Cancer treatment methods

Abstract

The present disclosure provides a method of treating cancer in a patient, comprising administering a therapeutically effective amount of sotorasib to the patient, wherein the patient has moderate or severe hepatic impairment prior to administration of sotorasib.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 418,695, filed October 24, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Sotorasib is a KRAS G12C Sotorasib is a small molecule that specifically and irreversibly inhibits the protein product of the mutant KRAS gene that encodes a protein with an amino acid substitution of glycine to cysteine ​​at position 12 (KRAS G12C). G12C It forms a specific covalent bond with mutant cysteines in KRAS, irreversibly locking the protein in an inactive conformation that impairs oncogenic signaling (Canon, 2019). KRAS inactivation has been demonstrated to inhibit cell proliferation and / or selectively promote apoptosis in tumor cells harboring KRAS mutations (Ostrem et al., 2016; Patricelli et al., 2016; Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017), and sotorasib may offer therapeutic benefit to patients with KRAS G12C-driven cancers. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Canon et al.,(2019)Nature,575:217-223 [Non-patent document 2] Ostrem et al.,(2013)Nature,503:548-55 [Non-patent document 3] Patricelli et al.,(2016)Cancer Discovery,6:316-329 [Non-patent document 4] Janes et al.,(2018)Cell,172(3):578-589 [Non-patent document 5] McDonald et al.,(2017)Cell,170(3):577-592 [Non-patent document 6] Xie et al.,(2017)Front Pharmacol.,8:823 Summary of the Invention [Means for solving the problem]

[0004] Described herein are methods for treating cancer in a patient, comprising administering a therapeutically effective amount of sotorasib to the patient, wherein the patient has moderate or severe liver dysfunction prior to administration of sotorasib. Provided herein are methods comprising administering sotorasib as a free base. In various embodiments, sotorasib is administered as a pharmaceutically acceptable salt. DETAILED DESCRIPTION OF THE INVENTION

[0005] The present disclosure is based on the discovery that patients with moderate or severe hepatic impairment can be treated with sotorasib without dose adjustment. References in this disclosure to "a patient" or "patient" are understood to refer to one or more subjects in need of treatment, for example, cancer treatment.

[0006] The U.S. Food and Drug Administration's ("FDA") guidance for industry related to pharmacokinetics in patients with hepatic impairment explains that "the liver is involved in the clearance of many drugs through various oxidative and conjugative metabolic pathways and / or biliary excretion of the unchanged drug or metabolites." See Guidance for the Industry, 2003, p. 2. FDA further notes that "alterations in these excretory and metabolic activities due to hepatic impairment can result in drug accumulation." Id. Numerous reports in the scientific literature indicate that liver disease can alter the absorption and distribution of drugs (pharmacokinetics ("PK")) as well as their efficacy and safety (pharmacodynamics ("PD")). Id. FDA explains that "clinically useful measures of liver function to predict a drug's PK and PD are not generally available, but clinical studies in patients with hepatic impairment, typically conducted during drug development, can provide information that can guide initial dosing in patients." Id. The FDA recommends "PK studies in patients with hepatic impairment when hepatic metabolism and / or excretion account for a significant portion (>20% of absorbed drug) of the elimination of the parent drug or active metabolites." Id., p. 3.

[0007] Sotoracive Sotorasib is a KRAS G12C Sotorasib is a small molecule that irreversibly inhibits mutant proteins. Sotorasib, also known as AMG 510 or 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, has the following structure (Formula I): [ka]

[0008] Sotorasib binds to the P2 pocket of KRAS adjacent to the mutant cysteine ​​at position 12, as well as to the nucleotide-binding pocket. This inhibitor covalently modifies the cysteine ​​residue and binds KRAS in the inactive guanosine diphosphate (GDP)-bound conformation. G12C It contains a thiol-reactive moiety that blocks the interaction of KRAS with effectors such as rapidly progressing fibrosarcoma (RAF), thereby preventing downstream signaling, such as extracellular signal-regulated kinase (ERK) phosphorylation (Cully and Downward, 2008; Ostrem et al., 2013; Simanshu et al., 2017). Inactivation of KRAS by RNA interference (RNAi) or small molecule inhibition has previously been demonstrated to inhibit cell proliferation and induce apoptosis in tumor cell lines and xenografts harboring KRAS mutations, including the KRAS G12C mutation (Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patrice et al., 2016). Studies with sotorasib have confirmed these in vitro findings and similarly demonstrated growth inhibition and regression of cells and tumors harboring the KRAS G12C mutation (Canon et al., 2019). See also LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (Amendment 5 / 2021), which is incorporated herein by reference in its entirety. In various embodiments, the methods disclosed herein comprise administering 960 mg of sotorasib to a patient once daily. In various embodiments, the methods disclosed herein comprise administering 480 mg of sotorasib to a patient once daily. In various embodiments, the methods disclosed herein comprise administering 240 mg of sotorasib to a patient once daily.

[0009] Methods are provided herein that include administering sotorasib as a free base. In various embodiments, sotorasib is administered as a pharmaceutically acceptable salt. For clarity, the term "sotorasib," as used herein, refers to sotorasib free base. Any method described herein that references sotorasib can also be practiced using a pharmaceutically acceptable salt of sotorasib. In some embodiments, sotorasib can be administered as a hydrochloride, phosphate, or mesylate salt. In some embodiments, sotorasib can be administered as a hydrochloride salt. In some embodiments, sotorasib can be administered as a phosphate salt. In some embodiments, sotorasib can be administered as a mesylate salt. For clarity, if the methods provided herein describe, for example, administering 240 mg of sotorasib or a pharmaceutically acceptable salt thereof to a subject, the method calls for administration of 240 mg of sotorasib free base or an amount of a pharmaceutically acceptable salt corresponding to 240 mg of sotorasib free base.

