein, by evaluating the amino acid sequence of the KRAS, STK11, KEAP1 or TP53 protein, or by evaluating the characteristics of a putative KRAS, STK11, KEAP1 or TP53 mutant protein, or by any other suitable method known in the art. The nucleotide and protein sequences of wild-type human KRAS (accession number BC010502; available at https: / / www.ncbi.nlm.nih.gov / nuccore / BC010502, accessed January 2020), STK11 (Gene ID: 6794; available at https: / / www.ncbi.nlm.nih.gov / gene / 6794; accessed January 2020), KEAP1 (Gene ID: 9817; https: / / www.ncbi.nlm.nih.gov / gene / 9817; accessed January 2020) and TP53 (Gene ID: 7157; https: / / www.ncbi.nlm.nih.gov / gene / 7157, accessed May 2021) are known in the art.

[0153] Methods for detecting mutations in KRAS, STK11, KEAP1 or TP53 nucleotide sequences are known by those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing and / or next generation sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay and microarray analysis. In some embodiments, samples are evaluated for mutations such as KRAS G12C mutation by real-time PCR. In real-time PCR, a fluorescent probe specific for a particular mutation such as KRAS G12C mutation is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, mutations are identified using direct sequencing of specific regions (e.g., exon 2 and / or exon 3) in the KRAS, STK11, KEAP1, or TP53 genes, which identifies all possible mutations in the sequenced region.

[0154] Methods for detecting mutations in KRAS, STK11, KEAP1 or TP53 proteins are known by those skilled in the art.These methods include, but are not limited to, detection of KRAS, STK11, KEAP1 or TP53 mutants using binding agents (e.g., antibodies) specific to mutant proteins, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0155] The method for determining whether a tumor or cancer contains a KRAS G12C, STK11, KEAP1 or TP53 mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded (FFPE) sample. In some embodiments, the sample is a circulating cell-free DNA and / or circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In certain embodiments, the sample is obtained by resection, core needle biopsy (CNB), fine needle aspiration (FNA), urine collection or hair follicle collection. In one embodiment, liquid cytology using whole blood or cerebrospinal fluid can be used to assess KRAS mutation status.

[0156] In one embodiment, a test approved by a regulatory agency such as the US Food and Drug Administration (FDA) is used to determine whether a subject has KRAS G12C mutated non-small cell lung cancer or whether a tumor or tissue sample obtained from such a subject contains cells with KRAS G12C mutation. In one embodiment, the test is therascreen® KRAS RGQ PCR kit (Qiagen). Therascreen® KRAS RGQ PCR kit is a real-time quantitative PCR assay for the detection of seven somatic mutations (G12A, G12D, G12R, G12C, G12S, G12V and G13D) in codons 12 and 13 of the human KRAS oncogene using a Rotor-Gene Q MDx 5plex HRM instrument. The kit is intended for use with DNA extracted from FFPE samples of NSCLC samples obtained by resection, CNB or FNA.

[0157] STK11 and KEAP1 mutation testing can be performed with commercially available tests such as the Resolution Bioscience Resolution ctDx Lung™ Assay, which includes 24 genes (including those with therapeutic implications in NSCLC). Tissue samples can be tested using the Tempus xT 648 panel.

[0158] TP53 mutation testing can be performed by commercially available tests such as Foundation One, Tempus xT, Illumina TSO500, Guardant 360 or Guardant Omni.

[0159] In one embodiment, the cancer is identified as having a KRAS G12C mutation. In one embodiment, the cancer is identified as having a STK11 mutation, such as a STK11 loss-of-function mutation. In one embodiment, the cancer is identified as having a KEAP1 mutation, such as a KEAP1 loss-of-function mutation. In one embodiment, the cancer is identified as having wild-type STK11. In one embodiment, the cancer is identified as having wild-type KEAP1.

[0160] In one embodiment, the cancer is identified as having a mutation in STK11, such as a loss-of-function mutation in STK11, and a wild-type KEAP1. In one embodiment, the cancer is identified as having a mutation in STK11, such as a loss-of-function mutation in STK11, and a mutation in KEAP1, such as a loss-of-function mutation in KEAP1. In one embodiment, the cancer is identified as having a wild-type STK11 and a wild-type KEAP1. In one embodiment, the cancer is identified as having a wild-type STK11 and a mutation in KEAP1, such as a loss-of-function mutation in KEAP1.

[0161] Methods for detecting PD-L1 protein expression PD-L1 expression can be determined by methods known in the art. For example, PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Meyers Squibb as a companion test for treatment with pembrolizumab. This is a quantitative assay that uses a monoclonal mouse anti-PD-L1, clone 22C3 PD-L1, and the EnVision FLEX visualization system on an automated stainer, Lin 48, to detect PD-L1 in FFPE samples such as human non-small cell lung cancer tissue. Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells that show partial or complete membrane staining at any intensity. Staining can range from 0% to 100% to indicate PD-L1 expression.

[0162] PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with nivolumab. This quantitative assay uses monoclonal rabbit anti-PD-L1, clone 28-8, and the EnVision FLEX visualization system on the automated stainer Lin 48 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human non-small cell lung cancer tissues.

[0163] Other commercially available tests for PD-L1 detection include the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca), which utilizes the monoclonal rabbit anti-PD-L1 clone SP263, and the Ventana SP142 assay (developed by Ventana in collaboration with Genentech / Roche), which uses the rabbit monoclonal anti-PD-L1 clone SP142. Determination of PD-L1 status is indication-specific, with assessment based on either the percentage of tumor area occupied by tumor-infiltrating immune cells expressing PD-L1 at any intensity (%IC) or the percentage of tumor cells expressing PD-L1 at any intensity (%TC). See, for example, the April 2021 revised atezolizumab prescribing information (available at https: / / www.gene.com / download / pdf / tecentriq_prescribing.pdf, accessed May 2021).

[0164] In one embodiment, PD-L1 TPS is determined using a test approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA). In another embodiment, PD-L1 TPS is determined using an immunohistochemistry (IHC) test. In a particular embodiment, the IHC test is the PD-L1 IHC 22C3 pharmDx test. In one embodiment, the IHC test is performed using a sample obtained, for example, by resection, CNB, or FNA.

[0165] In one embodiment, the subject has a PD-L1 TPS of less than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. In one embodiment, the subject has a PD-L1 TPS of less than 50% or less than 1%. In one embodiment, the subject has a PD-L1 TPS of 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% or greater. In one embodiment, the subject has a PD-L1 TPS of 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% or less. In one embodiment, the subject has a PD-L1 TPS of 50% or less or 1% or less. In one embodiment, the subject has a PD-L1 TPS of more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In one embodiment, the subject has a PD-L1 TPS score in a range bounded by any of the values ​​recited in the preceding embodiments. For example, the subject has a PD-L1 TPS score in the range of less than 50% and 1% or more, less than 50% and more than 1%, less than 50% and more than 1%, less than 50% and more than 1%, or less than 50% and more than 1%.

[0166] In one embodiment, the subject has a PD-L1 TPS Score ranging from less than 50% to greater than or equal to 1%. In another embodiment, the subject has a PD-L1 TPS Score ranging from greater than or equal to 0% to less than 1%. In yet another embodiment, the subject has a PD-L1 TPS Score ranging from greater than 50% to less than or equal to 100%.

[0167] Methods for detecting brain and bone metastases Methods for determining whether a subject has bone or brain metastases are known in the art.

[0168] In one embodiment, brain metastases can be diagnosed using, for example, computer axial tomography (CAT) scan or computer tomography (CT) with or without intravenous contrast and magnetic resonance imaging (MRI) with or without intravenous contrast. In one embodiment, the subject has a brain MRI performed within 28 days before the start of treatment. If MRI is contraindicated, a CT with contrast is performed.

[0169] In one embodiment, bone metastases may be diagnosed using, for example, any one of an X-ray bone scan (bone scintigraphy), CT, MRI, positron emission tomography (PET), and biopsy.

[0170] Methods for detecting tumor mutation burden Methods for determining tumor mutation burden (TMB) in a subject are known in the art. TMB can be measured by clinical testing using next generation sequencing of tumor tissues that broadly look for a wide range of mutations. Although not as established as measuring TMB from tumor tissue biopsy samples, studies are currently being conducted to evaluate the measurement of TMB from circulating tumor DNA in plasma, and in the future it may be possible to test TMB from blood. TMB is reported as the number of mutations found in a portion of DNA, reported as mutations per megabase (mut / Mb). Cancers with a TMB of 10 mut / Mb or more (called high TMB) may be more likely to respond to drugs called immune checkpoint inhibitors that promote activation of the immune system to better recognize cancer cells (Fusco et al. 2021). In one embodiment, the TMB tests used are commercially available tests such as Foundation One, Tempus xT, Guardant Omni and Illumina TSO500.

[0171] Subpopulations Further provided herein are certain methods for treating in a subject in need thereof, wherein the subject has certain characteristics or combinations thereof in addition to the conditions relating to KRAS, STK11, KEAP1, TP53, PD-L1 TPS, or bone or brain metastases discussed herein above.

