Methods of treating cancer using sotorasib

Abstract

The present disclosure provides 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 liver damage prior to administration of sotorasib.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 418,695, filed on October 24, 2022, which is hereby incorporated by reference in its entirety for all purposes. Background of the Invention

[0003] Sotorasib is a small molecule that specifically and irreversibly inhibits the protein product of the mutant KRAS gene (KRAS G12C) with a glycine - to - cysteine amino acid substitution at position 12, and this mutant gene encodes KRAS G12C protein. Sotorasib forms a specific covalent bond with the mutant cysteine of KRAS G12C and irreversibly locks the protein in an inactive conformation, thereby weakening oncogenic signal transduction (Canon, 2019). Since inactivation of KRAS has been shown to inhibit cell growth and / or selectively promote apoptosis in tumor cells containing KRAS mutations (Ostrem et al., 2016; Patricelli et al., 2016; Janes et al., 2018, McDonald et al., 2017; Xie et al., 2017), sotorasib can provide therapeutic benefits to patients with KRAS G12C - driven cancers. Summary of the Invention

[0004] Described herein are methods of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of sotorasib, wherein the patient has moderate or severe liver impairment prior to administration of sotorasib. Methods are provided that include administering sotorasib in the form of the free base. In various embodiments, sotorasib is administered in the form of a pharmaceutically acceptable salt. Detailed Description

[0005] This disclosure is based on the discovery that patients with moderate or severe liver impairment can be treated with sotorasib without dose adjustment. It should be understood that the "one or more patients" referred to in this disclosure refers to one or more subjects in need of treatment (e.g., cancer treatment).

[0006] The U.S. Food and Drug Administration ("FDA")'s Guidance for the Industry on Pharmacokinetics in Patients with Impaired Liver Function states that, "The liver is involved in the elimination of many drugs through various oxidative and conjugative metabolic pathways and / or through biliary excretion of the unchanged drug or metabolite." Guidance for the Industry, 2003, page 2. The FDA further notes that, "These alterations in excretory and metabolic activities caused by liver impairment can lead to drug accumulation...." Ibid. Many reports in the scientific literature indicate that liver disease can alter the absorption and disposition (pharmacokinetics ("PK")) of drugs, as well as their efficacy and safety (pharmacodynamics ("PD")). Ibid. The FDA explains that, "Although measures of clinically useful liver function generally do not predict drug PK and PD, clinical studies typically conducted in patients with liver impairment during drug development can provide information that may help guide initial dosing in patients." Ibid. The FDA recommends that "PK studies be conducted in patients with impaired liver function if hepatic metabolism and / or excretion account for a substantial portion (>20% of the absorbed drug) of the elimination of the parent drug or active metabolite." Ibid., page 3.

[0007] Sotorasib

[0008] Sotorasib is a small molecule that irreversibly inhibits the KRAS G12C mutant protein. Sotorasib is 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 and has the following structure (Formula I):

[0009]

[0010] Sotorasib binds to the P2 pocket and nucleotide-binding pocket of KRAS adjacent to the mutant cysteine at position 12. The inhibitor contains a thiol-reactive moiety that covalently modifies the cysteine residue and locks KRAS G12CLocked in an inactive guanosine diphosphate (GDP)-bound conformation. This blocks the interaction of KRAS with effectors such as rapidly accelerated fibrosarcoma (RAF), thereby preventing downstream signaling, including phosphorylation of extracellular signal-regulated kinase (ERK) (Cully and Downward, 2008; Ostrem et al., 2013; Simanshu et al., 2017). Inactivation of KRAS by RNA interference (RNAi) or small molecule inhibition has previously demonstrated inhibition of cell growth and induction of apoptosis in tumor cell lines and xenografts harboring KRAS mutations, including the KRAS G12C mutation (Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016). The study of sotorasib confirmed these in vitro findings and similarly demonstrated inhibition of the growth and regression of cells and tumors harboring the KRAS G12C mutation (Canon et al., 2019). See also US Prescribing Information, Amgen Inc., Thousand Oaks, California 91320 (Revised May 2021), which is hereby incorporated by reference in its entirety. In various embodiments, the methods disclosed herein include administering 960 mg of sotorasib to a patient once daily. In various embodiments, the methods disclosed herein include administering 480 mg of sotorasib to a patient once daily. In various embodiments, the methods disclosed herein include administering 240 mg of sotorasib to a patient once daily.

[0011] The present disclosure provides methods that include administering sotorasib in the form of the free base. In various embodiments, sotorasib is administered in the form of a pharmaceutically acceptable salt. For clarity, as used herein, the term "sotorasib" refers to the free base of sotorasib. Any method described herein that refers to sotorasib can also be implemented using a pharmaceutically acceptable salt of sotorasib. In some embodiments, sotorasib can be administered in the form of the hydrochloride, phosphate, or mesylate salt. In some embodiments, sotorasib can be administered in the form of the hydrochloride salt. In some embodiments, sotorasib can be administered in the form of the phosphate salt. In some embodiments, sotorasib can be administered in the form of the mesylate salt. For clarity, if a method described herein recites administering, for example, 240 mg of sotorasib or a pharmaceutically acceptable salt thereof to a subject, the method requires administering 240 mg of the free base of sotorasib or a pharmaceutically acceptable salt corresponding to the amount of the free base of 240 mg of sotorasib.