[0010] The term "pharmaceutically acceptable" refers to species or components that are generally safe, non-toxic, and not biologically or otherwise undesirable for use in subjects such as humans.

[0011] The term "pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g., 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). Pharmaceutically acceptable salts also include salts formed, for example, when an acidic proton present in the parent compound is replaced with a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine). Additionally, salts of the compounds described herein can exist in hydrated or anhydrous form or as solvates with other solvent molecules.

[0012] Sotorasib is eliminated primarily via the fecal route and is metabolized primarily by the hepatic enzyme CYP3A (LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (rev. 5 / 2021)), with CYP3A4 being the primary metabolic enzyme. Thus, patients with moderate or severe hepatic impairment may experience, e.g., increased exposure ("AUC") or Cmax, compared to patients without hepatic impairment, such that a particular dose of sotorasib in patients with moderate or severe hepatic impairment requires a reduction in said dose to maintain an acceptable PK / PD profile. maxIt would be expected that the PK profile would show changes that would indicate an increase in CYP3A4, or both. Previous studies on drug-drug interactions between sotorasib and a CYP3A4 inhibitor (e.g., itraconazole) and sotorasib and rifampin (a CYP3A4 inducer) support this expectation (see, e.g., Examples 1 and 2 below). However, it was surprisingly discovered that subjects with moderate or severe hepatic impairment exhibited PK and safety profiles that were clinically sufficiently similar to those of healthy subjects (Example 3). Thus, the data presented in this disclosure unexpectedly demonstrate that dose adjustment is not necessary for patients with moderate or severe hepatic impairment.

[0013] Liver dysfunction Patients suffering from liver dysfunction include, for example, patients diagnosed with clinically impaired liver function due to hepatic encephalopathy, hepatitis or cirrhosis.As used herein, patient is diagnosed using Child-Pugh score.Although there are other methods for measuring liver dysfunction (for example, model of end-stage liver disease (MELD) score, Conn score), Child-Pugh score is used herein to evaluate liver dysfunction.

[0014] The Child-Pugh score (also known as the Child-Turcotte-Pugh score) is used to assess the prognosis of chronic liver disease, primarily cirrhosis. It is a composite score of five clinical measures: bilirubin, serum albumin, international normalized ratio (INR), ascites, and hepatic encephalopathy. Each marker is assigned a value of 1 to 3, and the total score is used to provide a score classified as Grade A (5 to 6 points), Grade B (7 to 9 points), or Grade C (10 to 15 points), which can be correlated with 1- and 2-year survival rates. If a patient is determined to have Grade A on the Child-Pugh scoring scale, they are considered to have healthy / normal liver function. If a patient is determined to have Grade B on the Child-Pugh scoring scale, they are considered to have "moderate" liver dysfunction. If a patient is determined to have Grade C on the Child-Pugh scoring scale, they are considered to have "severe" liver dysfunction. Methods for determining and analyzing Child-Pugh scores are well known in the art (Figg et al., 1995).

[0015] Described herein are methods for treating cancer in a patient, comprising administering a therapeutically effective amount of sotorasib to the patient, wherein the patient has moderate or severe liver dysfunction prior to administration of sotorasib. Provided herein are methods comprising administering sotorasib as a free base. In various embodiments, sotorasib is administered as a pharmaceutically acceptable salt.

[0016] As used herein, the term "therapeutically effective amount" refers to an amount of a compound disclosed herein that elicits a desired biological or medical response in a cell, tissue, system, or subject.

[0017] In some embodiments, the method comprises administering a therapeutically effective amount of sotorasib to a patient with moderate hepatic impairment (i.e., Child-Pugh grade B) prior to administration of sotorasib. In some embodiments, the method comprises administering sotorasib once daily to a patient with moderate hepatic impairment in an amount ranging from 240 mg to 960 mg. In some embodiments, the method comprises administering 960 mg of sotorasib once daily to a patient with moderate hepatic impairment. In some embodiments, the method comprises administering 480 mg of sotorasib once daily to a patient with moderate hepatic impairment. In some embodiments, the method comprises administering 240 mg of sotorasib once daily to a patient with moderate hepatic impairment.

[0018] In some embodiments, the method comprises administering a therapeutically effective amount of sotorasib to a patient with severe hepatic impairment (i.e., Child-Pugh grade C) prior to administration of sotorasib. In some embodiments, the method comprises administering sotorasib once daily to a patient with severe hepatic impairment in an amount ranging from 240 mg to 960 mg. In some embodiments, the method comprises administering 960 mg of sotorasib once daily to a patient with severe hepatic impairment. In some embodiments, the method comprises administering 480 mg of sotorasib once daily to a patient with severe hepatic impairment. In some embodiments, the method comprises administering 240 mg of sotorasib once daily to a patient with severe hepatic impairment.

[0019] Determining KRAS G12C mutation in cancer The patient treated with the methods disclosed herein is a patient suffering from a cancer harboring a KRAS G12C mutation. In various embodiments, the patient has a cancer determined to have one or more cells expressing a KRAS G12C mutant protein prior to the administration methods disclosed herein. The presence or absence of a G12C mutation in the cancers described herein can be determined using methods known in the art. Determining whether a tumor or cancer contains a mutation can be performed, for example, by evaluating the nucleotide sequence encoding the protein, by evaluating the amino acid sequence of the protein, by evaluating the characteristics of the putative mutant protein, or by any other suitable method known in the art. The nucleotide and amino acid sequences of wild-type human KRAS (nucleotide sequence set forth in GenBank Accession No. BC010502; amino acid sequence set forth in GenBank Accession No. AGC09594) are known in the art.