[0172] Also provided herein is a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, as disclosed in various aspects of the invention above, wherein the subject has the following characteristics:

[0173] [Table 1]

[0174] [Table 2]

[0175] [Table 3]

[0176] For example, an entry in the above table where feature A is "PD-L1 TPS is <1%" and feature B is empty represents an embodiment relating to a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, as disclosed in various aspects of the invention above, wherein the subject has a PD-L1 tumor proportion score of less than 1%.

[0177] As a further example, an entry in the above table where feature A is "PD-L1 TPS is <1%" and feature B is "positive for loss of function mutation in STK11" represents an embodiment relating to a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, as disclosed in various aspects of the invention above, where (i) the subject has a PD-L1 tumor proportion score of less than 1% or (ii) the subject is positive for loss of function mutation in STK11 (A or B). The same entry also represents an embodiment relating to a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, as disclosed in various aspects of the invention above, where (i) the subject has a PD-L1 tumor proportion score of less than 1%, and (ii) the subject is positive for loss of function mutation in STK11 (A and B). The same item also represents an embodiment relating to a method of treating KRAS G12C mutant non-small cell lung cancer in a subject in need thereof, as disclosed in various aspects of the invention above, wherein (i) the subject has a PD-L1 tumor proportion score of less than 1%, (ii) the subject is positive for a loss-of-function mutation in STK11, or (iii) the subject has a PD-L1 tumor proportion score of less than 1% and the subject is positive for a loss-of-function mutation in STK11 (A or B or both).

[0178] The following embodiments disclose certain additional features of said object. In one embodiment, the object has one, two, three, four, five, six, seven, eight, nine, ten, or all of the following additional features. In certain embodiments, the object has one of the following additional features. In certain embodiments, the object has two of the following additional features. In certain embodiments, the object has three of the following additional features. In certain embodiments, the object has five of the following additional features. In certain embodiments, the object has seven of the following additional features. In certain embodiments, the object has ten of the following additional features. In certain embodiments, the object has all of the following additional features.

[0179] In one embodiment, the subject is male, hi another embodiment, the subject is female.

[0180] In one embodiment, the subject is 18 years of age or older.

[0181] In one embodiment, the subject has pathologically proven locally advanced or metastatic malignant tumors with a KRAS G12C mutation identified via molecular testing, hi certain embodiments, the mutation was confirmed by central laboratory testing prior to initiation of treatment.

[0182] In one embodiment, the subject has progressed after receiving anti-PD-1 or anti-PD-L1 immunotherapy (if not contraindicated) and / or platinum-based combination chemotherapy and targeted therapy (if therapeutic oncogenic driver mutations (i.e., EGFR, ALK, and ROS1) have been identified).

[0183] In one embodiment, the subject has not received more than 3 prior lines of therapy.

[0184] In one embodiment, an archived tumor tissue sample (formalin-fixed, paraffin-embedded [FFPE] sample taken within the last 5 years) is available and obtained from the subject. In a particular embodiment, a pre-treatment tumor biopsy sample is available and obtained from the subject. In another embodiment, an additional biopsy sample taken from the subject at the time of tumor progression is available, provided that the subject has a lesion that can be adequately biopsied.

[0185] In one embodiment, the subject has measurable disease according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1; Eisenhauer et al, 2009).

[0186] In one embodiment, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≦1 (Oken et al., 1982). In certain embodiments, the subject has an ECOG performance status of 0. In certain embodiments, the subject has an ECOG performance status of 1.

[0187] In one embodiment, the subject has a life expectancy of >3 months.

[0188] In one embodiment, the subject is capable of taking oral medication.

[0189] In one embodiment, the subject has a QTc≦470 msec (based on the average of screening triplets).

[0190] In one embodiment, the subject has one, two, or three of the following hematological laboratory tests: absolute neutrophil count (ANC) > 1.5 x 10 9 / L, platelet count ≥75×10 9 / L, hemoglobin ≥ 9 g / dL (90 g / L).

[0191] In one embodiment, the subject has a blood glucose level of ≧60 ml / min / 1.73 m 2 and estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal Disease) calculations.

[0192] In one embodiment, the subject has one, two or three of the following liver laboratory tests: aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) (if liver metastases are present, < 5 x ULN), alanine aminotransferase (ALT) < 2.5 x ULN (if liver metastases are present, < 5 x ULN), total bilirubin < 1.5 x ULN (< 2.0 x ULN for subjects with documented Gilbert's syndrome or < 3.0 x ULN for subjects with indirect bilirubin levels suggesting elevated extrahepatic sources).

[0193] In one embodiment, the subject has a prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x ULN or < 1.5 or an international normalized ratio (INR) within the target range if receiving prophylactic anticoagulant therapy.

[0194] In another embodiment, the subject does not have active brain metastases from non-brain tumors. In a particular embodiment, subjects who have had brain metastases resected or who have completed radiation therapy at least 4 weeks before starting treatment are eligible for treatment if they meet all of the following criteria: residual neurological symptoms of grade less than 2; if applicable, stable dose of dexamethasone; and follow-up MRI performed within 30 days shows no new lesions appearing.

[0195] In another embodiment, the subject has no evidence of disease for more than two years and no history or presence of hematological malignancies, unless cured by treatment.

[0196] In another embodiment, the subject does not have a myocardial infarction within 6 months of initiating treatment, symptomatic congestive heart failure (New York Heart Association>Class II), unstable angina, or cardiac arrhythmia requiring drug therapy.

[0197] In another embodiment, the subject does not have a gastrointestinal (GI) tract disease that would prevent them from taking oral medications, a malabsorption syndrome, the need for intravenous nutritional support, or an uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).

[0198] In another embodiment, the subject does not have an active infection requiring IV antibiotics within one week of initiating treatment.

[0199] In another embodiment, the subject does not have hepatitis infection. In a particular embodiment, the absence of hepatitis infection in a subject is determined based on the following results: positive hepatitis B surface antigen (HepBsAg) (indicating chronic hepatitis B or recent acute hepatitis B); negative HepBsAg is positive for hepatitis B core antibody (hepatitis B core antibody test is not necessary for screening, but if it is done and positive, hepatitis B surface antibody [anti-HBs] test is necessary); undetectable anti-HBs in this situation indicates the possibility of an uncertain infection and needs to be excluded); positive hepatitis C virus antibody: hepatitis C virus RNA by PCR is required (detectable hepatitis C virus RNA indicates chronic hepatitis C).

[0200] In another embodiment, the subject does not have a known positive test for HIV. In a particular embodiment, the subject is HIV negative.

[0201] In another embodiment, the subject has no unresolved toxicity from prior anti-tumor therapy defined as not resolved to CTCAE version 5.0 grade 0 or 1.

[0202] In another embodiment, the subject has not received anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormone therapy (except for subjects with breast cancer), or other investigational drugs) within 28 days of initiating treatment. In certain embodiments, the subject is concurrently receiving hormone deprivation therapy for hormone-refractory prostate cancer or breast cancer.

[0203] In another embodiment, the subject does not have any radiation therapy-related toxicity.

[0204] In another embodiment, the subject has not undergone major surgery within 28 days of starting treatment.

[0205] In another embodiment, the subject is not a woman with a positive pregnancy test.

[0206] In another embodiment, the subject has not been administered a known cytochrome P450 (CYP)3A4 sensitive substrate (narrow therapeutic window) within 14 days or within 5 half-lives of the drug or its major active metabolite prior to initiating treatment, whichever is longer.

[0207] In another embodiment, the subject has not been administered a strong inducer of CYP3A4 (including herbal supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to initiating treatment.

[0208] In another embodiment, the subject has not had another malignancy within the past two years prior to the initiation of treatment. In certain embodiments, the following exceptions apply: malignancies treated with curative intent that have been free of active disease for at least two years prior to the initiation of treatment and that are considered by the treating physician to be at low risk of recurrence; adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease; adequately treated in situ cervical cancer with no evidence of disease; adequately treated in situ ductal carcinoma of the breast with no evidence of disease; prostatic intraepithelial neoplasia with no evidence of prostate cancer; or adequately treated urothelial papillary non-invasive carcinoma or in situ carcinoma.

[0209] In another embodiment, the subject has KRAS G12C Not having been subjected to previous treatment with inhibitors.

[0210] Formulation and Route of Administration In the described use, the compound of formula I disclosed herein may be administered alone, but the compound administered will usually be present as an active ingredient in a pharmaceutical composition.Therefore, in one embodiment, the pharmaceutical composition provided herein comprises the compound of formula I disclosed herein in combination with one or more pharma- ceutically acceptable excipients and, if necessary, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, 22nd Edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), 1st Edition, edited by G. D. Tovey, Royal Society of Chemistry, 2018.

[0211] The compounds disclosed herein may be administered by any suitable route, in the form of a pharmaceutical composition adapted for such route, and in a dose effective for the intended treatment. The compounds and compositions provided herein may be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by injection techniques, in unit dosage forms containing conventional pharma- ceutically acceptable excipients.