[0012] The term "pharmaceutically acceptable" refers to a substance or component that is generally safe, non-toxic and not biologically or otherwise undesirable for a subject (such as a human).

[0013] The term "pharmaceutically acceptable salt" refers to a salt of a compound that has the desired pharmacological activity of the parent compound and is not biologically or otherwise undesirable for its ultimate 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 with 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, for example, salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or associated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, dicyclohexylamine). Additionally, salts of the compounds described herein can exist in hydrated or anhydrous forms or as solvates with other solvent molecules.

[0014] Sotorasib is eliminated primarily via the fecal route and is metabolized mainly by the hepatic enzyme CYP3A ( U.S. Prescribing Information, Amgen Inc., Thousand Oaks, California 91320 (Revised May 2021)), where CYP3A4 is the major metabolic enzyme. Thus, it is expected that patients with moderate or severe hepatic impairment will exhibit changes in the PK profile such that a given dose of sotorasib in patients with moderate or severe hepatic impairment will exhibit, for example, increased exposure ("AUC") or C max increased or both (compared to patients without hepatic impairment who require a reduced dose to maintain an acceptable PK / PD profile). Previous studies on drug-drug interactions between sotorasib and CYP3A4 inhibitors (e.g., itraconazole) and between sotorasib and rifampin (a CYP3A4 inducer) support this expectation (see, for example, Examples 1 and 2 below). However, surprisingly, it has been found that the PK and safety profiles of subjects with moderate or severe hepatic impairment are clinically similar enough to those of healthy subjects (Example 3). Thus, the data presented in this disclosure unexpectedly show that dose adjustment is not required for patients with moderate or severe hepatic impairment.

[0015] Hepatic impairment

[0016] Patients with liver impairment include those diagnosed with a clinical decline in liver function due to, for example, hepatic encephalopathy, hepatitis, or cirrhosis. As used herein, the Child-Pugh score is used to diagnose patients. Although there are other means for measuring liver impairment (e.g., Model for End-Stage Liver Disease (MELD) score, Conn score), the Child-Pugh score is used herein to assess liver impairment.

[0017] The Child-Pugh score (also known as the Child-Turcotte-Pugh score) is used to assess the prognosis of chronic liver disease, mainly cirrhosis, and 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 - 3, and the total value is used to provide a score classified as class A (5 - 6 points), class B (7 - 9 points), or class C (10 - 15 points), which can be correlated with one-year and two-year survival rates. If a patient is determined to be class A on the Child-Pugh score scale, the patient is considered to have healthy / normal liver function. If a patient is determined to be class B on the Child-Pugh score scale, the patient is considered to have "moderate" liver impairment. If a patient is determined to be class C on the Child-Pugh score scale, the patient is considered to have "severe" liver impairment. The methods for determining and analyzing the Child-Pugh score are well known in the art (Figg et al., 1995).

[0018] Described herein are methods of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of sotorasib, wherein the patient has moderate or severe liver impairment prior to administration of sotorasib. Provided herein are methods comprising administering sotorasib in the form of the free base. In various embodiments, sotorasib is administered in the form of a pharmaceutically acceptable salt.

[0019] As used herein, the term "therapeutically effective amount" means the amount of a compound that elicits the desired biological or medical response in a cell, tissue, system, or subject disclosed herein.

[0020] In some embodiments, the methods include administering to a patient a therapeutically effective amount of sotorasib, where the patient has moderate hepatic impairment (i.e., Child-Pugh class B) prior to administration of sotorasib. In some embodiments, the methods include administering sotorasib once daily to a patient with moderate hepatic impairment in an amount in the range of 240 mg to 960 mg. In some embodiments, the methods include administering 960 mg of sotorasib once daily to a patient with moderate hepatic impairment. In some embodiments, the methods include administering 480 mg of sotorasib once daily to a patient with moderate hepatic impairment. In some embodiments, the methods include administering 240 mg of sotorasib once daily to a patient with moderate hepatic impairment.

[0021] In some embodiments, the methods include administering to a patient a therapeutically effective amount of sotorasib, where the patient has severe hepatic impairment (i.e., Child-Pugh class C) prior to administration of sotorasib. In some embodiments, the methods include administering sotorasib once daily to a patient with severe hepatic impairment in an amount in the range of 240 mg to 960 mg. In some embodiments, the methods include administering 960 mg of sotorasib once daily to a patient with severe hepatic impairment. In some embodiments, the methods include administering 480 mg of sotorasib once daily to a patient with severe hepatic impairment. In some embodiments, the methods include administering 240 mg of sotorasib once daily to a patient with severe hepatic impairment.

[0022] Determination of KRAS G12C Mutation in Cancer

[0023] The patients treated in the methods disclosed herein are patients with cancer having a KRAS G12C mutation. In various embodiments, prior to administration as disclosed herein, the patient has a cancer determined to have one or more cells expressing a KRAS G12C mutant protein. Methods known in the art can be used to determine the presence or absence of the G12C mutation in a cancer as described herein. Whether a tumor or cancer contains a mutation can be determined, for example, by assessing the nucleotide sequence encoding the protein, by assessing the amino acid sequence of the protein, or by assessing the characteristics of the putative mutant protein or any other suitable method known in the art. The nucleotide and amino acid sequences of wild-type human KRAS (the nucleotide sequence listed in Genbank accession number BC010502; the amino acid sequence listed in Genbank accession number AGC09594) are known in the art.