[0020] Methods for detecting mutations include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing and / or next-generation sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for mutations, such as the KRAS G12C mutation, by real-time PCR. Real-time PCR uses a fluorescent probe specific to a particular mutation, such as the KRAS G12C mutation. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, mutations are identified using direct sequencing of specific regions in a gene. This technique identifies all possible mutations in the sequenced region. In some embodiments, the presence or absence of insertion mutations may be detected using gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and / or arrays. In some embodiments, methods include, but are not limited to, detection of mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0021] In some embodiments, multiplex PCR-based sequencing is used for mutation detection and may include several amplicons to provide improved sensitivity for detection of one or more genetic biomarkers. For example, the multiplex PCR-based sequencing may include about 60 amplicons (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 amplicons). In some embodiments, the multiplex PCR-based sequencing may include 61 amplicons. Amplicons generated using multiplex PCR-based sequencing may range from about 15 bp to about 1000 bp (e.g., about 25 bp to about 1000 bp, about 35 bp to about 1000 bp, about 50 bp to about 1000 bp, about 100 bp to about 1000 bp, about 250 bp to about 1000 bp, about 500 bp to about 1000 bp, about 750 bp to about 1000 bp, about 15 bp to about 750 bp, about 15 For example, an amplicon generated using multiplex PCR-based sequencing may contain a nucleic acid having a length of about 33 bp.

[0022] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using a sequencing technique (e.g., a next-generation sequencing technique). Various sequencing techniques are known in the art. For example, methods for detecting and characterizing circulating tumor DNA in cell-free DNA can be described elsewhere (see, e.g., Haber and Velculescu, 2014). Non-limiting examples of such techniques include SafeSeqs (see, e.g., Kinde et al., 2011), OnTarget (see, e.g., Forshew et al., 2012), and TamSeq (see, e.g., Thompson et al., 2012).

[0023] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using droplet digital PCR (ddPCR), a method known to be highly sensitive for detecting mutations. In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using other sequencing techniques, including, but not limited to, chain termination techniques, shotgun techniques, sequencing-by-synthesis methods, microfluidic techniques, other capture techniques, or other sequencing techniques known in the art to be useful for detecting small amounts of DNA in a sample (e.g., ctDNA in cell-free DNA samples).

[0024] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using an array-based method. For example, the step of detecting genetic alterations (e.g., one or more genetic alterations) in cell-free DNA is performed using a DNA microarray. In some embodiments, the DNA microarray can detect one or more of multiple cancer cell mutations. In some embodiments, the cell-free DNA is amplified before detecting genetic alterations. Non-limiting examples of array-based methods that can be used in any of the methods described herein include complementary DNA (cDNA) microarrays (see, e.g., Kumar et al. 2012; Laere et al. 2009; Mackay et al. 2003; DeRisi et al. 1996), oligonucleotide microarrays (see, e.g., Kim et al. 2006; Lodes et al. 2009), bacterial artificial chromosome (BAC) clone chips (see, e.g., Chung et al. 2004; Thomas et al. 2005), single nucleotide polymorphism (SNP) microarrays (see, e.g., Mao et al. 2007; Jasmine et al. 2012), microarray-based comparative genomic hybridization arrays (array-CGH) (see, e.g., Beers and Nederlof, 2006; Pinkel et al. 2005; Michels et al. 2012). al. 2007), and molecular inversion probe (MIP) assays (see, e.g., Wang et al. 2012; Lin et al. 2010). In some embodiments, the cDNA microarray is an Affymetrix microarray (see, e.g., Irizarry 2003; Dalma-Weiszhausz et al. 2006), a NimbleGen microarray (see, e.g., Wei et al. 2008; Albert et al. 2007), an Agilent microarray (see, e.g., Hughes et al. 2001), or a BeadArray array (see, e.g., Liu et al. 2017).In some embodiments, the oligonucleotide microarray is a DNA tiling array (see, e.g., Mockler and Ecker, 2005; Bertone et al. 2006). Other suitable array-based methods are known in the art.

[0025] Methods for determining whether a tumor or cancer contains a mutation may use a variety of samples. In some embodiments, the sample is obtained from a patient with a tumor or cancer. In some embodiments, the sample is a fresh tumor or cancer sample. In some embodiments, the sample is a frozen tumor or 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 has been processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In certain embodiments, the sample is obtained by excision, core needle biopsy (CNB), fine needle aspiration (FNA), urine collection, or hair follicle collection. In some embodiments, liquid biopsy tests using whole blood or cerebrospinal fluid may be used to assess mutation status.

[0026] In various embodiments, a test approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA), is used to determine whether a patient has a mutation (e.g., a KRAS G12C mutant cancer) or whether a tumor or tissue sample obtained from such a patient contains cells with the mutation. In some embodiments, the test for KRAS mutation used is the Therascreen® KRAS RGQ PCR Kit (Qiagen). The Therascreen® KRAS RGQ PCR Kit is a real-time qualitative 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. This kit is intended for use with DNA extracted from FFPE samples of NSCLC samples obtained by resection, CNB, or FNA. Mutation testing for STK11, KEAP1, EGFR, ALK, and / or ROS1 can be performed using commercially available tests such as the Resolution Bioscience Resolution ctDx Lung™ assay, which includes 24 genes (including those capable of functioning in NSCLC). Tissue samples can be tested using the Tempus xT 648 panel.