[0212] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension or oily suspension. Pharmaceutical compositions are usually made in the form of a dosage unit containing a particular amount of the active ingredient.

[0213] Compound of Formula I and Phase I Clinical Trial Results Without wishing to be bound by any particular theory, it is noted that the compound of formula I (AMG 510, sotorasib, U.S. Pat. No. 10,519,146 (Example 41-1)) inhibits the activation of KRAS proteins with a G12C substitution (KRAS G12C ) and lock it in an inactive state bound to guanine diphosphate (GDP) (see, e.g., U.S. Pat. No. 10,519,146). By doing so, the compounds of formula I inhibit the KRAS G12C It specifically binds to and irreversibly inhibits mutant proteins. The chemical name of the compound of formula I is 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one. The chemical structure is shown below. [ka]

[0214] The compounds of formula I inhibit recombinant KRAS G12C The compounds of formula I potently inhibit KRAS, but have little effect on wild-type KRAS or other mutant forms of KRAS. G12CCovalent irreversible binding and inhibition of KRAS requires a reactive thiol group adjacent to the binding pocket of the compounds of Formula I. This thiol is provided by a cysteine ​​at KRAS position 12 (G12C), which binds KRAS G12C The inhibitors covalently modify cysteine ​​residues to bind KRAS in the inactive, GDP-bound conformation. G12C It contains a thiol-reactive moiety that locks KRAS. It blocks the interaction of KRAS with effectors such as aggressive fibrosarcoma (RAF), thereby preventing downstream proliferation and survival signaling, including phosphorylation of extracellular signal-regulated kinase (ERK) (Canon et al., 2019; Simanshu et al., 2017; Ostrem et al., 2013; Cully and Downward, 2008). Treatment with compounds of formula I attenuates cell proliferation and induces apoptosis only in tumor cell lines and xenografts harboring the KRAS G12C mutation (Canon et al., 2019). Inhibition of KRAS by compounds of formula I G12C Blockade of signal transduction also enhances antigen presentation and inflammatory cytokine production in tumors, stimulating the tumor microenvironment and promoting antitumor immunity. Thus, the compounds of formula I represent an important advance for the treatment of subjects with KRAS G12C mutant tumors, such as NSCLC.

[0215] The compound of Formula I is the subject of investigation in an ongoing clinical trial titled "A Phase 1 / 2, Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 510 Monotherapy in Subjects with Advanced Solid Tumors Harboring a KRAS p.G12C Mutation and AMG 510 Combination Therapy in Subjects with Advanced NSCLC Harboring a KRAS p.G12C Mutation (CodeBreak 100)" (ClinicalTrials.gov Identifier: NCT03600883, available at https: / / www.clinicaltrials.gov / ct2 / show / NCT03600883, accessed January 2020).

[0216] The primary objective of the Phase 1 portion of the study was to evaluate the safety and tolerability of the compound of Formula I and to estimate the maximum tolerated dose of sotorasib and / or the recommended dose for Phase 2 studies. For the Phase 2 portion of the study, the primary objective was to evaluate the objective response rate (ORR) for the compound of Formula I as monotherapy in subjects with KRAS G12C mutated advanced solid tumors. Secondary objectives for both portions of the study included other measures of efficacy (response duration, disease control rate, time to response, progression-free survival (PFS) and overall survival (OS) endpoints), safety and pharmacokinetics of the compound of Formula I. Subjects in Phase 1 were treated with the compound of Formula I as monotherapy at 180, 360, 720 and 960 mg once daily (QD).

[0217] Certain results from the Phase 1 cohort of the CodeBreak 100 trial (NCT03600883) have been published (Hong et al., 2020). In particular, Hong et al. discuss a set of 59 subjects with NSCLC, of ​​which 53 (89.8%) had previously received anti-programmed cell death protein 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapy, and all 59 subjects had previously received platinum-based chemotherapy. Briefly, the compound of formula I was well tolerated and demonstrated a confirmed objective response (complete or partial response) rate of 32.2% across all doses tested in heavily pretreated subjects with NSCLC, a disease control rate (objective response or stable disease) of 88.1%, a median duration of response (DoR) of 10.9 months, and a median progression-free survival (mPFS) of 6.3 months.

[0218] The recommended dose for Phase 2, identified based on the results obtained in Phase 1, was 960 mg QD of the compound of Formula I as monotherapy. EXAMPLES

[0219] Example 1: Phase 2 Study Design This example presents certain results from the Phase 2 portion of the CodeBreak 100 clinical trial (ClinicalTrials.gov Identifier: NCT03600883). The data cutoff for the analyses presented herein was September 1, 2020, unless otherwise specified.

[0220] As discussed above, in the Phase 2 CodeBreak 100 trial (ClinicalTrials.gov Identifier: NCT03600883), subjects with locally advanced or metastatic KRAS G12C mutant NSCLC were treated with the compound of Formula I as monotherapy at 960 mg QD. Subjects were to continue sotorasib treatment until disease progression (unless the subject was eligible for continued treatment), treatment intolerance, withdrawal of consent, death, or other protocol-defined reasons.

[0221] Subjects were admitted to the Phase 2 portion of the trial based on the following inclusion and exclusion criteria:

[0222] Inclusion criteria ●Subjects provided informed consent prior to the initiation of any study-specific activities / procedures. ●Male or female: 18 years of age or older. Pathologically documented locally advanced or metastatic malignancies with KRAS G12C mutations identified via molecular testing. For Phase 2, mutations were confirmed by central laboratory testing prior to enrollment. ●Subjects had to have progressed after receiving anti-PD-1 or anti-PD-L1 immunotherapy (unless contraindicated) and / or platinum-based combination chemotherapy and targeted therapy (if actionable oncogenic driver mutations (i.e. EGFR, ALK, and ROS1) were identified). Subjects had to have received ≤3 lines of prior therapy. The following guidance was used: Adjuvant therapy was counted as a line of therapy if the subject progressed at the time of or within 6 months of receiving the adjuvant therapy. In locally advanced and unresectable NSCLC, disease progression at or within 6 months of the end of prior curative-intent multimodality therapy was counted as a line of therapy. If chemoradiation was followed by planned systemic therapy without documented progression between chemoradiation and systemic therapy, the entire treatment period was counted as one line of therapy. Maintenance therapy after platinum doublet chemotherapy was not considered as another line of therapy. ●Subjects willing to provide an archived tumor tissue sample (formalin-fixed, paraffin-embedded [FFPE] sample obtained within the last 5 years) or undergo a pre-treatment tumor biopsy. • Subjects with adequately biopsied lesions were required to undergo optional biopsy at the time of tumor progression. -Measurable disease according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1; Eisenhauer et al, 2009). • Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 (Oken et al., 1982). Life expectancy >3 months as determined by the investigator. Ability to take oral medications and willingness to record daily adherence to the investigational drug using a dosing diary provided by the sponsor. • QTc ≤ 470 msec (based on average of screening triplets). Adequate hematological laboratory tests, including: Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 / L. Platelet count ≥ 75 x 10 9 / L. Hemoglobin ≥ 9 g / dL (90 g / L). Adequate renal laboratory tests, including: ○ Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal Disease) calculations ≥ 60 ml / min / 1.73 m 2 . Adequate liver laboratory tests, including: Aspartate aminotransferase (AST) < 2.5 × upper limit of normal (ULN) (≤ 5 × ULN if liver metastases are present). Alanine aminotransferase (ALT) < 2.5 x ULN (≤ 5 x ULN if liver metastases are present). Total bilirubin <1.5 x ULN (<2.0 x ULN for subjects with documented Gilbert's syndrome or <3.0 x ULN for subjects with indirect bilirubin levels suggesting elevated extrahepatic sources). Adequate coagulation laboratory tests, including: Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x ULN or < 1.5 or international normalized ratio (INR) within target range if receiving prophylactic anticoagulation therapy.

