Sotorasib Dosing Regimen

Abstract

The present disclosure provides methods of administering sotorasib to a patient (e.g., a patient having a cancer containing a KRAS G12C mutation), wherein the patient is further in need of treatment with a breast cancer resistance protein (BCRP) substrate (e.g., rosuvastatin).

Description

[Background technology]

[0001] Sotorasib is a KRAS G12C Sotorasib is a small molecule that specifically and irreversibly inhibits the protein product of the mutant KRAS gene with an amino acid substitution of glycine to cysteine ​​at position 12 (KRAS G12C), which encodes a protein. 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]

[0002] [Non-Patent Document 1] Canon, 2019 [Non-patent document 2] Ostrem et al., 2016 [Non-patent document 3] Patricelli et al., 2016 [Non-patent document 4] Janes et al., 2018 [Non-patent document 5] McDonald et al., 2017 [Non-patent document 6] Xie et al., 2017 Summary of the Invention [Means for solving the problem]

[0003] In one aspect, described herein are methods of administering sotorasib to a patient (i.e., a subject in need thereof), wherein the patient is further in need of treatment with an initial dose of a breast cancer resistance protein (BCRP) substrate, the method comprising: (a) reducing the initial dose of the BCRP substrate to an adjustment dose of the BCRP substrate; and (b) administering to the patient (i) the adjustment dose of the BCRP substrate and (ii) sotorasib.

[0004] In another aspect, described herein are methods of administering a breast cancer resistance protein (BCRP) substrate to a patient, wherein the patient is further in need of treatment with sotorasib, the method comprising: (a) administering to the patient an adjusted dose of the BCRP substrate, wherein the adjusted dose is reduced compared to a patient not receiving treatment with sotorasib; and (b) administering sotorasib to the patient.

[0005] In another aspect, described herein are methods of treating cancer in a patient, wherein the patient is further in need of treatment with an initial dose of a breast cancer resistance protein (BCRP) substrate, the method comprising: (a) reducing the initial dose of the BCRP substrate to an adjustment dose of the BCRP substrate; and (b) administering to the patient (i) the adjustment dose of the BCRP substrate and (ii) a therapeutically effective amount of sotorasib.

[0006] In another aspect, described herein are methods of treating cancer in a patient, wherein the patient is further in need of treatment with an initial dose of a breast cancer resistance protein (BCRP) substrate, the method comprising: (a) administering to the patient a therapeutically effective amount of sotorasib while administering to the patient the initial dose of the BCRP substrate; (b) monitoring the patient after administration of sotorasib for an adverse reaction to the administered initial dose of the BCRP substrate; and if the patient has an adverse reaction, reducing the initial dose of the BCRP substrate to an adjustment dose of the BCRP substrate; and (c) administering to the patient (i) the adjustment dose of the BCRP substrate and (ii) a therapeutically effective amount of sotorasib. [Brief explanation of the drawings]

[0007] [Figure 1] 1 is a graph showing the arithmetic mean (+SD) of plasma concentration-time profiles for rosuvastatin after a single dose of 10 mg rosuvastatin alone and when co-administered with 960 mg sotorasib. [Figure 2] 1 is a graph showing the arithmetic mean (+SD) of the plasma concentration-time profile for sotorasib after a single dose of 960 mg sotorasib co-administered with 10 mg rosuvastatin. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present disclosure is based on the effect of sotorasib on pharmacokinetic (PK) breast cancer resistance protein (BCRP) substrates such as rosuvastatin.

[0009] BCRP substrate As used herein, the term "BCRP substrate" refers to a compound whose efflux from cells is mediated by BCRP. In vitro studies have shown that sotorasib is an inhibitor of BCRP, with a ratio of intestinal luminal concentration, estimated as dose / 250 mL (Igut) / half-maximal inhibitory concentration (IC50), exceeding the threshold for clinical evaluation set forth in the Food and Drug Administration (FDA) guidance (Food and Drug Administration. In Vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry; January 2020; available at https: / / www.fda.gov / regulatory-information / search-fda-guidance-documents / in-vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions; last accessed December 11, 2022). BCRP substrates include, but are not limited to, cytostatic agents such as cytostatic anthraquinones (e.g., mitoxantrone, bisantrene, azaanthrapyrazole), cytostatic anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, flavopiridol, or mitoxantrone), cytostatic antimetabolites (e.g., methotrexate), cytostatic camptothecins (e.g., 9-aminocamptothecin (Rubitecan), homocamptothecin, irinotecan, SN-38 (the active metabolite of irinotecan), SN-38-glucuronide, topotecan, or diflomotecan), and cytostatic epipodophyllotoxins (e.g., etoposide or teniposide).Other BCRP substrates include antibiotics such as ciprofloxacin, ofloxacin, norfoxacin, erythromycin, and nitrofurantoin, calcium channel inhibitors such as dipyridamole, nifedipine, and nitrendipine, glucuronide and sulfate conjugates such as benzo[a]pyrene-3-sulfate, benzo[a]pyrene-3-glucuronide, estrone-3-sulfate, dehydroepiandrosterone sulfate, and 17β-estradiosulfate, HMG- CoA reductase inhibitors such as rosuvastatin, pitavastatin, and cerivastatin, porphyrins such as heme, pheophorbide A, pyropheophorbide A-methyl ester, protoporphyrin IX, phytoporphyrin, antiviral drugs, especially nucleoside reverse transcriptase inhibitors such as zidovudine, lamivudine, abacavir, and combinations thereof, and substances such as cimetidine, folic acid, riboflavin, sulfasalazine, pantoprazole, imatinib mesylate (STI571), indocarbazole, and prazosin. In various cases, the BCRP substrate is rosuvastatin (see, e.g., Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 10 March 2020; available at www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers; last accessed December 11, 2022).