[0027] KRAS G12C mutant cancer The methods described herein include treating cancers with a KRAS G12C mutation in patients. Without wishing to be bound by any particular theory, it is noted that sotorasib inhibits the KRAS G12C mutation. G12CSotorasib is a small molecule that specifically and irreversibly inhibits KRAS (Hong et al., 2020). Hong et al. report that “[p]re-clinical studies demonstrated that sotorasib inhibited nearly all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, and led to durable complete tumor regression in mice bearing KRAS p.G12C tumors” (ibid.; see also Canon et al., 2019, and Lanman et al., 2020).

[0028] Sotorasib was evaluated in a Phase 1 dose-escalation and expansion study in 129 patients with locally advanced or metastatic cancer harboring histologically confirmed KRAS G12C mutations identified by local molecular testing of tumor tissue, including 59 patients with non-small cell lung cancer, 42 patients with colorectal cancer, and 28 subjects with other tumor types (Hong et al., 2020, pp. 1208-1209). Hong et al. reported disease control rates (95% CI) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer, and 75.0% for other tumor types (Hong et al., 2020, p. 1213, Table 3). The cancer types reported by Hong et al. showing either stable disease (SD) or partial response (PR) were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, cholangiocarcinoma, or melanoma (Hong et al., 2020, p. 1212 (Figure A), and appendix (p. 59 (Figure S5) and p. 63 (Figure S6))).

[0029] The KRAS G12C mutation occurs at the alteration frequencies shown in Table 1 below (Cerami et al., 2012; Gao et al., 2013). For example, Table 1 shows that 11.6% of patients with non-small cell lung cancer have cancer in which one or more cells have the KRAS G12C Therefore, KRAS G12CSotorasib, which specifically and irreversibly binds to, is useful for treating patients with cancers, including but not limited to those listed in Table 1 below.

[0030] [Table 1]

[0031] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary carcinoma, gastric cancer, paranasal sinus cancer, or bile duct cancer. In some embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, pancreatic cancer, melanoma, ampullary carcinoma, gastric cancer, paranasal sinus cancer, or bile duct cancer. In various embodiments, the cancer is non-small cell lung cancer, and in some specific embodiments, metastatic or locally advanced non-small cell lung cancer. In various embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In one embodiment, any of the above-identified cancers is a KRAS G12C mutant cancer.

[0032] Embodiment 1. A method of treating cancer in a patient, comprising administering a therapeutically effective amount of sotorasib to the patient, wherein the patient has moderate or severe hepatic impairment prior to administration of sotorasib. 2. The method of embodiment 1, wherein the patient has moderate hepatic impairment prior to administration of sotorasib. 3. The method of embodiment 1, wherein the patient has severe hepatic impairment prior to administration of sotorasib. The method of embodiment 1 or embodiment 2, comprising administering 4.960 mg of sotorasib to the patient once daily. 5. The method of embodiment 1, comprising administering 240 mg of sotorasib to the patient once daily. 6. The method of any one of embodiments 1 to 5, wherein the patient has a cancer comprising a KRAS G12C mutation. 7. The method of embodiment 6, wherein the cancer is a solid tumor. 8. The method of embodiment 6 or 7, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary site, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary carcinoma, gastric cancer, sinus cancer, or bile duct cancer. 9. The method of any one of embodiments 6 to 8, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinus cancer, or bile duct cancer. 10. The method of any one of embodiments 6 to 9, wherein the cancer is non-small cell lung cancer. 11. The method of embodiment 10, wherein the non-small cell lung cancer is locally advanced or metastatic. 12. The method of any one of embodiments 6 to 9, wherein the cancer is colorectal cancer. 13. The method of any one of embodiments 6-9, wherein the cancer is pancreatic cancer.

[0033] Alternative Embodiments 1. A method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of sotorasib, wherein the patient has moderate or severe hepatic impairment prior to administration of sotorasib, and the sotorasib is a compound represented by formula (I): [ka] The method is a compound of 2. The method of alternative embodiment 1, wherein the patient had moderate hepatic impairment prior to administration of sotorasib. 3. The method of alternative embodiment 1, wherein the patient had severe hepatic impairment prior to administration of sotorasib. 4. The method of Alternative Embodiment 1 or Alternative Embodiment 2, wherein the method further comprises determining whether the patient has moderate hepatic impairment. 5. The method of Alternative Embodiment 1 or Alternative Embodiment 3, wherein the method further comprises determining whether the patient has severe liver dysfunction. 6. The method of any one of alternative embodiments 1-5, wherein the therapeutically effective amount of sotorasib is 240 mg to 960 mg per day. 7. The method of any one of alternative embodiments 1-6, wherein the therapeutically effective amount of sotorasib is 240 mg of sotorasib daily. 8. The method of any one of alternative embodiments 1-6, wherein the therapeutically effective amount of sotorasib is 480 mg daily. 9. The method of any one of alternative embodiments 1-6, wherein the therapeutically effective amount of sotorasib is 960 mg daily. 10. The method of any one of alternative embodiments 1-9, wherein the patient has a cancer comprising a KRAS G12C mutation. 11. The method of alternative embodiment 10, wherein the method further comprises determining whether the patient has a cancer that contains a KRAS G12C mutation. 12. The method of any one of alternative embodiments 1-11, wherein the cancer is a solid tumor. 13. The method of any one of alternative embodiments 1-11, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary site, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary carcinoma, gastric cancer, sinus cancer, or bile duct cancer. 14. The method of any one of alternative embodiments 1-11, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinus cancer, or bile duct cancer. 15. The method of any one of alternative embodiments 1-11, wherein the cancer is non-small cell lung cancer. 16. The method of alternative embodiment 15, wherein the non-small cell lung cancer is locally advanced or metastatic. 17. The method of any one of alternative embodiments 1-11, wherein the cancer is colorectal cancer. 18. The method of any one of alternative embodiments 1-11, wherein the cancer is pancreatic cancer. 19. The method of any one of alternative embodiments 1-18, wherein sotorasib is administered as one or more tablets. 20. The method of any one of alternative embodiments 1-19, wherein sotorasib is administered orally. 21. The method of any one of alternative embodiments 1-20, wherein sotorasib is administered once daily. [Example]