[0024] 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 and / or next-generation sequencing-based, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, a sample is evaluated for a mutation (such as a KRAS G12C mutation) by real-time PCR. In real-time PCR, a fluorescent probe specific for a particular mutation (such as a KRAS G12C mutation) is used. In the presence of the mutation, the probe binds and fluorescence is detected. In some embodiments, direct sequencing of a specific region of a gene is used to identify mutations. This technique identifies all possible mutations in the sequenced region. In some embodiments, gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and / or arrays can be used to detect the presence or absence of an insertion mutation. In some embodiments, these methods include, but are not limited to, detecting mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0025] In some embodiments, multiplex PCR-based sequencing is used for mutation detection and can include a number of amplicons that provide increased sensitivity for the detection of one or more genetic biomarkers. For example, multiplex PCR-based sequencing can include about 60 amplicons (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 amplicons). In some embodiments, multiplex PCR-based sequencing can include 61 amplicons. The amplicons generated using multiplex PCR-based sequencing can include nucleic acids having a length of from about 15 bp to about 1000 bp (e.g., from about 25 bp to about 1000 bp, from about 35 bp to about 1000 bp, from about 50 bp to about 1000 bp, from about 100 bp to about 1000 bp, from about 250 bp to about 1000 bp, from about 500 bp to about 1000 bp, from about 750 bp to about 1000 bp, from about 15 bp to about 750 bp, from about 15 bp to about 500 bp, from about 15 bp to about 300 bp, from about 15 bp to about 200 bp, from about 15 bp to about 100 bp, from about 15 bp to about 80 bp, from about 15 bp to about 75 bp, from about 15 bp to about 50 bp, from about 15 bp to about 40 bp, from about 15 bp to about 30 bp, from about 15 bp to about 20 bp, from about 20 bp to about 100 bp, from about 25 bp to about 50 bp, or from about 30 bp to about 40 bp). For example, the amplicons generated using multiplex PCR-based sequencing can include nucleic acids having a length of about 33 bp.

[0026] In some embodiments, one or more mutations present in a sample obtained from a patient are detected using sequencing techniques (e.g., next-generation sequencing techniques). A variety of 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).

[0027] In some embodiments, droplet digital PCR (ddPCR), a method known to be highly sensitive for mutation detection, is used to detect the presence of one or more mutations in a sample obtained from a patient. In some embodiments, other sequencing techniques are used to detect the presence of one or more mutations in a sample obtained from a patient, and these other sequencing techniques include, but are not limited to, chain termination techniques, shotgun techniques, sequencing by synthesis, methods utilizing microfluidics, other capture techniques, or any other sequencing technique known in the art that can be used to detect small amounts of DNA in a sample (e.g., ctDNA in a cell-free DNA sample).

[0028] In some embodiments, array-based methods are used to detect the presence of one or more mutations in a sample obtained from a patient. For example, a DNA microarray is used to perform the step of detecting genetic alterations (e.g., one or more genetic alterations) in cell-free DNA. In some embodiments, the DNA microarray can detect one or more of a variety of cancer cell mutations. In some embodiments, cell-free DNA is amplified prior to detecting the genetic alteration. Non-limiting examples of array-based methods that can be used in any of the methods described herein include: 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), array-based comparative genomic hybridization arrays (array-CGH) (see, e.g., Beers and Nederlof, 2006; Pinkel et al. 2005; Michels et 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.

[0029] Methods for determining whether a tumor or cancer contains a mutation can use a variety of samples. In some embodiments, the sample is taken 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 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 excision, core needle biopsy (CNB), fine needle aspiration (FNA), urine collection, or hair follicle collection. In some embodiments, a liquid biopsy test using whole blood or cerebrospinal fluid can be used to evaluate the mutation status.

[0030] In various embodiments, tests approved by a regulatory agency, such as the US Food and Drug Administration (FDA), are 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 a mutation. In some embodiments, the test used for the KRAS mutation is the KRAS RGQ PCR Kit (Qiagen). The KRAS RGQ PCR Kit is a real-time quantitative PCR assay for detecting 7 somatic mutations in codons 12 and 13 of the human KRAS oncogene (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) 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 excision, CNB, or FNA. STK11, KEAP1, EGFR, ALK, and / or ROS1 mutation tests can be performed using commercially available tests, such as the Resolution Bioscience Resolution ctDx LungTM assay, which includes 24 genes (including those actionable in NSCLC). Tissue samples can be tested using the Tempus xT 648 panel.

[0031] KRAS G12C mutant cancer

[0032] The methods described herein include treating a patient with a cancer having a KRAS G12C mutation. Without wishing to be bound by any particular theory, note the following: Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C(Hong et al., 2020). Hong et al. reported that "preclinical studies showed that [sotorasib] inhibited almost all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, resulting in durable complete tumor regression in mice bearing KRAS p.G12C tumors." (Ibid., see also Canon et al., 2019 and Lanman et al., 2020).

[0033] Sotorasib was evaluated in a phase 1 dose escalation and expansion trial in which 129 patients had histologically confirmed, locally advanced or metastatic cancer with a KRAS G12C mutation (identified by local molecular testing of tumor tissue), including 59 patients with non-small cell lung cancer, 42 patients with colorectal cancer, and 28 patients with other tumor types (Hong et al., 2020, pp. 1208 - 1209). Hong et al. reported a disease control rate (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. to show stable disease (SD) or partial response (PR) were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small intestine cancer, sinus cancer, cholangiocarcinoma, or melanoma (Hong et al., 2020, p. 1212 (Figure A) and Supplementary Appendix (p. 59 (Figure S5) and p. 63 (Figure S6))).