[0010] Methods for determining whether a compound is a substrate of BCRP are known in the art. For example, BCRP efflux activity can be assessed by monitoring the basolateral-to-apical / apical-to-basolateral (B-to-A / A-to-B) efflux ratio of a compound of interest in cells or cell lines expressing BCRP (see, e.g., Xia et al., 2005).

[0011] Rosuvastatin is a selective competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase indicated as adjunctive therapy to diet in adult patients with primary hyperlipidemia or mixed dyslipidemia. It is a known clinical substrate and probe for breast cancer resistance protein (BCRP) drug-drug interaction testing (see, e.g., Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 10 March 2020; available at www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers; last accessed December 11, 2022).

[0012] Clinical pharmacology results showed that peak plasma concentrations of rosuvastatin were achieved within 3 to 5 hours after oral administration. maxBoth RI and AUC increased approximately dose-proportionally. Absolute bioavailability was approximately 20%. Rosuvastatin was 88% bound to plasma proteins (primarily albumin), and the binding properties were reversible and independent of plasma concentration. It was largely unmetabolized, with approximately 10% of the radiolabeled dose recovered as metabolites. Rosuvastatin and its metabolites were primarily excreted in the feces (90%). The elimination half-life of the statin was approximately 19 hours. From a database of controlled clinical trials of rosuvastatin, the most commonly reported adverse reactions (incidence ≥2%) included headache, myalgia, abdominal pain, asthenia, and nausea. See Prescribing Information for CRESTOR® (rosuvastatin calcium) Tablets, May 2022 Update, AstraZeneca, which is incorporated herein by reference in its entirety.

[0013] Rosuvastatin is approved at a starting dose of 10-20 mg once daily, with 40 mg once daily being used only for patients who have not reached LDL-C goals with the 10-20 mg once daily dose. The 20 mg starting dose is typically used for patients with homozygous familial hypercholesterolemia. Rosuvastatin may be administered at a dose of 5-40 mg once daily, taking into account the patient's lipid levels that responded to the 20 mg starting dose. Rosuvastatin is available as tablets (i.e., CRESTOR® tablets) in dosage strengths of 5 mg, 10 mg, 20 mg, and 40 mg, or as capsules (i.e., EZALLOR® Sprinkle) in dosage strengths of 5 mg, 10 mg, 20 mg, and 40 mg. Rosuvastatin may be administered as a tablet or capsule.

[0014] Sotoracive Sotorasib is a KRAS G12CSotorasib is a small molecule that irreversibly inhibits mutant proteins. 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: [ka] It has the following characteristics.

[0015] 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. G12CIt 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 have 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.

[0016] BCRP is expressed in various tissues, including, but not limited to, the gastrointestinal tract, liver, kidney, and brain. Therefore, BCRP transporters may affect the oral bioavailability, tissue distribution, and hepatic and renal excretion of substrates. According to Food and Drug Administration (FDA) guidance, certain compounds may induce I-mediated BCRP transport when orally administered. gut / I C 50 or K i ≧10(I gut= dose of inhibitor / 250 mL), it has the ability to inhibit BCRP in vivo. Sotorasib has been found to be an inhibitor of the BCRP transporter in vitro. Therefore, coadministration of sotorasib with a BCRP substrate may increase exposure of this substrate, which may lead to an increased risk of adverse reactions of this substrate. Specifically, in vitro studies have shown that sotorasib inhibits BCRP at doses / 250 mL (I gut ) / half-maximal inhibitory concentration (IC 50 It has been shown to be an inhibitor of BCRP, with the ratio of estimated intestinal luminal concentration as β-lactam / β-lactam 2 (β-lactam / β-lactam 2) exceeding the threshold for clinical evaluation set forth by FDA guidance.