[0223] Exclusion criteria Active brain metastases from non-brain tumors. Subjects whose brain metastases had been resected or who had completed radiation therapy at least 4 weeks prior to Study Day 1 were eligible if they met all of the following criteria: ○ Residual neurological symptoms of grade less than 2; o Administration of a stable dose of dexamethasone, if applicable; and A follow-up MRI performed within 30 days showed no new lesions. No evidence of disease for more than two years and no history or presence of hematologic malignancy, unless cured by treatment. ● Myocardial infarction, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina or cardiac arrhythmia requiring medical therapy within 6 months prior to Day 1 of the study. Gastrointestinal (GI) tract disease making it impossible to take oral medications, malabsorption syndromes, need for intravenous nutritional support, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis). • Active infection requiring IV antibiotics within 1 week of study enrollment (Day 1). Exclusion of hepatitis infection based on the following results and / or criteria: Positive hepatitis B surface antigen (HepBsAg) (indicating chronic hepatitis B or recent acute hepatitis B). Negative HepBsAg that is positive for hepatitis B core antibody (hepatitis B core antibody testing is not necessary for screening, but if this was done and positive, a hepatitis B surface antibody [anti-HBs] test was required. Undetectable anti-HBs in this situation suggests the possibility of uncertain infection, which needs to be ruled out). Positive hepatitis C virus antibody: hepatitis C virus RNA by PCR was required. Detectable hepatitis C virus RNA is indicative of chronic hepatitis C. • Known positive test for HIV. Unresolved toxicities attributable to previous antineoplastic therapy defined as CTCAE version 5.0 grade 0 or 1 or not resolved to the level indicated in the eligibility criteria, except for alopecia (grade 2 or 3 toxicities attributable to previous antineoplastic therapy that were deemed irreversible [defined as present for >6 months and stable], such as ifosfamide-associated proteinuria, were allowed if they were not listed in the exclusion criteria and agreement was obtained by both the investigator and sponsor). ●Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormone therapy [excluding subjects with breast cancer], or investigational drug) within 28 days of Study Day 1; concomitant use of hormone-refractory prostate cancer or hormone deprivation therapy for breast cancer is permitted. - Curative or palliative radiation therapy within 2 weeks of Study Day 1. Subjects must have recovered from all radiation therapy-related toxicities. ●Currently enrolled in another investigational device or investigational drug trial, or is less than 28 days away from completing another investigational device or investigational drug trial, or receiving another investigational drug. Other investigational treatments are excluded. ●Major surgery within 28 days of study day 1. ● Men and women of childbearing potential (WOCBP) who were not willing to practice an acceptable method of birth control during treatment and for at least 7 days (women) or 7 days (men) after the last dose of a compound of Formula I. Acceptable methods of birth control with high effectiveness for women included abstinence (abstaining from heterosexual intercourse); vasectomy with testing showing the absence of sperm in the semen (women with one male sexual partner); bilateral tubal ligation or occlusion; or an intrauterine device. Acceptable methods of birth control for men included abstinence (abstaining from heterosexual intercourse); vasectomy with testing showing the absence of sperm in the semen; bilateral tubal ligation or occlusion in the partner; or condoms (female partners should also consider this form of birth control). Women who were lactating / breastfeeding or planned to breastfeed during the study until 7 days after receiving the last dose of study drug. •Women with a positive pregnancy test. ●Women who plan to become pregnant during the study up to 7 days after receiving the last dose of study drug. - The subject had a known sensitivity to any of the products that will be administered during dosing. ● To the best of the subject's and the investigator's knowledge, the subject was not available for any study visits or procedures required by the protocol. ● The subject had any disability that, in the opinion of the investigator, may impair the subject's ability to give written informed consent and / or to comply with all necessary study procedures. History or evidence of any other clinically significant disorder, condition or disease (other than those outlined above) that, in the opinion of the investigator or physician, may jeopardize the subject's safety or interfere with the evaluations, procedures or completion of the study. Use of known cytochrome P450 (CYP) 3A4 sensitive substrates (narrow therapeutic window) within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that have not been reviewed and approved by the investigator and the sponsor's medical monitor. Use of strong inducers of CYP3A4 (including herbal supplements such as Hypericum perforatum) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 that have not been reviewed and approved by the principal investigator and sponsor's medical monitor. History of other malignancies within the past 2 years with the following exceptions: Malignant tumors that have been treated with curative intent, have had no active disease for at least 2 years prior to enrollment, and are considered by their treating physician to be at low risk of recurrence. o Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease. o Fully treated in situ cervical cancer with no evidence of disease. o Adequately treated ductal carcinoma in situ with no evidence of disease. o Prostatic intraepithelial neoplasia with no evidence of prostate cancer. Sufficiently treated urothelial papillary non-invasive carcinoma or carcinoma in situ. Direct KRAS G12C Previous treatment with an inhibitor.

[0224] Tumor tissue sampling for central laboratory testing For example, samples were collected for biomarker analysis to evaluate potential biomarkers that may correlate with treatment response. Subjects were not enrolled until central laboratory test results were reported demonstrating that the subject had a KRAS G12C mutation.

[0225] For subjects with NSCLC, archival tumor samples (formalin-fixed, paraffin-embedded (FFPE) samples taken within 5 years of enrollment) or pretreatment tumor biopsies (core needle or fine needle aspirate or resected FFPE samples) were submitted prior to enrollment for central laboratory testing and subsequent exploratory biomarker analysis. Tumor tissue was submitted to the central laboratory as either FFPE blocks or unstained glass slides.

[0226] KRAS G12C mutation testing was performed using the therascreen® KRAS RGQ PCR kit (Qiagen). The kit is a real-time quantitative PCR assay performed on a Rotor-Gene Q MDx instrument for the detection of seven somatic mutations in the human KRAS oncogene using DNA extracted from FFPE tissues. The mutations detected are G12A, G12D, G12R, G12C, G12S, G12V and G13D.

[0227] PD-L1 testing was performed at a central laboratory using the Dako PharmDx 22C3 immunohistochemistry FDA-approved kit according to the instructions for use. More specifically, immunohistochemistry assessment of programmed death-ligand 1 (PD-L1) expression on tumor cells was performed using the PD-L1 IHC 22C3 pharmDx assay on a BOND III automated staining system (Leica Microsystems) according to the manufacturer's instructions for use (IFU). All slides were reviewed and scored by a board-certified pathologist trained to score the PD-L1 IHC 22C3 pharmDx assay. Reporting of tumor cell PD-L1 expression (% tumor proportion score) and test results (positive / negative) was performed according to established companion diagnostic guidelines by the Food and Drug Administration (FDA) for 22C3.

[0228] Subject testing with therascreen® KRAS RGQ assay and Dako PharmDx 22C3 was performed at the NeoGenomics Central Testing Laboratory in Houston, Texas.

[0229] STK11, KEAP1 and TP53 mutation testing was performed using the Resolution Bioscience Resolution ctDx Lung™ Assay, which included 24 genes (including those with therapeutic implications in NSCLC). Tissue samples were tested using the Tempus xT 648 panel. In addition, STK11 and KEAP1 mutation testing was also performed using Qiagen's comprehensive cancer panel (NGS). STK11 / KEAP1 / TP53 co-mutation analysis determined mutation status from baseline tissue and / or plasma samples, where mutations included nonsense, missense, frameshift or splice site mutations and insertions / deletions predicted to be loss of function, and excluded variants of unknown significance. Subjects with variants of unknown significance (VUS) in STK11, KEAP1 or TP53 were not included in the corresponding comparison of mutants to wild type for each gene. Subjects with any recognized variant were considered mutated for that gene, otherwise wild type. Due to platform differences in reporting content, filtering methods were customized for each platform. Tempus filtered molecular master files (MMFs) were processed to retain nonsynonymous variants (including splice site mutations, deletions, frameshifts), rearrangements, and copy number variants (CNVs). Excluded variants were those not present in COSMIC or dbSNP, were nonpathogenic and had an allele frequency of at least 0.40 or one of the following examples: unknown significance, benign, likely benign, or germline. Germline status was provided by Tempus based on matched normal samples. Resolution Biosciences cfDNA NGS results were annotated using SnpEff v4.3t and variants were further annotated with information from COSMIC (v92) and dbSNP (build 154) using SnpSift v4.3t.Variants were then filtered to retain nonsynonymous variants (including splice site mutations, deletions, and frameshifts), variants with a ClinVar clinical significance of at least 4 (likely pathogenic), indels, CNVs, and variants in at least 3 COSMIC samples. Variants excluded were those not present in COSMIC or dbSNP, with an allele frequency of at least 0.40, or of unknown significance, benign, or likely benign in ClinVar clinical significance.

[0230] result Demographics and baseline characteristics As shown in Table 1.1 below, a total of 126 subjects with KRAS G12C-mutated locally advanced or metastatic NSCLC were enrolled in the Phase 2 portion of the CodeBreak 100 trial and received one or more doses of the compound of Formula I as monotherapy (960 mg once daily). Of these, 123 subjects received one or more doses of the compound of Formula I, had ≥1 measurable lesion according to RECIST 1.1 (based on a central review committee) at baseline, and were included in the full analysis population for efficacy evaluation (Table 2.1). As of the data cutoff date of September 1, 2020, 69 of the 126 subjects with NSCLC (54.8%) continued to participate in the study. Of the 57 subjects (45.2%) who discontinued the study, 47 subjects (37.3%) died and 10 subjects (7.9%) withdrew consent. Eighty-nine subjects (70.6%) discontinued treatment with the compound of formula I; the most common reasons for discontinuation were disease progression (70 subjects [55.6%]) and adverse events (11 subjects [8.7%]). The median (range) duration of treatment with the compound of formula I was 24.1 (1.0, 52.1) weeks, with 47.6% and 28.6% of subjects receiving treatment for ≥ 6 and ≥ 9 months, respectively. The median relative dose intensity was 100%.