[0034] Example 1 - An Open-Label Study to Evaluate the Drug-Drug Interaction Effect of Itraconazole, a CYP3A4 Inhibitor, on the Pharmacokinetics of Sotorasib in Healthy Subjects the purpose This was a phase 1, single-center, open-label, fixed-sequence study to investigate the effect of coadministration of itraconazole (a CYP3A4 and P-gp inhibitor) on the PK of sotorasib in healthy men and women of non-childbearing potential. Subjects received a single dose of sotorasib on day 1 and QD doses of itraconazole on days 3-7 (with a second [loading] dose of itraconazole on day 3). On day 6, a single dose of sotorasib was coadministered with itraconazole. Blood was collected at predetermined time points to characterize plasma concentrations of sotorasib and itraconazole. Safety and tolerability monitoring was performed throughout the study.

[0035] A total of 14 healthy subjects (2 women and 12 men) enrolled and completed the study. Nine of the 14 subjects were Caucasian and five were Black or African American. The mean (SD) age was 44.2 (12.55) years. Pharmacokinetic (PK) data for single-dose sotorasib were obtained from 14 subjects who received sotorasib alone and sotorasib coadministered with itraconazole after 4 days of multiple daily doses of itraconazole. Sotorasib alone and sotorasib with itraconazole treatment periods showed significant differences in sotorasib t max The AUC of sotorasib were 0.51 and 1.00 hours, respectively. inf and C maxThe geometric least squares mean ratios (test / reference) were 1.261 and 1.040 when comparing sotorasib co-administered with itraconazole (test) with sotorasib administered alone (reference), respectively (Table 2).

[0036] [Table 2]

[0037] Example 2 - An Open-Label Study to Evaluate the Drug-Drug Interaction Effect of Rifampin, a CYP3A4 Inducer, on the Pharmacokinetics of AMG 510 in Healthy Subjects This was a phase 1, single-center, open-label, fixed-sequence study to investigate the effect of coadministration of rifampin on the PK of sotorasib in healthy men and women. Subjects received a single dose of sotorasib on day 1, single doses of rifampin (a potent OATP1B1 / 1B3 inhibitor) and sotorasib on day 3, and QD doses of rifampin (a potent CYP3A4 inducer) on days 5-17 and 19. On day 18, a single dose of sotorasib was coadministered with rifampin. Blood was collected at predetermined time points to characterize sotorasib plasma concentrations. Safety and tolerability monitoring was performed throughout the study.

[0038] A total of 14 healthy subjects (1 female and 13 males) enrolled and completed the study. Of the 14 subjects, 3 were Caucasian, 10 were Black or African American, and 1 was Asian. The mean (SD) age was 35.2 (8.80) years.

[0039] Single-dose plasma sotorasib PK data were obtained from 14 subjects who received sotorasib alone (Day 1), sotorasib co-administered with a single dose of rifampin (Day 3), and sotorasib co-administered with rifampin after 14 days of multiple daily doses of rifampin (Day 18). Median t max AUC and C were similar across all treatment periods. maxThe geometric mean exposure of sotorasib based on the AUC was low after coadministration with rifampin on days 3 and 18. inf and C max The geometric least squares mean ratios (test / reference) for sotorasib co-administered with a single dose of rifampin (test) compared with sotorasib administered alone (reference) were 0.766 and 0.840, respectively (Table 3). inf and C max The geometric least squares mean ratios (test / reference) for sotorasib co-administered with multiple daily doses of rifampin (test) compared with sotorasib administered alone (reference) were 0.487 and 0.647, respectively.

[0040] [Table 3]

[0041] Example 3 - An open-label, single-dose study evaluating the pharmacokinetics of sotorasib in subjects with moderate or severe hepatic impairment compared to healthy subjects This example describes an open-label, single-dose study of sotorasib conducted in healthy subjects and subjects with moderate or severe hepatic impairment (see inclusion / exclusion criteria):

[0042] the purpose: The primary objective of the study was to evaluate the pharmacokinetics (PK) of a single oral dose of sotorasib administered to subjects with moderate or severe hepatic impairment compared with subjects with normal hepatic function. A secondary objective of the study was to evaluate the safety and tolerability of sotorasib administered to subjects with moderate or severe hepatic impairment compared with subjects with normal hepatic function.

[0043] Study design: This was a Phase 1, parallel-arm, multicenter (US), open-label, non-randomized study to evaluate the PK of a single oral dose of sotorasib administered to subjects with normal hepatic function (controls) and subjects with moderate or severe hepatic impairment (according to the Child-Pugh classification) in the fasted state. On Day 1 after at least 10 hours of fasting, all subjects received a single oral dose of 960 mg sotorasib (8 x 120 mg tablets).

[0044] Subjects who met the eligibility requirements were assigned to one of three groups: Group 1 - normal function (no impairment, n = 6-12); Group 2 - moderate impairment (Child-Pugh class B, n = 6-8); Group 3 - severe impairment (Child-Pugh class C, n = 6-8). Classification was based on the Child-Pugh score according to Figg et al. (1995).