[0017] Methods for determining whether a compound is an inhibitor of BCRP are known in the art. For example, methods include determining the ability of a compound to inhibit the BCRP transporter and to what extent (i.e., IC 50 or K i The ability of a drug to inhibit up to 100% BCRP uptake can be determined by measuring the efflux ratio or net flux of known BCRP substrates in Caco-2 cells, where BCRP is overexpressed, or by measuring the uptake of the substrate when membrane vesicles are used. See, e.g., Food and Drug Administration. In Vitro Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry; January 2020; available at www.fda.gov / regulatory-information / search-fda-guidance-documents / in-vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions; last accessed December 11, 2022.

[0018] Dose adjustment for patients taking BCRP substrates and sotorasib The potential impact on patients receiving sotorasib therapy and BCRP substrate therapy must be assessed, and dosage adjustments may be necessary to ensure adequate BCRP substrate exposure. Accordingly, provided herein are methods of administering sotorasib to a patient, the patient further requiring treatment with a BCRP substrate at an initial dose, comprising: (a) reducing the initial dose of the BCRP substrate to an adjustment dose of the BCRP substrate; and (b) administering to the patient (i) the adjustment dose of the BCRP substrate and (ii) sotorasib. Also provided are methods of administering a BCRP substrate to a patient further requiring treatment with sotorasib, the method comprising: (a) administering to the patient an adjustment dose of the BCRP substrate, the adjustment dose being reduced compared to a patient not receiving sotorasib treatment; and (b) administering sotorasib to the patient.

[0019] The adjusted dose of the BCRP substrate is reduced (compared to the initial dose) to compensate for the increased exposure of the BCRP substrate from inhibition of the BCRP transporter by sotorasib. Inhibiting the BCRP transporter slows the clearance of the BCRP substrate, thereby increasing the exposure of the BCRP substrate. By adjusting (reducing) the dose of the BCRP substrate (the "adjusted dose"), when this adjusted dose is administered with sotorasib, the patient's final exposure to the BCRP substrate is maintained approximately the same as when the BCRP substrate is administered at the initial dose in the absence of sotorasib, so as to maintain the therapeutic efficacy of the BCRP substrate.

[0020] One skilled in the art can identify the initial dose or titration dose of a BCRP substrate by referring to the prescribing information associated with the BCRP substrate.

[0021] In various embodiments, the BCRP substrate is rosuvastatin. As described in the CRESTOR prescribing information, the initial dose of rosuvastatin for patients in need thereof is 10-20 mg once daily (see Section 2.1). The 40 mg once daily dose should only be used for patients who are not achieving LDL-C goals utilizing the 20 mg dose (ibid.). Rosuvastatin may be administered at doses of 5-40 mg once daily (ibid.). In various embodiments, the initial dose of rosuvastatin is 10 mg once daily. In various embodiments, the initial dose of rosuvastatin is 20-40 mg once daily. In various embodiments, the dose of rosuvastatin for patients not receiving sotorasib treatment is 20-40 mg once daily.

[0022] In the methods disclosed herein, the titration dose of rosuvastatin is 10 to less than 20 mg once daily (or 40 mg for patients not achieving LDL-C goals utilizing the 20 mg dose). In various embodiments, the titration dose of rosuvastatin is 5 mg once daily. In various embodiments, the titration dose of rosuvastatin is 10 mg once daily. In various embodiments, the titration dose of rosuvastatin is 20 mg once daily.

[0023] 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 described 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 sequence and amino acid sequence 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.

[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 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.

[0025] 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.

[0026] 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).

[0027] 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).

[0028] 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 may 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; Alizadeh 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.

[0029] 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.

[0030] 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 quantitative PCR assay for the detection of seven somatic mutations (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) in codons 12 and 13 of the human KRAS oncogene using a Rotor-Gene Q MDx 5plex HRM instrument. 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.

[0031] 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).

[0032] 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 showing either stable disease (SD) or partial response (PR) reported by Hong et al. 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))).

[0033] The KRAS G12C mutation occurs at the alteration frequencies shown in the table below (Cerami et al., 2012; Gao et al., 2013). For example, this table shows that 11.6% of patients with non-small cell lung cancer have cancer in which one or more cells have the KRAS G12C mutation. G12C Therefore, KRAS G12C Sotorasib, which specifically and irreversibly binds to, is useful for treating patients with cancers, including but not limited to those listed in Table 1 below.