[0034] The alteration frequencies of the KRAS G12C mutation are 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 express the KRAS G12C protein. Thus, sotorasib, which binds specifically and irreversibly to KRAS G12C can be used to treat patients with cancer (including but not limited to the cancers listed in Table 1 below).

[0035] Table 1

[0036]

[0037]

[0038] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, hepatobiliary duct cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastroenteropancreatic neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, sinus cancer, or bile duct cancer. In some embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinus cancer, or bile duct cancer. In various embodiments, the cancer is non-small cell lung cancer, and in some specific embodiments, the cancer is 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.

[0039] Embodiment

[0040] 1. A method of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of sotorasib, wherein the patient has moderate or severe liver impairment prior to administration of the sotorasib.

[0041] 2. The method according to embodiment 1, wherein the patient has moderate liver impairment prior to administration of the sotorasib.

[0042] 3. The method according to embodiment 1, wherein the patient has severe liver impairment prior to administration of the sotorasib.

[0043] 4. The method according to embodiment 1 or embodiment 2, the method comprising administering to the patient 960 mg of sotorasib once daily.

[0044] 5. The method according to embodiment 1, the method comprising administering to the patient 240 mg of sotorasib once daily.

[0045] 6. The method according to any one of embodiments 1 to 5, wherein the patient has a cancer comprising a KRAS G12C mutation.

[0046] 7. The method according to embodiment 6, wherein the cancer is a solid tumor.

[0047] 8. The method according to embodiment 6 or 7, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, pancreatic cancer, hepatobiliary duct cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastroenteric neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, sinus cancer or bile duct cancer.

[0048] 9. The method according to any one of embodiments 6 to 8, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinus cancer or bile duct cancer.

[0049] 10. The method according to any one of embodiments 6 to 9, wherein the cancer is non-small cell lung cancer.

[0050] 11. The method according to embodiment 10, wherein the non-small cell lung cancer is locally advanced or metastatic.

[0051] 12. The method according to any one of embodiments 6 to 9, wherein the cancer is colorectal cancer.

[0052] 13. The method according to any one of embodiments 6-9, wherein the cancer is pancreatic cancer.

[0053] Alternative embodiment

[0054] 1. A method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of sotorasib, wherein the patient has moderate or severe liver impairment prior to administration of sotorasib, and wherein sotorasib is a compound having formula (I):

[0055]

[0056] 2. The method according to claim 1, wherein the patient has moderate liver impairment prior to administration of sotorasib.

[0057] 3. The method according to claim 1, wherein the patient has severe liver impairment prior to administration of sotorasib.

[0058] 4. The method according to claim 1 or claim 2, wherein the method further comprises the step of determining whether the patient has moderate liver impairment.

[0059] 5. The method according to claim 1 or claim 3, wherein the method further comprises the step of determining whether the patient has severe liver impairment.

[0060] 6. The method according to any one of claims 1 to 5, wherein the therapeutically effective amount of sotorasib is 240 mg to 960 mg per day.

[0061] 7. The method according to any one of claims 1 to 6, wherein the therapeutically effective amount of sotorasib is 240 mg of sotorasib per day.

[0062] 8. The method according to any one of claims 1 to 6, wherein the therapeutically effective amount of sotorasib is 480 mg per day.

[0063] 9. The method according to any one of claims 1 to 6, wherein the therapeutically effective amount of sotorasib is 960 mg per day.

[0064] 10. The method according to any one of claims 1 to 9, wherein the patient has cancer comprising a KRAS G12C mutation.

[0065] 11. The method according to claim 10, wherein the method further comprises determining whether the patient has cancer comprising a KRAS G12C mutation.

[0066] 12. The method according to any one of claims 1 to 11, wherein the cancer is a solid tumor.

[0067] 13. The method according to any one of claims 1 to 11, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, hepatobiliary duct cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastroenteropancreatic neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, nasal sinus cancer, or bile duct cancer.

[0068] 14. The method according to any one of claims 1 to 11, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, nasal sinus cancer, or bile duct cancer.

[0069] 15. The method according to any one of claims 1 to 11, wherein the cancer is non-small cell lung cancer.

[0070] 16. The method according to claim 15, wherein the non-small cell lung cancer is locally advanced or metastatic.

[0071] 17. The method according to any one of claims 1 to 11, wherein the cancer is colorectal cancer.

[0072] 18. The method according to any one of claims 1 to 11, wherein the cancer is pancreatic cancer.

[0073] 19. The method according to any one of claims 1 to 18, wherein the sotorasib is administered in the form of one or more tablets.

[0074] 20. The method according to any one of claims 1 to 19, wherein the sotorasib is administered orally.

[0075] 21. The method according to any one of claims 1 to 20, wherein the sotorasib is administered once daily.

[0076] Example 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

[0077] Objective:

[0078] This was a Phase 1, single-center, open-label, fixed-sequence study to investigate the effect of co-administration of itraconazole (a CYP3A4 and P-gp inhibitor) on the PK of sotorasib in healthy men and women of non-reproductive potential. Subjects received a single dose of sotorasib on Day 1 and a QD dose of itraconazole from Day 3 to Day 7 (where a second [loading] dose of itraconazole was received on Day 3). On Day 6, a single dose of sotorasib was co-administered with itraconazole. Blood was collected at pre-specified time points to characterize the plasma concentrations of sotorasib and itraconazole. Safety and tolerability were monitored throughout the study.