[0231] Of the 126 enrolled subjects with NSCLC, 81.7% were white and 50% were male. Median (range) age was 63.5 (37, 80) years. Most subjects had non-squamous NSCLC (99.2%) and stage IV disease (96.0%) at screening. Per protocol eligibility criteria, subjects had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (38 subjects [30.2%] and 88 subjects [69.8%], respectively). Subjects had received a median of 2 lines of prior anticancer therapy: 54 subjects (42.9%) had received 1 prior line, 44 (34.9%) had received 2 prior lines, 28 (22.2%) had received 3 prior lines, and no subjects had received 4 or more prior lines. A total of 113 subjects (89.7%) had received prior platinum-based chemotherapy and 115 subjects (91.3%) had received prior anti-PD-1 / PD-L1 immunotherapy. A total of 102 subjects (81.0%) had received treatment with both checkpoint inhibitors and platinum-based chemotherapy and progressed on that treatment. The majority of subjects were former smokers (102 subjects, 81.0%) or current smokers (15 subjects, 11.9%). Overall, 7.1% had received targeted small molecule therapy and progressed on that therapy (there was no approved therapy / combination for the treatment-leading mutation). Based on available data reported by the study site and consistent with the literature, a small number of subjects had co-mutations (10.3% of subjects for TP53, 5.6% for STK11, 2.4% for EGFR, and <1.6% for all other co-mutations; based on data available at the local site, no subjects had co-mutations in ALK or ROS). Overall, 96.8% of subjects had metastatic disease. Per the eligibility criteria in the clinical trial protocol, subjects with treated, stable brain metastases were eligible to enroll in the study, while subjects with active brain metastases were excluded. This is in line with the standard of care of treating active brain metastases with surgery or radiation before initiating medical therapy.

[0232] [Table 4]

[0233] Additionally, as of data cutoff on March 15, 2021, a total of 126 patients with previously treated, KRAS p.G12C-mutated NSCLC were enrolled and received at least one dose of sotorasib. According to the independent central review committee, two patients did not have measurable disease at baseline and were ineligible for response evaluation. Among the remaining 124 patients, one patient did not have KRAS p.G12C as confirmed by the central review committee; this patient had stable disease and was included in the response evaluation as prespecified by the study protocol. The data cutoff was March 15, 2021, with a median follow-up time of 15.3 months (range, 1.1+ to 18.4, + indicates that the value includes patient data that were censored at the time of data cutoff). The median treatment duration was 5.5 months (range, 0.2 to 17.8). A total of 88 patients (69.8%) received sotorasib for ≥3 months, 60 (47.6%) for ≥6 months, and 41 (32.5%) for ≥9 months. Dose reductions were performed in 26 patients (20.6%). At the cutoff time, 103 patients (81.7%) had discontinued treatment with sotorasib; disease progression (n=83, 65.9%) and adverse events of any cause (n=11, 8.7%) were the most common reasons for discontinuation.

[0234] Baseline characteristics are summarized in Table 1.2 and further detailed in Table 1.3. Among the 126 patients enrolled, the median age was 63.5 years (range, 37-80), and 117 (92.9%) were current or former smokers. Patients had received a median of 2 lines of prior systemic anticancer therapy. Prior therapy included platinum-based chemotherapy (n=113, 89.7%), checkpoint inhibitors (n=116, 92.1%), and antiangiogenic therapy (n=25, 19.8%). In total, 102 patients (81.0%) had received both platinum-based chemotherapy and PD-1 / L1 inhibitors.

[0235] [Table 5]

[0236] [Table 6]

[0237] [Table 7]

[0238] [Table 8]

[0239] Overall Efficacy Results Key efficacy results for tumor response in subjects with NSCLC from the Phase 2 portion of the CodeBreak 100 trial (full analysis population) are provided below in Table 2.1.

[0240] Based on a blinded independent central review committee using RECIST 1.1, the ORR among subjects with NSCLC in the phase 2 portion of the CodeBreak 100 trial was 37.4% (95% CI: 28.8, 46.6) with 46 of 123 evaluable subjects achieving a complete or partial response, including 2 subjects (1.6%) with a complete response and 44 subjects (35.8%) with a partial response. The lower limit of the 95% CI excluded the pre-specified benchmark ORR of 23%. Among the 46 responders in the phase 2 NSCLC arm, the median time to response was 1.35 months (range: 1.2-6.1). The median duration of response (DOR) was 8.4 months (95% CI: 6.9, 8.4). As of the data cutoff date, 24 of 46 responder subjects (52.2%) were still receiving treatment and had ongoing responses; median follow-up for DOR was 6.9 months (range: 1.3-8.4+).

[0241] Among 99 subjects with prior treatment with both platinum-based chemotherapy and anti-PD-1 or anti-PD-L1, the ORR was 32.3% (95% CI: 23.3, 42.5) with median duration of response not estimable (95% CI: 6.9 months, not estimable). This subset of subjects receives the most effective available therapies in NSCLC and therefore has limited favorable treatment options.

[0242] Thus, the rapid and durable observed ORR represents a clinically meaningful advantage when considering the target patient population with life-threatening disease and limited available therapies.

[0243] The PFS and OS results provide additional evidence of the efficacy of the compound of formula I. The median follow-up for PFS was 8.3 months (range: 0.3-11.5+). The median PFS based on the central review committee was 6.7 months (95% CI: 4.9, 8.1); the Kaplan-Meier estimate for PFS at 6 months was 51.5% and at 9 months was 36.2%. The median follow-up for OS was 9.3 months (range: 1.1-12.2). The median OS was 12.0 months (95% CI: 9.5, not estimable); the Kaplan-Meier estimate for OS at 6 months was 75.5% and at 9 months was 63.4%. As of the data cut-off date (September 1, 2020), 69 (54.8%) of 126 subjects were alive at their last follow-up visit, 9 (7.1%) had withdrawn consent, and 48 (38.1%) had died.

[0244] Furthermore, the compound of formula I was well tolerated with no treatment-emergent deaths and low incidence of grade 3 or 4 treatment-related adverse events, treatment discontinuations and dose modifications.

[0245] [Table 9]

[0246] [Table 10]

[0247] As of data cutoff on March 15, 2021, the following efficacy information is available:

[0248] Among 124 patients evaluated for response, 4 (3.2%) had a complete response and 42 (33.9%) had a partial response, resulting in an objective response rate of 37.1% (95% CI, 28.6-46.2). The objective response rate was independent of KRAS p.G12C mutant allele frequency (MAF), with an odds ratio of 1.11 (95% CI: 0.88, 1.39) for each 0.10 increase in MAF. Disease control (complete response, partial response, or stable disease) was achieved in 100 patients (80.6%, 95% CI, 72.6-87.2) (Table 2.2). Tumor shrinkage of any magnitude was observed in 102 patients (82%); the median percentage of best tumor shrinkage among all responders was 60%. Disease progression was the best overall response in 20 patients. A total of 4 patients were not evaluable (n=2) or had missed scans (n=2).

[0249] [Table 11]

[0250] Objective response rates were consistent across patient subgroups prespecified by number of lines of prior therapy and prior treatment with anti-PD-1 or anti-PD-L1 therapy (Table 2.3).

[0251] [Table 12]

[0252] Among the 46 patients with an objective response, the median time to response was 1.4 months, and the median duration of response was 11.1 months (95% CI, 6.9 to not estimable). Responses were observed at approximately the 6th week of first tumor evaluation in 71.7% (33 / 46) of responders. At the cutoff time, 16 (34.7%) responders remained on treatment without progression. The 3-, 6-, and 9-month Kaplan-Meier estimates for duration of response among responding patients were 90.5% (95% CI, 76.7 to 96.3), 70.8% (95% CI, 54.3 to 82.2), and 57.3% (95% CI, 40.4 to 71.0), respectively.

[0253] Median progression-free survival among the 124 evaluable patients was 6.8 months (95% CI, 5.1 to 8.2). The 6- and 9-month Kaplan-Meier estimates for PFS were 52.2% (95% CI, 42.6 to 60.9) and 37.5% (95% CI, 28.4 to 46.5). Median overall survival among all 126 patients enrolled was 12.5 months (95% CI, 10.0 to not evaluable).

[0254] According to local investigator assessment including all 126 patients, 2 (1.6%) had a complete response, 37 (29.4%) had a partial response, 69 (54.8%) had stable disease, and 15 (11.9%) had progressive disease (Table 2.4).

[0255] [Table 13]

[0256] Efficacy results by subgroup Analyses were performed to explore treatment effects across subgroups (e.g., age, race, previous line anticancer therapy, previous immunotherapy treatment, ECOG status, histopathology type, disease status, presence of liver or brain metastases, smoking history, region, best response to last prior therapy) among subjects with NSCLC in phase 2 (Table 3). Although interpretation of subgroup analyses may be limited due to small sample sizes in each subgroup, certain noteworthy effects and trends were observed.

[0257] Previous platinum-based chemotherapy The ORR was significantly higher for subjects who had received prior platinum-based chemotherapy and for those who had not compared with the overall subject population (69.2% [9 of 13 subjects] vs. 33.6% [37 of 110 subjects] and 37.4% [46 of 123 subjects], respectively).