[0034] [Table 1]

[0035] 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, hi some embodiments, the cancer is pancreatic cancer.

[0036] Embodiment 1. A method of administering sotorasib to a patient, the patient further requiring treatment with a breast cancer resistance protein (BCRP) substrate at an initial dose, the method comprising: (a) reducing the initial dose of the BCRP substrate to the adjustment dose of the BCRP substrate; and (b) administering to the patient (i) a titration dose of a BCRP substrate and (ii) sotorasib. A method comprising:

[0037] 2. A method of administering a breast cancer resistance protein (BCRP) substrate to a patient, wherein the patient is further in need of treatment with sotorasib, the method comprising: (a) administering to the patient an adjusted dose of a BCRP substrate, the adjusted dose being reduced compared to a patient not receiving treatment with sotorasib; and (b) administering sotorasib to the patient; A method comprising:

[0038] 3. The method of embodiment 1 or 2, wherein sotorasib is administered at a dose of 960 mg per day.

[0039] 4. The method of embodiment 1 or 2, wherein sotorasib is administered at a dose of 240 mg per day.

[0040] 5. The method according to any one of embodiments 1-3, wherein sotorasib is administered orally once daily.

[0041] 6. The method of any one of embodiments 1-5, wherein the BCRP substrate is rosuvastatin.

[0042] 7. The method of embodiment 6, wherein the initial dose of rosuvastatin is 20 to 40 mg orally per day.

[0043] 8. The method of embodiment 6, wherein the dose of rosuvastatin for patients not receiving treatment with sotorasib is 20-40 mg orally per day.

[0044] 9. The method of embodiment 6, wherein the adjusted dose of rosuvastatin is 10 mg orally per day.

[0045] 10. The method of embodiment 6, wherein the initial dose of rosuvastatin is 10 mg orally per day.

[0046] 11. The method of embodiment 6, wherein the dose of rosuvastatin for patients not receiving treatment with sotorasib is 10 mg orally per day.

[0047] 12. The method of embodiment 10 or 11, wherein the adjusted dose of rosuvastatin is 5 mg orally per day.

[0048] 13. The method according to any one of embodiments 6-12, wherein rosuvastatin is administered once daily.

[0049] 14. The method according to any one of embodiments 6 to 13, wherein rosuvastatin is administered as a tablet.

[0050] 15. The method according to any one of embodiments 6-13, wherein rosuvastatin is administered as a capsule.

[0051] 16. The method of embodiment 15, wherein the capsule is administered whole.

[0052] 17. The method according to embodiment 15, wherein the capsule is opened, mixed with a liquid, and then administered as a drink.

[0053] 18. The method of any one of embodiments 1-17, wherein the patient has a cancer comprising a KRAS G12C mutation.

[0054] 19. The method of embodiment 18, wherein the cancer is a solid tumor.

[0055] 20. The method of embodiment 18 or 19, 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.

[0056] 21. The method of any one of embodiments 18-20, 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, sinonasal cancer, or bile duct cancer.

[0057] 22. The method of any one of embodiments 18-20, wherein the cancer is non-small cell lung cancer.

[0058] 23. The method of embodiment 22, wherein the non-small cell lung cancer is locally advanced or metastatic.

[0059] 24. The method of any one of embodiments 18-20, wherein the cancer is colorectal cancer.

[0060] Alternative Embodiments 1. A method of administering sotorasib to a patient, the patient further requiring treatment with a breast cancer resistance protein (BCRP) substrate at an initial dose, the method comprising: (a) reducing the initial dose of the BCRP substrate to the adjustment dose of the BCRP substrate; and (b) administering to the patient (i) a titration dose of a BCRP substrate and (ii) sotorasib. A method comprising:

[0061] 2. A method of administering a breast cancer resistance protein (BCRP) substrate to a patient, wherein the patient is further in need of treatment with sotorasib, the method comprising: (a) administering to the patient an adjusted dose of a BCRP substrate, the adjusted dose being reduced compared to a patient not receiving treatment with sotorasib; and (b) administering sotorasib to the patient; A method comprising:

[0062] 3. A method of treating cancer in a patient, wherein the patient is further in need of treatment with a breast cancer resistance protein (BCRP) substrate at an initial dose, the method comprising: (a) reducing the initial dose of the BCRP substrate to the adjustment dose of the BCRP substrate; and (b) administering to the patient (i) a titrated dose of a BCRP substrate and (ii) a therapeutically effective amount of sotorasib. A method comprising:

[0063] 4. The method of any one of embodiments 1-3, further comprising monitoring the patient for adverse reactions to the BCRP substrate after administration of the first dose of the BCRP substrate.