[0045] Child-Pugh classification of cirrhosis severity (Table 4)

[0046] [Table 4]

[0047] Inclusion Criteria: Subjects were required to meet all of the following criteria prior to enrollment, unless otherwise stated:

[0048] All targets Male or female subjects aged 18 to 70 years (inclusive) at the time of screening. Body mass index at screening: 18.0 to 38.0 kg / m 2 (inclusive). Women of non-childbearing potential, defined as permanent infertility (i.e., due to hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal (defined as 12 months of amenorrhea without an alternative medical cause and a follicle-stimulating hormone [FSH] level ≥ 40 mIU / mL, and at least 45 years of age).

[0049] Subjects with normal liver function only (Group 1) Be in good health as determined by clinically significant findings from medical history, physical examination, 12-lead electrocardiogram (ECG), vital sign measurements, and clinical laboratory evaluation (congenital nonhemolytic hyperbilirubinemia [e.g., suspected Gilbert syndrome based on total and direct bilirubin] is not permitted) as assessed by the investigator.

[0050] Subjects with only hepatic dysfunction (Groups 2 and 3) Child-Pugh B (Group 2) or C (Group 3) classification defined by both screening and check-in laboratory values ​​and clinical laboratory findings (see Table 4). Clinically stable liver disease in the opinion of the investigator (e.g., not including rapidly progressive primary or secondary hepatic malignancies). Documented history of chronic liver disease, including but not limited to cirrhosis, hepatitis B infection, alcoholic liver disease, or previous hepatitis C virus (HCV) infection (HCV RNA was undetectable in all subjects enrolled at screening), as assessed by the investigator (or designee). Subjects with moderate or severe hepatic impairment may have medical findings consistent with such impairment as determined by medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations at screening and check-in. Subjects with abnormal findings that are not deemed clinically significant by the investigator will be eligible.

[0051] Exclusion criteria: Subjects were excluded from the study if they met any one of the following criteria prior to enrollment, unless otherwise stated:

[0052] All targets Hospitalization within 21 days prior to check-in, major surgery within 6 months prior to check-in, or any unstable medical condition defined as unstable in the judgment of the investigator and / or medical monitor (e.g., risk of complications or adverse events unrelated to study participation). History or evidence of a clinically significant disorder, condition, or disease at screening or check-in that, in the opinion of the investigator (or designee), poses a risk to the subject's safety or interferes with any evaluation, procedure, or completion of the study Venous thromboembolism in the past 6 months. History of any type of malignancy except: intraepithelial cervical carcinoma or surgically resected non-melanoma skin cancer more than 5 years prior to receiving sotorasib. History or evidence of clinically significant arrhythmia at screening (including clinically significant findings on ECG taken at check-in). PR interval >200 msec at screening or check-in, 2 nd 3rd degree atrioventricular (AV) block or rd Degree AV block. History of a medical condition suggestive of esophageal (including esophageal spasm, esophagitis), gastric, or duodenal ulcer or intestinal disease (including, but not limited to, peptic ulcer, gastrointestinal bleeding, ulcerative colitis, Crohn's disease, or irritable bowel syndrome); or history of uncomplicated appendectomy, cholecystectomy, and hernia repair. Inability to swallow oral medications or history of malabsorption syndrome. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance unless approved by the investigator (or designee) and discussed with the sponsor. Poor peripheral venous access. At screening or check-in, 45 mL / min / 1.73 m as calculated by the Dietary Therapy in Renal Disease (MDRD) formula 2 Less than an estimated glomerular filtration rate (eGFR). Positive human immunodeficiency virus test at screening. Use of over-the-counter or prescription medications within 30 days or 5 half-lives (whichever is longer) prior to enrollment, except for the following: - Ibuprofen and hormone replacement therapy (e.g., estrogen, thyroid, etc.) are permitted. - Treatment for liver disease and related disorders that has been stable for at least 30 days prior to study drug administration and is deemed acceptable by the investigator (or designee) and sponsor to be administered concomitantly with sotorasib during the study. Administration of an approved (licensed) coronavirus disease 2019 (COVID-19) vaccine within the past 28 days prior to administration, or administration of a COVID-19 vaccine that has received Emergency Use Authorization (US) within the past 30 days prior to administration. All herbal medicines (e.g., St. John's wort), vitamins, and supplements consumed by the subject within 30 days prior to enrollment, unless deemed acceptable by the investigator (or designee) and in discussion with the sponsor. Consumption of food and beverages containing poppy seeds, grapefruit, or Seville oranges within seven days prior to check-in. Use of known CYP3A4 and P-gp sensitive substrates (narrow therapeutic window) within 30 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 (or designee) and sponsor. Use of strong inducers of CYP3A4 (including herbal supplements such as St. John's wort) within 30 days or 5 half-lives (whichever is longer) prior to study day 1. Use of PPIs within 5 days or H2 receptor antagonists within 1 day prior to study day 1. History of alcoholism or drug / chemical abuse within the past three months prior to check-in. Alcohol consumption within 48 hours prior to check-in. Regular alcohol consumption of more than 14 units per week for men and more than 7 units per week for women. One unit of alcohol is equivalent to 12 ounces (360 mL) of beer, 1 1 / 2 ounces (45 mL) of liquor, or 5 ounces (150 mL) of wine. Use of tobacco or nicotine-containing products within 3 months prior to check-in. Testing positive for illegal drugs, cotinine (tobacco or nicotine use), and / or alcohol use at screening or check-in. Consume caffeinated foods and beverages within 48 hours prior to check-in. Female subjects with a positive pregnancy test at screening or check-in. Male subjects with a female partner of childbearing potential who practice abstinence (abstaining from heterosexual intercourse) or who are unwilling to use contraception for 7 days after sotorasib administration. Unwilling to abstain from sperm or egg donation for 7 days after sotorasib administration. Male subjects who have a female partner of childbearing potential and do not want their partner to know about their participation in this clinical trial. Male subjects with a pregnant partner or a partner planning pregnancy who are unwilling to practice abstinence or use condoms for 7 days after administration of sotorasib. Subjects have received an investigational drug (new chemical entity) within the past 30 days or 5 half-lives (whichever is longer) prior to check-in. Have previously completed or discontinued this or any other study investigating sotorasib, or have previously received an investigational drug. Donate blood within three months prior to check-in, plasma within two weeks prior to check-in, or platelets within six weeks prior to check-in. Receiving blood products within 2 months prior to check-in. Unwillingness to adhere to exam restrictions. A subject who, in the opinion of the Investigator (or designee), should not participate in this study.