[0079] A total of 14 healthy subjects (2 females and 12 males) were recruited and completed the study. Nine of the 14 subjects were white and 5 were black or African American. The mean (SD) age was 44.2 (12.55) years. Single-dose plasma sotorasib pharmacokinetic (PK) data were obtained from 14 subjects who received sotorasib alone and sotorasib co-administered with itraconazole after 4 days of multiple daily dosing of itraconazole. During sotorasib alone and sotorasib plus itraconazole combination treatment, the t max 1 / 2 values of sotorasib were 0.51 and 1.00 hours, respectively. When comparing sotorasib co-administered with itraconazole (test) and sotorasib administered alone (reference), the geometric least squares mean ratios of sotorasib AUC inf and C max (test / reference) were 1.261 and 1.040, respectively (Table 2).

[0080] Geometric Least Squares Mean of Pharmacokinetic Parameters of Sotorasib after Single Oral Administration of 360 mg Sotorasib Alone (Day 1) or in Combination with 200 mg Itraconazole (Day 6) in Healthy Subjects

[0081]

[0082] AUC inf = Area Under the Concentration-Time Curve from Time 0 to Infinity; AUC last = Area Under the Concentration-Time Curve from Time 0 to the Time of the Last Measurable Concentration; GLSM = Geometric Least Squares Mean; CI = Confidence Interval; C max = Observed Maximum Drug Concentration; CV = Coefficient of Variation; n = Number of Subjects with Valid Observations

[0083] Example 2 - Open-Label Study to Evaluate the Drug-Drug Interaction Effect of Rifampin (a CYP3A4 Inducer) on the Pharmacokinetics of AMG 510 in Healthy Subjects

[0084] This was a Phase 1, single-center, open-label, fixed-sequence study to investigate the effect of co-administration of rifampin on the PK of sotorasib in healthy men and women. Subjects received a single dose of sotorasib on Day 1, a single dose of rifampin (a strong OATP1B1 / 1B3 inhibitor) and sotorasib on Day 3, and QD doses of rifampin (a strong CYP3A4 inducer) from Day 5 to Day 17 and Day 19. On Day 18, a single dose of sotorasib was co-administered with rifampin. Blood was collected at pre-specified time points to characterize the plasma concentration of sotorasib. Safety and tolerability were monitored throughout the study.

[0085] A total of 14 healthy subjects (1 female and 13 males) were recruited and completed the study. Three of the 14 subjects were white, 10 were black or African American, and 1 was Asian. The mean (SD) age was 35.2 (8.80) years.

[0086] 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 dosing of rifampin (Day 18). The median t max was similar throughout the treatment period. After co-administration with rifampin on Day 3 and Day 18, the geometric mean exposure of sotorasib (based on AUC and C max)Lower. When comparing the co - administration (test) of sotorasib with a single dose of rifampin and the administration of sotorasib alone (reference), the geometric least - squares mean ratios (test / reference) of sotorasib AUC inf and C max were 0.766 and 0.840, respectively (Table 3). When comparing the co - administration (test) of sotorasib with multiple daily doses of rifampin and the administration of sotorasib alone (reference), the geometric least - squares mean ratios (test / reference) of sotorasib AUC inf and C max were 0.487 and 0.647, respectively.

[0087] Table 3

[0088]

[0089]

[0090] AUC last = Area under the concentration - time curve from time 0 to the time of the last measurable concentration; AUC inf = Area under the concentration - time curve from time 0 to infinity; CI = Confidence interval; C max = Observed maximum drug concentration; GLSM = Geometric least - squares mean; n = Number of subjects with valid observations Example 3 - Open - label single - dose study to evaluate the pharmacokinetics of sotorasib in subjects with moderate or severe hepatic impairment compared to healthy subjects

[0091] This example describes an open - label single - dose study of sotorasib in healthy subjects and subjects with moderate or severe hepatic impairment (see inclusion / exclusion criteria):

[0092] Purpose:

[0093] The primary objective of this study was to evaluate the pharmacokinetics (PK) of a single oral dose of sotorasib administered in subjects with moderate or severe hepatic impairment compared to subjects with normal liver function. The primary objective of this study was to evaluate the safety and tolerability of sotorasib administered in subjects with moderate or severe hepatic impairment compared to subjects with normal liver function.

[0094] Study design:

[0095] This is a Phase 1, parallel-arm, multi-center (USA), open-label, non-randomized study designed to evaluate the PK of a single oral dose of sotorasib administered under fasting conditions in subjects with normal liver function (controls) and subjects with moderate or severe liver impairment (according to Child-Pugh classification). 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).

[0096] Eligible subjects were assigned to 1 of 3 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). This classification was based on the Child-Pugh score (according to Figg et al. (1995)).