[0064] 5. A method of treating cancer in a patient, wherein the patient is further in need of treatment with a breast cancer resistance protein (BCRP) substrate at an initial dose, the method comprising: (a) administering to the patient a therapeutically effective amount of sotorasib while administering to the patient a first dose of a BCRP substrate; (b) monitoring the patient for adverse reactions to the initial dose of the BCRP substrate after administration of sotorasib; and, if the patient experiences an adverse reaction, reducing the initial dose of the BCRP substrate to the titration dose of the BCRP substrate; and (c) administering to the patient (i) a titrated dose of a BCRP substrate and (ii) a therapeutically effective amount of sotorasib. A method comprising:

[0065] 6. The method according to any one of embodiments 1-5, wherein sotorasib is administered at a dose of 960 mg per day.

[0066] 7. The method of any one of embodiments 1-6, wherein sotorasib is administered at a dose of 240 mg per day.

[0067] 8. The method according to any one of embodiments 1-7, wherein sotorasib is administered orally once daily.

[0068] 9. The method of any one of embodiments 1-8, wherein the patient is (a) an adult patient with primary hyperlipidemia and mixed dyslipidemia; (b) a pediatric patient aged 8 to 7 years with heterozygous familial hypercholesterolemia (HeFH); (c) a pediatric patient aged 7 to 17 years with homozygous familial hypercholesterolemia (HoFH); (d) an adult patient with hypertriglyceridemia; (e) an adult patient with primary dysbetalipoproteinemia (type III hyperlipoproteinemia); or (f) an adult patient with homozygous familial hypercholesterolemia (HoFH).

[0069] 10. The method of any one of embodiments 1-9, wherein the BCRP substrate is rosuvastatin.

[0070] 11. The method of any one of embodiments 1-10, wherein the initial dose of rosuvastatin is 20-40 mg orally per day.

[0071] 12. The method of embodiment 10, wherein the dose of rosuvastatin for patients not receiving treatment with sotorasib is 20-40 mg orally per day.

[0072] 13. The method of embodiment 10, wherein the adjusted dose of rosuvastatin is 10 mg orally per day.

[0073] 14. The method of embodiment 10, wherein the initial dose of rosuvastatin is 10 mg orally per day.

[0074] 15. The method of embodiment 10, wherein the dose of rosuvastatin for patients not receiving treatment with sotorasib is 10 mg orally per day.

[0075] 16. The adjusted dose of rosuvastatin is 5 mg orally per day, embodiment 14. Or the method described in 15.

[0076] 17. The method according to any one of embodiments 10-16, wherein rosuvastatin is administered once daily.

[0077] 18. The method according to any one of embodiments 10-17, wherein rosuvastatin is administered as a tablet.

[0078] 19. The method according to any one of embodiments 10-18, wherein rosuvastatin is administered as a capsule.

[0079] 20. The method of embodiment 19, wherein the capsule is administered whole.

[0080] 21. The method according to embodiment 19, wherein the capsule is opened, mixed with a liquid, and then administered as a drink.

[0081] 22. The method of any one of embodiments 1-21, wherein the patient has a cancer comprising a KRAS G12C mutation.

[0082] 23. The method of embodiment 22, wherein the cancer is a solid tumor.

[0083] 24. The method of embodiment 22 or 23, 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.

[0084] 25. The method of any one of embodiments 22-24, 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, sinonasal cancer, or bile duct cancer.

[0085] 26. The method of any one of embodiments 22-24, wherein the cancer is non-small cell lung cancer.

[0086] 27. The method of embodiment 26, wherein the non-small cell lung cancer is locally advanced or metastatic.

[0087] 28. The method of any one of embodiments 22-24, wherein the cancer is colorectal cancer. [Example]

[0088] Example 1 - A Phase I, Open-Label, Fixed-Sequence, Crossover Study to Investigate the Effect of Co-Administration of Sotorasib on the Pharmacokinetics of Rosuvastatin, a Breast Cancer Resistance Protein Substrate, in Healthy Subjects The objective of this study was to evaluate the effect of coadministration of sotorasib on the PK of rosuvastatin (a BCRP substrate) after oral administration in healthy subjects.

[0089] the purpose The primary objectives of this study were to determine the effect of sotorasib on the PK of rosuvastatin and to evaluate the PK of rosuvastatin when administered alone in healthy subjects.

[0090] The secondary objectives of this study were: - To evaluate the safety and tolerability of sotorasib when co-administered with rosuvastatin and when administered alone in healthy subjects; and - To evaluate the PK of sotorasib when co-administered with rosuvastatin.

[0091] endpoint The primary endpoints of this study were the following rosuvastatin PK parameters: -C max - AUC from time 0 to the time of the last quantifiable concentration (AUC last ) - AUC extrapolated from time 0 to infinity (AUC inf ).