[0053] Subjects with normal liver function only (Group 1) Positive Hepatitis B or C panel at screening. Subjects with results compatible with prior immunization (vaccination or prior infection) can be included. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN) at screening or check-in. Total bilirubin level >ULN at screening or check-in. A heart rate corrected QT (QTcF) interval based on Fridericia correction of greater than 450 msec for male subjects or greater than 470 msec for female subjects at screening or check-in, confirmed by calculating the mean of the original value and two replicates, or history / evidence of long QT syndrome.

[0054] Subjects with only hepatic dysfunction (Groups 2 and 3) Liver function test values ​​outside the normal range that are inconsistent with liver status as determined by the investigator (or designee). A QTcF interval of >470 msec for male subjects or >480 msec for female subjects at screening or check-in, confirmed by calculating the mean of the original value and two replicates. Use of new medications or changes in dosage for the treatment or worsening of hepatic encephalopathy within 30 days prior to check-in. Recent history of or treatment for gastrointestinal bleeding (within the past 6 months). Presence of portosystemic shunt. Recent history of paracentesis within 30 days prior to check-in. Currently receiving a functioning organ transplant or waiting for an organ transplant Evidence of severe ascites. History or current symptoms of grade 2 or greater hepatic encephalopathy within 60 days prior to the screening visit.

[0055] Combination therapy: Unless previously agreed by the investigator (or designee) or sponsor, subjects will refrain from use of any prescription or non-prescription drugs or products during the study until EOS.

[0056] Subjects refrain from use of any PPI within 5 days or H2 receptor antagonists within 1 day prior to study day 1 until at least 4 hours after IMP administration.

[0057] For patients with hepatic impairment, treatment of underlying liver disease and comorbid conditions (including prescribed analgesics) is permitted if prescribed by the subject's personal physician and approved by the medical monitor and investigator in consultation with the sponsor, as appropriate. Medication should be withheld for at least 4 hours after study drug administration, unless necessary, at the investigator's discretion, to treat an adverse event. Throughout the study, the investigator may prescribe any concomitant medications or treatments deemed necessary to provide appropriate supportive care, except for those listed in the exclusion criteria.

[0058] Foods and drugs that are known strong CYP3A4 inducers (e.g., rifampin, corticosteroids, anticonvulsants, and St. John's wort) or CYP3A4 or P-gp substrates with narrow therapeutic indices, as specified in the exclusion criteria above, are prohibited during and until the end of the study prior to IMP administration.

[0059] Ibuprofen and hormone replacement therapy are acceptable concomitant medications. Administration of any other concomitant medications during this study is prohibited without the prior approval of the investigator (or designee), unless their use is deemed necessary for the treatment of an adverse event. Any medications taken by subjects during the course of the study, and the reason for their use, will be recorded in the source data.

[0060] Pharmacokinetic analysis: Plasma PK parameters of sotorasib will be calculated using standard non-compartmental methods.

[0061] The primary PK parameter was C max , AUC last , and AUC inf Other PK parameters of sotorasib were not subjected to inferential statistical analysis and max time, apparent terminal plasma elimination half-life (t 1 / 2,z ), apparent total plasma clearance (CL / F), apparent volume of distribution during the terminal elimination phase (V z / F), uncombined fraction (f u ), Cmax,u , AUC last,u , AUC inf,u , C.L. u / F, and V z,u / F. Log-transformed primary PK parameters are analyzed using a linear model. Data from subjects with impaired hepatic function (Groups 2 and 3; Study) and control subjects (normal hepatic function [Group 1]; Reference) are included in the analysis. max The geometric mean ratios (test / reference) of the serotonin and AUC values ​​and associated 90% confidence intervals will be estimated.

[0062] Additional parameters may be calculated and analyzed for sotorasib metabolites. Metabolite PK parameters, if calculated, will not be subject to inferential statistical analysis. Specific details are provided in the statistical analysis plan for this study.

[0063] Test results: Pharmacokinetic Results: Median t after administration of a single dose of 960 mg sotorasib to subjects with normal liver function and subjects with moderate or severe hepatic impairment max Values ​​were similar, ranging from 1.00 to 1.47 hours. Estimated half-lives were similar across groups (arithmetic mean range 6.42 to 8.18 hours), with no apparent trends associated with hepatic dysfunction.