[0097] Child-Pugh classification of cirrhosis severity (Table 4)

[0098] Table 4

[0099]

[0100] 1 Grade 0: Normal consciousness, personality, neurological examination, electroencephalogram

[0101] Grade 1: Restlessness, disturbed sleep, irritability / agitation, tremor, impaired handwriting, 5 cycles / second waves

[0102] Grade 2: Drowsiness, time disorientation, inappropriate, asterixis, ataxia, slow triphasic waves

[0103] Grade 3: Somnolence, coma, disorientation to place, hyperreflexia, stupor, slower waves

[0104] Grade 4: Unarousable coma, no personality / behavior, decerebration, slow 2 - 3 cycles / second δ activity

[0105] 2 Ascites was graded according to the following criteria:

[0106] Absent: No detectable ascites by manual examination

[0107] Mild: Suspected ascites thrill

[0108] Moderate: Ascites detectable by palpation

[0109] Severe: Paracentesis necessary, unresponsive to medical treatment.

[0110] Inclusion criteria:

[0111] Unless otherwise specified, all of the following criteria must be met by the subjects prior to enrollment:

[0112] All subjects

[0113] Male or female subjects between 18 and 70 years of age (inclusive) at screening.

[0114] Body mass index between 18.0 and 38.0 kg / m 2 inclusive at screening.

[0115] Women with no reproductive potential who are defined as permanently sterile (i.e., due to hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal (defined as at least 45 years old, amenorrhea for 12 months without other medical reasons, and follicle-stimulating hormone [FSH] level ≥ 40 mIU / mL).

[0116] Subjects with only normal liver function (Group 1)

[0117] In good health, determined by no clinically significant findings based on the investigator's assessment of medical history, physical examination, 12-lead electrocardiogram (ECG), vital sign measurements, and clinical laboratory evaluations (congenital non-hemolytic hyperbilirubinemia [e.g., suspected Gilbert's syndrome based on total and direct bilirubin] is unacceptable).

[0118] Subjects with only liver damage (Groups 2 and 3)

[0119] Child-Pugh B (group 2) or C (group 3) classification (see Table 4) as defined by screening and enrollment clinical laboratory values and clinical examination results.

[0120] Liver diseases considered clinically stable by the investigator (e.g., excluding rapidly progressive primary or secondary liver malignancies). History of documented 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 enrolled subjects at screening)) or history as evaluated by the investigator (or designee).

[0121] As determined by medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations at screening and enrollment, the medical outcomes of subjects with moderate or severe liver impairment may be consistent with their liver dysfunction. Subjects with abnormal results considered not clinically significant by the investigator will be eligible.

[0122] Exclusion criteria:

[0123] Unless otherwise specified, a subject is excluded from the study if they meet any of the following criteria prior to enrollment:

[0124] All subjects

[0125] Any unstable medical condition, defined as hospitalization within 21 days prior to enrollment, major surgery within 6 months prior to enrollment, or other conditions judged to be unstable by the investigator and / or medical monitor (e.g., risk of complications or adverse events unrelated to participation in the study).

[0126] History or evidence of clinically significant obstacles, conditions, or diseases (not otherwise excluded) that, at the time of screening or enrollment, the investigator (or designee) believes pose a risk to the safety of the subject or interfere with the study assessment, procedures, or completion.

[0127] Venous thromboembolic disease within the last 6 months.

[0128] History of any type of malignancy, except for carcinoma in situ of the cervix or surgically resected non-melanoma skin cancer more than 5 years prior to treatment with sotorasib.

[0129] History or evidence of clinically significant arrhythmias at the time of screening, including any clinically significant findings on the ECG performed at the time of enrollment.

[0130] At the time of screening or enrollment, a PR interval > 200 milliseconds, second-degree atrioventricular (AV) block, or third-degree AV block.

[0131] History of conditions suggestive of esophageal (including esophageal spasm, esophagitis), gastric, or duodenal ulcers or bowel disease (including but not limited to peptic ulcer, gastrointestinal bleeding, ulcerative colitis, Crohn's disease, or irritable bowel syndrome); or history of gastrointestinal surgery other than simple appendectomy, cholecystectomy, and hernia repair.

[0132] Inability to swallow oral medications or history of malabsorption syndrome.

[0133] History of significant hypersensitivity, intolerance, or allergy to any pharmaceutical compound, food, or other substance, unless approved by the investigator (or designee) in consultation with the sponsor.

[0134] Poor peripheral venous access.

[0135] At the time of screening or enrollment, an estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) formula of less than 45 mL / min / 1.73m 2 .

[0136] Positive human immunodeficiency virus test at the time of screening.

[0137] Use of any over-the-counter or prescription medications within 30 days or 5 half-lives (whichever is longer) prior to enrollment, except for the following:

[0138] - Ibuprofen and hormone replacement therapies (e.g., estrogen, thyroid) will be permitted.

[0139] - Therapies for the treatment of liver diseases and related disorders that are stable and considered acceptable by the investigator (or designee) and the sponsor at least 30 days prior to the administration of the study drug and are given concurrently with sotorasib during the study.

[0140] Administration of an approved (authorized) coronavirus disease 2019 (COVID-19) vaccine within the past 28 days prior to dosing, or administration of a COVID-19 vaccine with emergency use authorization (USA) within the past 30 days prior to dosing.

[0141] All herbs (such as St. John’s wort), vitamins, and supplements taken by the subject within 30 days prior to enrollment, unless considered acceptable by the investigator (or designee) in consultation with the sponsor.

[0142] Consumption of foods and beverages containing poppy seeds, grapefruit, or Seville orange within 7 days prior to registration.

[0143] Use of known CYP3A4- and P-gp-sensitive substrates (with a narrow therapeutic window) without review and approval by the investigator (or designee) and the sponsor within 30 days or 5 half-lives (whichever is longer) of the drug or its major active metabolite prior to Day 1 of the study.