[0258] Brain metastases The ORR was significantly higher for subjects without brain metastases than for those with brain metastases (15.4% [4 of 26 subjects] vs. 43.3% [42 of 97 subjects]). The ORR was significantly lower for subjects with brain metastases compared with the overall subject population (37.4% [46 of 123 subjects] vs. 15.4% [4 of 26 subjects]).

[0259] Bone metastases A trend towards a higher ORR was observed for subjects without bone metastases compared with those with bone metastases (32.8% [19 of 58 subjects] vs. 41.5% [27 of 65 subjects]).

[0260] PD-L1 protein expression Table 3 provides the locally obtained PD-L1 protein expression results. A trend towards higher ORR was observed in subjects with lower PD-L1 protein expression as measured by tumor proportion score (TPS). The group with PD-L1 TPS ≥ 50% had a lower ORR compared to overall response (37.4% [46 of 123 subjects] vs. 26.5% [9 of 34 subjects]), while the group with PD-L1 TPS < 1% and the groups with PD-L1 TPS ≥ 1% and < 50% both had higher ORR compared to overall response (37.4% [46 of 123 subjects] vs. 48.5% [16 of 33 subjects] and 40.9% [9 of 22 subjects]).

[0261] Retrospective PD-L1 central laboratory testing was performed using the Dako PharmDx 22C3 immunohistochemistry FDA-approved kit according to the instructions for use for the target population based on a data cutoff of December 1, 2020, and evaluated 124 subjects evaluable for efficacy by the central adjudication committee who had biomarker data available. This retrospective analysis, shown in Figure 1, confirms the trends observed with the locally obtained results described above (see Table 3). Specifically, the group with a PD-L1 TPS ≥ 50% had a lower ORR compared to an overall response (42% [36 of 86 subjects] vs. 22% [2 of 9 subjects]), while the group with a PD-L1 TPS of < 1% and the groups with a PD-L1 TPS of ≥ 1% and < 50% both had higher or similar ORR compared to an overall response (42% [36 of 86 subjects] vs. 48% [21 of 44 subjects] and 39% [13 of 33 subjects]).

[0262] STK11 / KEAP1 / TP53 coexisting mutations ORR (%, non-responders / responders) by coexisting STK11 / KEAP1 mutation in the population of subjects evaluable for efficacy according to the central review committee (N=124) who had available biomarker data (N=104) (data cutoff December 1, 2020) is shown in Figure 2. STK11 / KEAP1 comutation analysis determined mutation status from baseline tissue and / or plasma samples, and mutations included nonsense, missense, frameshift, or splice site mutations and insertions / deletions predicted to be loss of function, and excluded variants of unknown significance. For clarification, the term "coexisting mutation" refers to either or both of STK11 and KEAP1 having a mutation that coexists with a KRAS G12C mutation.

[0263] As discussed herein above, STK11 and KEAP1 coexisting mutations are associated with poorer overall survival (OS) in KRAS mutant NSCLC (see Background). Although OS remains the criterion in clinical trials, analyses exploring the association between ORR and survival have demonstrated patient- and study-level associations between ORR, PFS, and OS (Blumenthal et al., 2015; Clarke et al., 2015). Against this background, it is noteworthy that clinically meaningful ORRs were observed across the entire STK11 / KEAP1 coexisting mutation profile. Notably, KEAP1 coexisting loss-of-function mutations, independent of STK11 mutation status (loss-of-function or wild-type), demonstrated an ORR of 20% (4 of 20 subjects). Moreover, it is particularly noteworthy that STK11 coexisting loss-of-function mutations, independent of KEAP1 mutation status (loss-of-function mutation or wild type), demonstrated similar ORR compared to overall response in this subject population (39% [41 of 104 subjects] vs. 40% [14 of 35 subjects], see also Figure 3). It is even more noteworthy that subjects with STK11 coexisting loss-of-function mutations and KEAP1 wild type or STK11 wild type and KEAP1 wild type, respectively, showed higher ORR compared to overall response in this subject population (39% [41 of 104 subjects] vs. 50% [11 of 22 subjects]) and (39% [41 of 104 subjects] vs. 42% [26 of 62 subjects]).

[0264] Figure 3, generated based on a data cutoff of March 15, 2021, shows responses by coexisting mutations for TP53, STK11, and KEAP1 (wild type vs. mutant). While the ORRs for TP53 and STK11 (as described above) did not show significant differences between wild type and mutant, higher ORRs were observed for KEAP1 wild type compared to subjects with KEAP1 mutant. See also Table 4. As shown in Table 5, longer survival was seen with sotorasib in the STK11 mutant group with concurrent wild type KEAP1, while the KEAP1 mutant group appeared to benefit less due to limitations of the small sample size and exploratory nature of this study.

[0265] Figures 4, 5 and 6 show the objective response rates by PD-L1 expression level group per TPS superimposed by STK11, KEAP1 and TP53 coexisting mutations (data cutoff March 15, 2021).

[0266] Additionally, Figures 7 and 8 show progression-free survival (PFS) by STK11 and KEAP1 mutation status (data cutoff March 15, 2021).

[0267] Tumor mutation burden As of the cutoff of March 15, 2021, in the subset of patients evaluated for tumor mutation burden (n=84), the response rate was 42% (95% CI, 30%-55%) for the low tumor mutation burden group (<10 Mut / Mb) and 40% (95% CI, 16%-68%) for the high tumor mutation burden group (≥10 Mut / Mb) (see Table 6).

[0268] [Table 14]

[0269] [Table 15]

[0270] [Table 16]

[0271] [Table 17]

[0272] [Table 18]

[0273] Example 2: A Phase 2, Multicenter, Open-Label Study of Sotorasib (AMG 510) in Subjects with Stage IV NSCLC Whose Tumors Harbor KRAS G12C Mutations Requiring First-Line Treatment (CodeBreak 201) Overall Design An open-label, multicenter Phase 2 study is being set up to explore the antitumor efficacy of sotorasib monotherapy in subjects with metastatic non-small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations whose tumors express <1% programmed death-ligand 1 (PD-L1) and / or have serine / threonine kinase 11 (STK11) mutations requiring first-line treatment. Subjects will be randomized in a 1:1 design for treatment with sotorasib 960 mg per day (QD) orally (PO) and stratified by the known presence of STK11 mutations. The study is listed under ClinicalTrials.gov Identifier: NCT04933695 (https: / / clinicaltrials.gov / ct2 / show / NCT04933695; version October 13, 2021; last accessed December 15, 2021).

[0274] An independent Data Review Team (DRT) will monitor the study. Non-binding futility guidelines based on Bayesian posterior probability will be used to facilitate discontinuation in the event of inadequate efficacy. Subjects will be treated until disease progression as confirmed by a blinded independent central review committee (BICR), unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first. All subjects are required to attend a Safety Follow-Up (SFU) visit approximately 30 (+7) days after the end of the last dosing interval of protocol-required therapy or approximately 30 (+7) days before any new anti-tumor treatment is initiated. After the SFU visit, subjects will enter the long-term follow-up (LTFU) phase of the study in clinic or via telephone every 12 weeks (± 2 weeks) for assessment of survival and documentation of anti-cancer treatment until death, withdrawal of consent, or termination of the study, whichever occurs first. Subjects who discontinue sotorasib for reasons other than radiographic disease progression will undergo LTFU imaging for disease status until disease progression is radiographically documented per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, they initiate off-study cancer treatment, or they withdraw consent or end of the study, whichever occurs first.

[0275] Additional plasma / blood / tissue biopsy samples will be collected for exploratory biomarker identification and quantification of biomarker expression at the protein, RNA and DNA levels.

[0276] Sotorasib tablets are administered PO QD with or without food for a 21-day treatment cycle. Sotorasib tablets are formulated as a solid dosage form, PO, in a strength of 120 mg. The sotorasib dose used during the study is 960 mg per day.

[0277] The total study duration for each subject is approximately 6 years: 28 days of screening, 6-12 months of treatment and up to approximately 46 cycles, SFU and LTFU 5 years from the last subject enrolled.

[0278] Concomitant administration of sotrasib with proton pump inhibitors (PPIs, e.g., omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, and dexlansoprazole) or H2RAs (e.g., famotidine, ranitidine, cimetidine, nizatidine, roxatidine, and lafutidine) is prohibited. If treatment with antacids cannot be avoided, sotrasib should be administered 4 hours before or 10 hours after topical antacids such as sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide.

[0279] Efficacy subgroup analyses will be performed for subjects with PD-L1<1%, STK11 co-mutations and other coexisting mutations of interest. For the primary and final analyses, subgroups will be determined based on central data.