[0064] The geometric least squares mean (GLSM) ratio of test / reference (90% CI) for subjects with moderate hepatic impairment compared with subjects with normal liver function was calculated as AUC inf , AUC last , and C max The GLSM ratios for test / reference (90% CI) for subjects with severe hepatic impairment compared with subjects with normal liver function were 0.746 (0.431, 1.29), 0.749 (0.431, 1.30), and 0.955 (0.512, 1.78), respectively. inf , AUC last , and C max The values ​​were 1.04 (0.545, 1.97), 1.04 (0.544, 1.99), and 1.43 (0.688, 2.96), respectively.

[0065] Metabolite M10 appears in plasma with a median t max occurred 6 to 8 hours after administration, which was approximately 2 hours faster in subjects with moderate and severe hepatic impairment compared with subjects with normal liver function. max and AUC values ​​increased with increasing severity of hepatic impairment, resulting in higher geometric mean exposure in subjects with hepatic impairment than in normal subjects.

[0066] Metabolite M18 median t for all groups max occurred between 2 and 2.55 hours after administration. Geometric mean C max The AUC and AUC values ​​decreased with increasing severity of liver dysfunction. Exposure to the metabolite M18 was highest in normal subjects. The arithmetic mean t 1 / 2 Values ​​were similar in subjects with normal liver function and in subjects with moderate and severe liver impairment, with values ​​ranging from 7.28 to 9.35 hours.

[0067] Metabolite M24 appears in plasma with a median t max The geometric mean C occurred between 4.00 and 7.97 hours after administration and showed high variability in all groups. max and AUC values ​​increased with increasing severity of liver dysfunction, and the mean AUC inf was higher in subjects with severe impairment. 1 / 2 Values ​​were similar in subjects with normal liver function and in subjects with moderate and severe liver impairment, ranging from 23.0 to 28.2 hours.

[0068] Safety results: Four of 20 subjects (20%) reported nine treatment-emergent adverse events during the study, five of which were considered by the investigator to be related to sotorasib.

[0069] All adverse events were considered mild in severity. No serious or treatment-emergent adverse events led to study discontinuation. All adverse events resolved by the end of the study. There were no clinically significant findings in clinical laboratory evaluations, physical examinations, ECGs, and vital sign measurements during the study.

[0070] Conclusion: Sotorasib AUC of Test / Reference (90% CI) for Subjects with Moderate Hepatic Impairment Compared to Subjects with Normal Hepatic Function inf , AUC last , and C max The GLSM ratios were 0.746 (0.431, 1.29), 0.749 (0.431, 1.30), and 0.955 (0.512, 1.78), respectively.

[0071] Sotorasib AUC of test / reference (90% CI) for subjects with severe hepatic impairment compared with subjects with normal hepatic function inf , AUC last , and C max The GLSM ratios were 1.04 (0.545, 1.97), 1.04 (0.544, 1.99), and 1.43 (0.688, 2.96), respectively.

[0072] Arithmetic mean t of sotorasib 1 / 2 Values ​​were similar in subjects with normal liver function and in subjects with moderate or severe liver impairment.

[0073] Exposure to metabolites M10 and M24 (C max and AUC values) increased with increasing severity of liver dysfunction, whereas exposure to the metabolite M18 decreased with increasing severity of liver dysfunction.

[0074] Single doses of sotorasib were safe and well tolerated when administered to healthy subjects with normal hepatic function and to subjects with moderate or severe hepatic impairment.

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Claims

1. 1. A method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of sotorasib, wherein the patient has moderate or severe hepatic impairment prior to administration of the sotorasib, and wherein the sotorasib is a compound represented by formula (I): 【Chemical 1】 The method is a compound of

2. 10. The method of claim 1, wherein the patient had moderate hepatic impairment prior to administration of sotorasib.

3. 10. The method of claim 1, wherein the patient had severe hepatic impairment prior to administration of sotorasib.

4. 3. The method of claim 1 or claim 2, further comprising determining whether the patient has moderate liver dysfunction.

5. 4. The method of claim 1 or claim 3, further comprising determining whether the patient has severe liver dysfunction.

6. 6. The method of any one of claims 1 to 5, wherein the therapeutically effective amount of sotorasib is 240 mg to 960 mg per day.

7. 7. The method of any one of claims 1 to 6, wherein the therapeutically effective amount of sotorasib is 240 mg of sotorasib daily.

8. 7. The method of any one of claims 1 to 6, wherein the therapeutically effective amount of sotorasib is 480 mg daily.

9. 7. The method of any one of claims 1 to 6, wherein the therapeutically effective amount of sotorasib is 960 mg daily.

10. The method of any one of claims 1 to 9, wherein the patient has a cancer comprising a KRAS G12C mutation.

11. 11. The method of claim 10, wherein the method further comprises determining whether the patient has a cancer that contains a KRAS G12C mutation.

12. The method of any one of claims 1 to 11, wherein the cancer is a solid tumor.

13. 12. The method of any one of claims 1 to 11, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary site, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary carcinoma, gastric cancer, sinus cancer, or bile duct cancer.

14. 12. The method of any one of claims 1 to 11, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, paranasal sinus cancer, or bile duct cancer.

15. The method of any one of claims 1 to 11, wherein the cancer is non-small cell lung cancer.

16. 16. The method of claim 15, wherein the non-small cell lung cancer is locally advanced or metastatic.

17. The method of any one of claims 1 to 11, wherein the cancer is colorectal cancer.

18. The method according to any one of claims 1 to 11, wherein the cancer is pancreatic cancer.

19. 19. The method of any one of claims 1 to 18, wherein the sotorasib is administered as one or more tablets.

20. 20. The method of any one of claims 1 to 19, wherein the sotorasib is administered orally.

21. 21. The method of any one of claims 1 to 20, wherein the sotorasib is administered once daily.

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