[0092] Secondary endpoints of this study were: - Adverse events - Clinical testing - 12-lead electrocardiogram (ECG) - Vital signs - Sotorasib PK parameters following administration of sotorasib in combination with rosuvastatin, including but not limited to: -C max - AUC last - AUC inf .

[0093] Overall study design and plan: This was a Phase I, open-label, fixed-sequence, crossover study to investigate the effect of coadministration of sotorasib on the PK of rosuvastatin in healthy male and healthy female subjects. To ensure that 12 subjects completed the study, approximately 14 subjects were planned for enrollment, with 13 subjects ultimately enrolled. All subjects received one of the following treatments: - Day 1: A single oral dose of 10 mg rosuvastatin (1 x 10 mg tablet) after an overnight fast of at least 10 hours. - Day 6: A single oral dose of 960 mg sotorasib (8 x 120 mg tablets) immediately followed by a single oral dose of 10 mg rosuvastatin (1 x 10 mg tablet) after an overnight fast of at least 10 hours.

[0094] Potential subjects were screened to assess eligibility for study participation within 21 days prior to receiving their first dose. Subjects were admitted to the Clinical Research Unit (CRU) on Day -1 and remained in the CRU until discharge on Day 11.

[0095] The total duration of study participation for each subject (from screening to end-of-study [EOS] discharge) was expected to be approximately 4.5 weeks.

[0096] Selection of study population: Healthy male and female subjects were used in this study.

[0097] treatment The study treatments administered were sotorasib and rosuvastatin.

[0098] Rosuvastatin was administered as a single 10 mg dose (1 x 10 mg tablet) on day 1. On day 6, sotorasib was administered as a single 960 mg dose (8 x 120 mg tablets) followed immediately (within 5 minutes) by a single 10 mg dose of rosuvastatin.

[0099] Rosuvastatin on Day 1 and sotorasib and rosuvastatin on Day 6 were administered orally with 8 ounces (240 mL) of water (with additional water as needed during dosing). All subjects fasted overnight (at least 10 hours) and abstained from water intake for 1 hour prior to dosing. Subjects abstained from water intake until 2 hours after dosing, excluding the amount of water ingested at the time of dosing, and fasted until 4 hours after dosing. At all other time points during the study, subjects had free access to water.

[0100] Subjects were dosed in an upright position and were not permitted to assume a supine position for 2 hours after administration of investigational and non-investigational medications unless required by the occurrence of an adverse event or for study procedures.

[0101] Method of assigning subjects to treatment groups: This was a non-randomized study with a fixed treatment sequence, in which each subject received 10 mg rosuvastatin on day 1 and 960 mg sotorasib co-administered with 10 mg rosuvastatin on day 6.

[0102] Previous and concomitant treatments Unless previously agreed to by the investigator (or designee), the sponsor, or both, subjects were to refrain from using any prescription or non-prescription medications or products during the study until the EOS visit.

[0103] Acetaminophen (paracetamol; maximum 2 g / day) and hormone replacement therapy were acceptable concomitant medications. Administration of any other concomitant medications during this study was prohibited without prior approval of the investigator (or designee), unless their use was deemed necessary for the treatment of an adverse event / serious adverse event. All medications taken by subjects during the course of the study, and the reason for their use, were recorded in the source data.

[0104] Specific Restrictions and Requirements (1) Meals - While housed in the testing facility, subjects consumed standardized meals at scheduled times consistent with other test-related activities. Subjects fasted overnight (at least 8 hours) before blood samples were taken for clinical laboratory evaluation. - No food or drink containing poppy seeds, grapefruit, or Seville oranges was permitted from 7 days before check-in until the end of the study. - No food or drink containing caffeine was permitted from 48 hours before check-in until the end of the study. - No alcohol was permitted from 48 hours before check-in until the end of the study.

[0105] (2) Smoking - Subjects were not permitted to use tobacco or nicotine-containing products within 6 months prior to check-in until the end of the study.

[0106] (3) Exercise - Subjects were asked to refrain from strenuous exercise from 7 days prior to check-in until the end of the study and to otherwise maintain their usual level of physical activity during this period (i.e., not starting a new exercise program or participating in any unusually strenuous physical activity).

[0107] (4) Blood donation - Subjects were asked to refrain from donating blood for 90 days before check-in, from donating plasma components for 2 weeks before check-in, and from donating platelets for 6 weeks before check-in until 3 months after the end of the study.