[0280] [Table 19]

[0281] Study population Inclusion criteria included the following: Untreated stage IV (per American Joint Committee on Cancer (AJCC) v8, see Amin et al., 2017) NSCLC. Subjects who have received adjuvant or neoadjuvant therapy are eligible if the adjuvant / neoadjuvant therapy was completed >12 months prior to the onset of metastatic disease. Pathologically documented metastatic NSCLC with KRAS p.G12C mutation identified via molecular testing, which must be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or equivalent. ●Age ≥ 18 years. A PD-L1 TPS score <1% as determined by pharm Dx DAKO 22C3 or Ventana SP263 IHC. If a subject does not have a PD-L1 TPS score <1%, then an STK11 loss-of-function mutation must be present as determined by NGS. Subjects with a PD-L1 TPS score <1% may also have an STK11 mutation present. ●Subjects must be willing to provide an archived tumor tissue sample (formalin-fixed, paraffin-embedded [FFPE] sample obtained within the last 5 years) or be willing to undergo a pre-treatment tumor biopsy. Measurable disease according to investigator interpretation using RECIST 1.1 criteria (Eisenhauer et al, 2009). Previously irradiated lesions are not considered measurable unless they have progressed after radiation. • Eastern Cooperative Oncology Group (ECOG, Oken et al., 1982) performance status of ≤1. Life expectancy >3 months as determined by the investigator. -Ability to take oral medications and willingness to document daily adherence to the study drug. Adequate hematological laboratory tests: ○Absolute neutrophil count (ANC) ≧1500 cells / μL Hemoglobin ≥ 9.0 g / dL ○Platelet count ≥75000 / μL. Adequate renal laboratory tests defined as follows: Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculations ≥ 30 ml / min / 1.73 m 2 Estimated glomerular filtration rate = 175 x serum creatinine -1.154 ×Age -0.203 × gender (for women, 0.742) × race (for blacks, 1.210). Adequate liver laboratory tests, including: Aspartate aminotransferase (AST) ≦2.5 × upper limit of normal (ULN) Alanine aminotransferase (ALT) ≦2.5×ULN Total bilirubin (TBL) ≦1.5×ULN for subjects with documented Gilbert's syndrome or <3.0×ULN for subjects with indirect bilirubin levels suggesting elevated extrahepatic sources. Adequate coagulation laboratory tests, including: Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 × ULN, or International normalized ratio (INR) < 1.5 x ULN or within target range if receiving prophylactic anticoagulation therapy • QTc ≦470 msec in women or ≦450 msec in men (based on average screening triplets).

[0282] Exclusion criteria included the following: Disease-related • Mixed small cell lung cancer and NSCLC histology. ● Subjects have been previously treated for metastatic NSCLC. Subjects receiving adjuvant or neoadjuvant therapy are eligible if the adjuvant / neoadjuvant therapy was completed >12 months prior to the onset of metastatic disease.

[0283] Other medical conditions No history or presence of malignancy unless treated with curative intent and no evidence of disease for ≥ 3 years with the following exceptions: Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease - Fully treated in situ cervical cancer with no evidence of disease Well-treated in situ ductal carcinoma with no evidence of disease Prostatic intraepithelial neoplasia without evidence of prostate cancer Sufficiently treated urothelial papillary non-invasive carcinoma or carcinoma in situ. Spinal cord compression, active brain metastases, and / or carcinomatous meningitis. Subjects who have had brain metastases resected or completed whole brain radiation therapy at least 4 weeks prior to Study Day 1 (or completed stereotactic radiosurgery at least 2 weeks prior) are eligible if the subject meets all of the following criteria: No remaining neurological symptoms No need for corticosteroids to control neurological symptoms Follow-up MRI performed within 30 days prior to enrollment shows no new or enlarging lesions No single lesion larger than 10 mm. ● Myocardial infarction, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina or cardiac arrhythmia requiring medical therapy within 6 months prior to Day 1 of the study. Gastrointestinal (GI) tract disease making oral medications impossible, malabsorption syndromes, need for intravenous (IV) nutritional support, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis). Evidence of hepatitis infection based on the following results and / or criteria: Positive hepatitis B surface antigen (HepBsAg) (indicating chronic hepatitis B or recent acute hepatitis B). o Negative HepBsAg that is positive for hepatitis B core antibody (Hepatitis B core antibody testing is not necessary for screening, but if it is done and positive, hepatitis B surface antibody [anti-HBs] testing is necessary. Undetectable anti-HBs in this situation suggests the possibility of uncertain infection, which needs to be ruled out). Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chain reaction (PCR) is required. Detectable Hepatitis C virus RNA will disqualify the subject. Positive Hepatitis B or C Viral Load: If the above antibody / antigen tests cannot be obtained, obtain a Hepatitis B or C viral load. Uncontrolled pleural, pericardial or ascites effusion requiring recurrent drainage procedures more frequently than monthly. Subjects with a PleurX catheter in place may be considered for the study only with approval of the Medical Monitor. • Known positive test for Human Immunodeficiency Virus (HIV). - History of or current interstitial pneumonia requiring steroids (non-infectious). • Active infection within 2 weeks of study day 1 requiring therapeutic oral or IV antibiotics. ●Major surgery within 28 days of study day 1. Unresolved toxicities attributable to prior antineoplastic therapy defined as not having resolved to the level indicated in the eligibility criteria, except for CTCAE version 5.0 grade 0 or 1, or alopecia (any grade accepted). Grade 2 or 3 toxicities attributable to prior antineoplastic therapy that are deemed irreversible (defined as present for >6 months and stable), such as ifosfamide-associated proteinuria or neuropathy, may be acceptable if they are not otherwise described in the exclusion criteria and agreement was obtained by both the investigator and sponsor.

[0284] Previous / Concurrent Therapies ●Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy or investigational drug) within 12 months. - Curative or palliative radiation therapy within 2 weeks of Study Day 1. Subjects must have recovered from all radiation therapy-related toxicities to Grade 1 or less. - Received radiation therapy to the lungs >30 Gy within 6 months of the first dose of study treatment. • Prior treatment with a covalent KRAS p.G12C inhibitor. Use of known cytochrome P450 (CYP) 3A4 sensitive substrates or P-gp substrates (with narrow therapeutic window) within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that have not been reviewed and approved by the investigator and medical monitor. Use of strong inducers of CYP3A4 (including herbal supplements such as Hypericum perforatum) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 that have not been reviewed and approved by the principal investigator and medical monitor. Use of a proton pump inhibitor (PPI) or histamine 2 (H2) receptor antagonist (H2RA) within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that has not been reviewed and approved by the investigator and medical monitor.

[0285] Previous / concurrent clinical trial experience Currently receiving treatment in another investigational device or drug study, or less than 28 days after completing treatment in another investigational device or drug study. Other investigational processes while participating in this study are excluded.

[0286] Other Exclusions ● Female subjects of childbearing potential who are not willing to use contraception methods specified in the protocol (see Section 11.5) during treatment and for an additional 7 days after the last dose of sotorasib. ●Women who are breastfeeding or plan to breastfeed up to 7 days after the last dose of sotorasib during the study. -Women who plan to become pregnant within 7 days of the last dose of sotorasib during the study. ● Female subjects of childbearing potential with a positive pregnancy test by high-sensitivity urine or serum pregnancy test at Screening or Day 1. - Male subjects with a female partner of childbearing potential who practice abstinence (abstaining from heterosexual intercourse) or are not willing to use contraception during treatment and for an additional 7 days after the last dose of sotorasib. - Male subjects with a pregnant partner who are not willing to practice abstinence or use condoms during treatment and an additional 7 days after the last dose of sotorasib. - Male subjects who are willing to abstain from donating sperm during treatment and for an additional 7 days after the last dose of sotorasib. - The subject has a known sensitivity to any of the products or ingredients that will be administered during the medication. • A subject who, to the best of the subject's and the investigator's knowledge, is unlikely to be able to complete all protocol-required study visits or procedures and / or will be unable to comply with all required study procedures (e.g., clinical outcome assessments). • Subjects who are unable to tolerate both iodized contrast agents for computed tomography (CT) scans and gadolinium contrast agents for MRI scans. History or evidence of any other clinically significant disorder, condition or disease (other than those outlined above) that the investigator or physician determines, if presented, would pose a risk to the subject's safety or interfere with the evaluations, procedures or completion of the study.