[0144] 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 Day 1 of the study.

[0145] Use of a PPI within 5 days or an H2 receptor antagonist within 1 day prior to Day 1 of the study.

[0146] History of alcohol abuse or drug / chemical substance abuse within the last 3 months prior to registration.

[0147] Alcohol consumption within 48 hours prior to registration.

[0148] Regular alcohol consumption of > 14 units per week for men and > 7 units per week for women. One unit of alcohol is equivalent to 12 oz (360 mL) of beer, 1 1 / 2 oz (45 mL) of spirits, or 5 oz (150 mL) of wine.

[0149] Using a tobacco or nicotine-containing product within 3 months before registration.

[0150] Testing positive for illegal drugs, cotinine (tobacco or nicotine use), and / or alcohol use at screening or registration.

[0151] Consuming caffeine-containing food and beverages within 48 hours before registration.

[0152] Female subjects testing positive for pregnancy at screening or registration.

[0153] Male subjects (with a female partner of childbearing potential) who are unwilling to practice sexual abstinence (avoid heterosexual intercourse) or comply with contraceptive requirements within 7 days after administration of sotorasib.

[0154] Unwilling to abstain from sperm donation and egg donation within 7 days after administration of sotorasib.

[0155] Male subjects with a female partner of childbearing potential who are unwilling to inform their partner of their participation in this clinical study.

[0156] Male subjects with a pregnant partner or a partner planning to become pregnant who are unwilling to abstain from sex or use a condom within 7 days after administration of sotorasib.

[0157] The subject received a dose of the study drug (new chemical entity) within the past 30 days or 5 half-lives (whichever is longer) before registration.

[0158] Previously completed or withdrawn from this study or any other study of sotorasib, or previously received a study product.

[0159] Donating blood within 3 months before registration, donating plasma within 2 weeks before registration, or donating platelets within 6 weeks before registration.

[0160] Receiving a blood product within 2 months before registration.

[0161] Unwilling to comply with the study restrictions.

[0162] Subjects whom the investigator (or designee) deems should not participate in this study.

[0163] Subjects with only normal liver function (Group 1)

[0164] Testing positive for hepatitis B or hepatitis C at screening. Subjects with results consistent with previous immunity (vaccination or previous infection) may be included.

[0165] Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN) at screening or registration.

[0166] Total bilirubin level > ULN at screening or enrollment.

[0167] QTcF (QT interval corrected for heart rate using Fridericia's correction) interval > 450 milliseconds in male subjects and > 470 milliseconds in female subjects at screening or enrollment, or history / evidence of long QT syndrome, confirmed by calculating the mean of the initial value and 2 repeats.

[0168] Subjects with only liver damage (Groups 2 and 3)

[0169] Values outside the normal range of liver function tests inconsistent with the liver condition, as determined by the investigator (or designee).

[0170] QTcF interval > 470 milliseconds in male subjects and > 480 milliseconds in female subjects at screening or enrollment, confirmed by calculating the mean of the initial value and 2 repeats.

[0171] Use of a new drug or change in dose within 30 days prior to enrollment to treat or exacerbate hepatic encephalopathy.

[0172] History of recent gastrointestinal bleeding or received treatment (within the past 6 months).

[0173] Presence of portosystemic shunt.

[0174] History of recent puncture within 30 days prior to enrollment.

[0175] Current functional organ transplant or awaiting organ transplant.

[0176] Evidence of severe ascites.

[0177] History of hepatic encephalopathy or current symptoms of grade 2 or higher hepatic encephalopathy within 60 days prior to the screening visit.

[0178] Concomitant therapies:

[0179] Avoid use of any prescription or over-the-counter drugs / products by the subject during the study until EOS, unless previously agreed to by the investigator (or designee) and / or the sponsor.

[0180] The subject will avoid use of any PPIs within 5 days prior to study day 1 or H2 receptor antagonists within 1 day until at least 4 hours after IMP administration.

[0181] For subjects with liver impairment, treatment of underlying liver disease and co-existing conditions (including prescription analgesia) is permitted if prescribed by the subject's private physician and approved by the medical monitor and the investigator, and in consultation with the sponsor as needed. Based on the investigator's judgment, in clinically appropriate cases, drug administration should be discontinued for at least 4 hours after the administration of the investigational drug, unless treatment of an adverse event is required. Throughout the study, the investigator may prescribe any concomitant medications or treatments considered necessary to provide adequate supportive care, except those listed in the exclusion criteria.

[0182] Before administration of the IMP as defined by the above exclusion criteria and during the study, use of known strong CYP3A4 inducers (e.g., rifampin, corticosteroids, antiepileptic drugs, and St. John's wort) or foods and drugs that are CYP3A4 or P-gp substrates with a narrow therapeutic index is prohibited until the end of the study.

[0183] Ibuprofen and hormone replacement therapy are acceptable concomitant medications. Administration of any other concomitant medications during the study is prohibited without prior approval by the investigator (or designee), unless their use is considered necessary for the treatment of an adverse event. Any medications taken by the subject during the course of the study and the reasons for their use will be recorded in the source data.

[0184] Pharmacokinetic analysis:

[0185] Plasma PK parameters of sotorasib will be calculated using standard non-compartmental methods.