[0108] Pharmacokinetic and safety variables Blood samples were collected by venipuncture or intubation to measure the plasma concentrations of sotrasib and rosuvastatin. Blood samples for determining plasma concentrations and PK parameters of rosuvastatin were collected at 0 hours and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 120 hours after rosuvastatin administration on days 1 and 6.

[0109] Blood samples for determination of sotorasib plasma concentrations and PK parameters were collected at 0 hours and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hours after sotorasib administration on Day 6. The PK sample collected 30 minutes after administration had a sampling window of ±2 minutes. Samples taken 1 to 3 hours after administration had a sampling window of ±5 minutes. Samples taken 4 to 10 hours after administration had a sampling window of ±10 minutes. Samples taken 12 to 48 hours post-dose had a sampling window of ±20 minutes. Times for all PK samples were recorded in minutes.

[0110] Pharmacokinetic analysis was performed using the actual administered dose (mg) and actual post-dose blood sampling time. If the actual time was not recorded, it was set as missing and excluded from the PK analysis and statistics with the sponsor's approval.

[0111] Parameter C max , the time of the last quantifiable plasma concentration (t last ), and t max was obtained directly from the concentration-time profile. For multiple peaks, the highest post-dose concentration was designated C max When multiple peaks were of equal magnitude, the earliest t max reported.

[0112] Vital signs Supine blood pressure, supine heart rate, respiratory rate, and oral temperature were assessed.

[0113] All measurements were performed independently and were to be repeated once if outside the relevant clinical reference range.

[0114] Subjects were required to be in the supine position for at least 5 minutes before blood pressure and heart rate measurements. If vital signs were scheduled at the same time as blood draw, they were drawn at the scheduled time, and vitals were obtained as close as possible to the scheduled blood draw but before the blood draw.

[0115] Electrocardiography A resting 12-lead ECG was recorded after the subject was in the supine position and had been at rest for at least 5 minutes.

[0116] A single 12-lead ECG was repeated twice, and the three readings were averaged if any of the following criteria were met: - QT interval corrected for heart rate using the Fridericia formula (QTcF) was greater than 500 ms. - The change in QTcF from baseline (pre-dose) was greater than 60 milliseconds.

[0117] Additional 12-lead ECGs may be performed at other time points if deemed clinically appropriate or if continuing examination of the data suggests the need for more detailed evaluation of the ECG. The investigator (or designee) performed a clinical evaluation of each 12-lead ECG.

[0118] Demographic and other baseline characteristics All subjects met the inclusion and exclusion criteria prior to participation in this study. None of the subjects had baseline signs or symptoms of clinical concern prior to dosing. A summary of screening demographics is shown in Table 2.

[0119] [Table 2]

[0120] Pharmacokinetic evaluation The following PK analysis considerations were noted: Per sponsor request, three plasma samples (from two subjects) were re-assayed to identify statistical outliers or abnormalities. The repeat PK analysis confirmed the initial results, and therefore no changes were applied to the initial data tables. As a result, no data were excluded from the PK analysis.

[0121] The PK sampling time (4 hours post-dose on Day 6) for one subject was not recorded; the data point was set to missing and excluded from the PK analysis and statistics.

[0122] A quantifiable pre-dose concentration of rosuvastatin for one subject was excluded from summary statistics and PK analysis due to an abnormal value on Day 1; the pre-dose value was C max Quantifiable pre-dose concentrations of rosuvastatin on day 6 for the same subjects were not excluded from the summary statistics because they were less than 5% of the mean.

[0123] The arithmetic mean (+SD) of the plasma concentration-time profiles of rosuvastatin after a single dose of 10 mg rosuvastatin alone and when co-administered with 960 mg sotorasib are shown in Figure 1. A summary of the PK parameters of rosuvastatin is shown in Table 3, and a summary of the statistical analysis of the PK data is shown in Table 4.

[0124] [Table 3]

[0125] t of rosuvastatin after coadministration max The median exposure was 2 hours, compared with 3 hours when administered alone. The geometric mean exposure of rosuvastatin was measured by AUC and C max Based on the data, it was numerically higher after coadministration with sotorasib.

[0126] The intersubject variability (geometric CV%) of rosuvastatin for AUC and Cmax when administered alone and in combination with sotorasib ranged from 57.0% to 136.0%. Two subjects (one subject at 2 hours post-dose and another subject at 2 and 3 hours post-dose) had plasma concentration values ​​determined as outliers or abnormal values ​​on Day 6, which may have contributed to the high variability in the results.

[0127] [Table 4]

[0128] The ratio (test / reference) of GLSM for rosuvastatin co-administered with sotorasib compared with rosuvastatin alone was AUC last , AUC inf , and C max The corresponding values ​​were 1.3389, 1.3382, and 1.6999, respectively.