[0287] References American Association for Cancer Research(AACR)Project GENIE Consortium.AACR Project GENIE:Powering Precision Medicine through an International Consortium.Cancer Discov.2017;7(8):818-831. Amin MB, et al., AJCC Cancer Staging Manual, Eighth Edition. New York; Springer International Publishing; 2017. An J, Yan M, Yu N, et al.Outcomes of patients with stage III non-small cell lung cancer(NSCLC) that harbor a STK11 mutation.J Clin Oncol.2020;38(15 suppl):9033-9033. Barbacid M.Ras genes.Annual Rev Biochem.1987;56:779-827. Arbour KC,Jordan E,Kim HR,et al.Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer.Clin Cancer Res.2018;24(2):334-340. Atezolizumab Prescribing Information,revised April 2021(available at https: / / www.gene.com / download / pdf / tecentriq_prescribing.pdf,accessed May 2021). Biernacka A,Tsongalis PD,Peterson JD,et al.The potential utility of re-mining results of somatic mutation testing:KRAS status in lung adenocarcinoma.Cancer Genet.2016;209(5):195-198. Blumenthal,SW,Karuri SW,Zhan H,et al.Overall Response Rate,Progression-Free Survival,and Overall Survival With Targeted and Standard Therapies in Advanced Non-Small-Cell Lung Cancer:US Food and Drug Administration Trial-Level and Patient-Level Analyses.J Clin Oncol.2015;Mar 20;33(9):1008-1014. Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med.2015;373(17):1627-1639. Canon,J,Rex,K,Saiki,AY,et al.The clinical KRAS(G12C)inhibitor AMG 510 drives anti-tumour immunity.Nature.2019;575;217-223. Clarke J,Wang X,and Ready N.Surrogate clinical endpoints to predict overall survival in non-small cell lung cancer trials - are we in a new era? Transl Lung Cancer Res.2015;Dec;4(6):804-808. Cully M,Downward J.SnapShot:Ras Signaling.Cell.2008;133:1292. Davis AA,Patel VG.The role of PD-L1 expression as a predictive biomarker:an analysis of all US Food and Drug Administration(FDA)approvals of immune checkpoint inhibitors.J Immunother Cancer.2019;7(1):278. Eisenhauer EA,Therasse P,Bogaerts J,et al.New response evaluation criteria in solid tumours:revised RECIST guideline(version 1.1).Eur J Cancer.2009;45:228-247. Ettinger DS,Wood DE,Aggarwal C,et al.NCCN Guidelines Insights:Non-small Cell Lung Cancer,Version 1.2020.J Natl Compr Canc Netw.2019;17(12):1464-1472. Fernandez-Medarde A,Santos E.Ras in cancer and developmental diseases.Genes Cancer.2011;2(3):344-358. Fusco MJ,West H,Walko CM.Tumor Mutation Burden and Cancer Treatment.JAMA Oncol.2021;7(2):316. Gainor JF,Varghese AM,Ou SH,et al.ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS:an analysis of 1,683 patients with non-small cell lung cancer.Clin Cancer Res.2013;19(15):4273-4281. GLOBOCAN 2018 - Lung.Available at http: / / gco.iarc.fr / today / home.Accessed August 2019. Goeman F,De Nicola F,Scalera S,et al.Mutations in the KEAP1-NFE2L2 pathway define a molecular subset of rapidly progressing lung adenocarcinoma.J Thorac Oncol.2019;14(11):1924-1934. Gridelli C,Catalono PJ,Meropol NJ,et al.Safety and efficacy of bevacizumab plus standard-of-care treatment beyond disease progression in patients with advanced non-small cell lung cancer.The AvaALL randomized clinical trial.JAMA Onc.2018;4(12):e183486. Herbst RS,Baas P,Kin DW,et al.Pembrolizumab versus docetaxel for previously treated,PD-L1-positive,advanced non-small-cell lung cancer(KEYNOTE-010):a randomised controlled trial.Lancet.2016;387:1540-1550. Herbst RS,O’Neill,Fehrenbacher L,et al.Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung cancer.J Clin Oncol.2007;25(30):4743-4750. Hong DS,Fakih MG,Strickler JH,et al.KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors.N Engl J Med.2020;383:1207-1217. Jeong Y,Hellyer JA,Stehr H,et al.Role of KEAP1 / NFE2L2 mutations in the chemotherapeutic response of patients with non-small cell lung cancer.Clin Cancer Res.2020;26(1):274-281. Jones RP,Sutton PA,Evans JP,et al.Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer.Br J Cancer.2017;116(7):923-929. Martorell MP,Huerta M,Compan Quilis A,et al.Coexistence of EGFR,KRAS,BRAF,and PIK3CA Mutations and ALK Rearrangement in a Comprehensive Cohort of 326 Consecutive Spanish Nonsquamous NSCLC Patients.Clin Lung Cancer.2017;Nov;18(6):e395-e402. McCormick F.K-Ras protein as a drug target.J Mol Med(Berl).2016;94(3):253-258. McCormick F.Progress in targeting RAS with small molecule drugs.Biochem J.2019;476 365-374. Oken M,Creech R,Tormey D,et al.Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol.1982;5:649-655. Ostrem JM,Peters U,Sos ML,Wells JA,Shokat KM.K-Ras(G12C)inhibitors allosterically control GTP affinity and effector interactions.Nature.2013;503:548-551. Pavan A,Zulato E,Calvetti L,et al.Plasma next-generation sequencing(NGS)in advanced non-small cell lung cancer(aNSCLC)patients(pts)treated with immune checkpoint inhibitors(ICIs):impact of STK11 and TP53 mutations on outcome.J Clin Oncol.2020;38(15 suppl):3046-3046. Prembrolizumab Prescribing Information,revised November 2020,https: / / www.merck.com / product / usa / pi_circulars / k / keytruda / keytruda_pi.pdf;accessed January 2020. Planchard S,Popat K,Kerr S,et al.Metastatic non-small cell lung cancer:ESMO Clinical Practice Guidelines for diagnosis,treatment and follow-up.Ann Oncol.2018;29(Supplement 4):iv192-iv237. Prior IA,Lewis PD,Mattos C.A comprehensive survey of Ras mutations in cancer.Cancer Res.2012;72(10):2457-2467. Ricciuti B,Arbour KC,Lin JJ,et al.Effect of STK11 mutations on efficacy of PD-1 inhibition in non-small cell lung cancer(NSCLC)and dependence on KRAS mutation status.J Clin Oncol.2020;38(15 suppl):e15113-e15113. Rittmeyer A,Barlesi F,Waterkamp D,et al.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer(OAK):a phase 3,open-label,multicentre randomised controlled trial.Lancet.2017;380:255-265. Roman M,Baraibar I,Lopez I,et al.KRAS oncogene in non-small cell lung cancer:clinical perspectives on the treatment of an old target.Mol Cancer.2018;17(1):33. Scheffler M,Ihle MA,Hein R,et al.K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways.J Thorac Oncol.2019;14(4):606-616. Simanshu DK,Nissley DV,McCormick F.RAS proteins and their regulators in human disease.Cell.2017;170:17-33. Solis LM,Behrens C,Dong W,et al.Nrf2 and KEAP1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features.Clin Cancer Res.2010;16(14):3743-3753. Surveillance,Epidemiology,and End Results(SEER)Program(www.seer.cancer.gov)SEER*Stat Database:Incidence - SEER 21 Regs Limited-Field Research Data + Hurricane Katrina Impacted Louisiana Cases,Nov 2018 Sub(2000-2016)<Katrina / Rita Population Adjustment> - Linked To County Attributes - Total U.S.,1969-2017 Counties,National Cancer Institute,DCCPS,Surveillance Research Program,released April 2019,based on the November 2018 submission.Accessed 10 February 2020. Tamiya Y,Zenke Y,Matsumoto S,et al.Therapeutic impact of mutation subtypes and concomitant STK11 mutations in KRAS-mutated non-small cell lung cancer(NSCLC):A result of nationwide genomic screening project(LC-SCRUM-Japan).J Clin Oncol.2020;38(15_suppl):9589-9589. Tian Y,Wu K,Liu Q,et al.Modification of platinum sensitivity by KEAP1 / NRF2 signals in non-small cell lung cancer.J Hematol Oncol.2016;9(1):83. Uba R, Raez LE, Dumais K, et al.Serine / threonine kinase 11(STK11) mutations and immunotherapy resistance in patients with non-small cell lung cancer.J Clin Oncol.2020;38(15 suppl):e15055-e15055. Van Cutsem E, Cervantes A, B. Nordlinger B, Arnold D. ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.2014:25(Supplement 3):iii1-iii9. World Health Organization.2018 Statistics.Available at https: / / www.who.int / en / news-room / fact-sheets / detail / cancer.Accessed October 2020.

[0288] All references cited in this specification, e.g., scientific articles or published patent applications, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

1. 2. A compound of formula I: 【Chemistry 1】 or a pharma- ceutical composition comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof, the treatment comprising administering to the subject a total daily dose of 960 mg of the compound or a pharma- ceutically acceptable salt thereof; the non-small cell lung cancer comprises cells with a KRAS G12C mutation; The pharmaceutical composition, wherein the subject has not previously received systemic platinum-based chemotherapy.

2. 2. The pharmaceutical composition of claim 1, wherein the subject has a PD-L1 Tumor Percentage Score (TPS) in the range of greater than or equal to 0% and less than 1%.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the total daily dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day.

4. 3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is in a solid dosage form.

5. 3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is for oral administration.

6. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a tablet.

7. 2. A compound of formula I: 【Chemistry 2】 A pharmaceutical composition comprising a compound of said treatment comprising administering to said subject a total daily dose of 960 mg of the compound once daily; the non-small cell lung cancer comprises cells with a KRAS G12C mutation; The pharmaceutical composition, wherein the subject has not previously received systemic platinum-based chemotherapy.

8. 8. The pharmaceutical composition of claim 7, wherein the subject has a PD-L1 Tumor Percentage Score (TPS) in the range of greater than or equal to 0% and less than 1%.

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