[0186] The primary PK parameters of sotorasib are C max , AUC last and AUC inf . Other PK parameters of sotorasib will not be analyzed for inferential statistics and may include t max time, apparent plasma terminal 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), free fraction (f u ), C max,u , AUC last,u , AUC inf,u , CL u / F and V z,u / F. Linear models will be used to analyze the log-transformed primary PK parameters. Data from subjects with liver impairment (Groups 2 and 3; test) and control subjects (normal liver function [Group 1]; reference) will be included in the analysis. The geometric mean ratio (test / reference) of C max and AUC values and the associated 90% confidence intervals will be estimated.

[0187] Other parameters can be calculated, and sotorasib metabolites can be analyzed. If PK parameters of the metabolites are calculated, inferential statistical analysis will not be performed. Specific details will be presented in the statistical analysis plan of this study.

[0188] Study results:

[0189] Pharmacokinetic results :

[0190] After single-dose administration of 960 mg sotorasib to subjects with normal liver function and subjects with moderate or severe liver impairment, the median t max values were similar, ranging between 1.00 and 1.47 hours. The estimated half-lives of each group were similar (arithmetic mean range was 6.42 to 8.18 hours), and there was no obvious trend associated with liver impairment.

[0191] For AUC inf 、AUC last and C max , compared with subjects with normal liver function, the geometric least-squares mean (GLSM) ratios of test / reference (90% CI) for subjects with moderate liver impairment were 0.746 (0.431, 1.29), 0.749 (0.431, 1.30), and 0.955 (0.512, 1.78), respectively. For AUC inf 、AUC last and C max , compared with subjects with normal liver function, the GLSM ratios of test / reference (90% CI) for subjects with severe liver impairment were 1.04 (0.545, 1.97), 1.04 (0.544, 1.99), and 1.43 (0.688, 2.96), respectively.

[0192] Metabolite M10 appeared in plasma, with the median t max appearing between 6 and 8 hours after dosing, approximately 2 hours faster in subjects with moderate and severe liver impairment compared with subjects with normal liver function. The geometric mean C max and AUC values increased with the severity of liver impairment, so the geometric mean exposure in subjects with liver impairment was higher than that in normal subjects.

[0193] For all groups, the median t max of metabolite M18 appeared between 2 and 2.55 hours after dosing. The geometric mean C max and AUC values decreased with the severity of liver impairment. The exposure of metabolite M18 was the highest in normal subjects. The arithmetic mean t 1 / 2 values of M18 in subjects with normal liver function and subjects with moderate and severe liver impairment were similar, with values between 7.28 and 9.35 hours.

[0194] Metabolite M24 appeared in plasma, with a median t max appearing between 4.00 and 7.97 hours after dosing, and there was high variability across all groups. The geometric mean C max and AUC values increased with increasing severity of liver impairment, with the mean AUC inf being higher in subjects with severe impairment. The arithmetic mean t 1 / 2 values of M24 were similar in subjects with normal liver function and those with moderate and severe liver impairment, with values between 23.0 and 28.2 hours.

[0195] Safety results:

[0196] Among 20 subjects, 4 subjects (20%) reported 9 treatment-emergent adverse events during the study. The investigator considered 5 of these treatment-emergent adverse events to be related to sotorasib.

[0197] The severity of all adverse events was considered mild. There were no serious adverse events or treatment-emergent adverse events leading to study discontinuation. All adverse events resolved by the end of the study. There were no clinically significant findings in the clinical laboratory assessments, physical examinations, ECGs, and vital sign measurements during the study.

[0198] Conclusion:

[0199] Compared with subjects with normal liver function, the test / reference (90% CI) GLSM ratios of sotorasib AUC inf , AUC last and C max in subjects with moderate liver impairment were 0.746 (0.431, 1.29), 0.749 (0.431, 1.30), and 0.955 (0.512, 1.78), respectively.

[0200] Compared with subjects with normal liver function, the test / reference (90% CI) GLSM ratios of sotorasib AUC inf , AUC last and C max in subjects with severe liver impairment were 1.04 (0.545, 1.97), 1.04 (0.544, 1.99), and 1.43 (0.688, 2.96), respectively.

[0201] The arithmetic mean t 1 / 2 values of sotorasib were similar in subjects with normal liver function and those with moderate or severe liver impairment.

[0202] Exposures of metabolites M10 and M24 (based on C max and AUC values) increased with the increasing severity of liver impairment, while the exposure of metabolite M18 decreased with the increasing severity of liver impairment.

[0203] Single-dose sotorasib was safe and well-tolerated when administered to healthy subjects with normal liver function and subjects with moderate or severe liver impairment.

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Claims

1. A method of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of sotorasib, wherein the patient has moderate or severe liver impairment prior to administration of the sotorasib, and wherein sotorasib is a compound having formula (I):

2. The method according to claim 1, wherein the patient has moderate liver impairment prior to administration of the sotorasib.

3. The method according to claim 1, wherein the patient has severe liver impairment prior to administration of the sotorasib.

4. The method according to claim 1 or claim 2, wherein the method further comprises the step of determining whether the patient has moderate liver impairment.

5. The method according to claim 1 or claim 3, wherein the method further comprises the step of determining whether the patient has severe liver impairment.

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

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

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

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

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

11. The method according to claim 10, wherein the method further comprises the step of determining whether the patient has cancer comprising a KRAS G12C mutation.

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

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

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

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

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

17. The method according to 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. The method according to any one of claims 1 to 18, wherein the sotorasib is administered in the form of one or more tablets.

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

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

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