[0129] Pharmacokinetic evaluation of sotorasib administered in combination with rosuvastatin The arithmetic mean (+SD) of the plasma concentration-time profile of sotorasib after a single dose of 960 mg sotorasib co-administered with 10 mg rosuvastatin is shown in Figure 2. A summary of the PK parameters of sotorasib is shown in Table 5.

[0130] [Table 5]

[0131] Sotrasib t max The median (range) of C was 1.00 hours (0.500-3.00 hours). The geometric mean (geometric CV) C for sotorasib max , AUC last , and AUC inf were 4650 (86.2) ng / mL, 22500 (74.3) h*ng / mL, and 22900 (71.7) h*ng / mL, respectively.

[0132] AUC and C when sotorasib is administered in combination with rosuvastatin max The inter-subject variability (geometric CV%) of sotorasib was 71.7% to 86.2%.

[0133] Adverse events Treatment-emergent adverse events were classified as follows: (1) Treatment-emergent adverse events occurring during or after administration on Day 1 and before administration on Day 6 were assigned to "10 mg rosuvastatin," or (2) Treatment-emergent adverse events occurring during or after administration on Day 6 were assigned to "960 mg sotorasib + 10 mg rosuvastatin."

[0134] No treatment-emergent adverse events were reported during or after administration of rosuvastatin alone or co-administration of sotorasib and rosuvastatin. There were no deaths, treatment-emergent adverse events leading to study discontinuation, or other serious treatment-emergent adverse events.

[0135] conclusion When rosuvastatin was coadministered with sotorasib, the AUC and C max were approximately 1.3 to 1.7 times those of rosuvastatin alone, respectively. A single oral dose of 10 mg of rosuvastatin alone or in combination with 960 mg of sotorasib was safe and well tolerated when administered to healthy male and female subjects in this study.

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Claims

1. 1. A pharmaceutical composition comprising sotorasib for use in a method of administering sotorasib to treat cancer in a patient, wherein the patient is further in need of treatment with a breast cancer resistance protein (BCRP) substrate at an initial dose; The method comprises: (a) reducing said initial dose of BCRP substrate to a titration dose of BCRP substrate; and (b) administering to said patient (i) the titration dose of a BCRP substrate, wherein the titration dose is 10 mg or 5 mg, and (ii) sotorasib, wherein the titration dose is 240 mg or 960 mg per day. A pharmaceutical composition comprising:

2. 1. A pharmaceutical composition comprising sotorasib for use in a method of administering a breast cancer resistance protein (BCRP) substrate to a patient, wherein the patient is further in need of treatment with sotorasib; The method comprises: (a) administering to the patient an adjusted dose of a BCRP substrate, wherein the adjusted dose is reduced compared to a patient not receiving sotorasib treatment and is 10 mg or 5 mg; and (b) administering to said patient sotorasib at a dose of 240 mg or 960 mg per day. A pharmaceutical composition comprising:

3. 1. A pharmaceutical composition comprising sotorasib for use in a method of treating cancer in a patient, wherein the patient is further in need of treatment with a breast cancer resistance protein (BCRP) substrate at an initial dose; The method comprises: (a) administering to said patient a dose of 240 mg or 960 mg per day of sotorasib while administering to said patient an initial dose of said BCRP substrate; (b) monitoring the patient after administration of sotorasib for an adverse reaction to the initial dose of BCRP substrate; and, if the patient experiences an adverse reaction, reducing the initial dose of BCRP substrate to a 10 mg or 5 mg adjustment dose of BCRP substrate; and (c) administering to said patient (i) said adjusted dose of a BCRP substrate and (ii) said sotorasib. A pharmaceutical composition comprising:

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein sotorasib is administered at a dose of 960 mg per day.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein sotorasib is administered at a dose of 240 mg per day.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein sotorasib is orally administered once a day.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the BCRP substrate is rosuvastatin.

8. 8. The pharmaceutical composition of claim 7, wherein the initial dose of rosuvastatin is 20 to 40 mg orally per day.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient has a cancer comprising a KRAS G12C mutation.

10. The pharmaceutical composition of claim 9, wherein the cancer is a solid tumor.

11. 10. The pharmaceutical composition of claim 9, 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, paranasal sinus cancer, or bile duct cancer.

12. 10. The pharmaceutical composition of claim 9, 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, sinonasal cancer, or bile duct cancer.

13. The pharmaceutical composition of claim 9, wherein the cancer is non-small cell lung cancer.

14. The pharmaceutical composition of claim 13, wherein the non-small cell lung cancer is locally advanced or metastatic.

15. The pharmaceutical composition of claim 9, wherein the cancer is colorectal cancer.

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