WO2025101623A1 - Methods of treating cancer - Google Patents

Abstract

Provided herein are methods of treating cancer comprising a KRAS G12C mutation in a patient in need of treatment, the method comprising administering to the patient (a) a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of an epidermal growth factor receptor (EGFR) antibody, and (c) (1) a therapeutically effective amount of oxaliplatin, (2) a therapeutically effective amount of leucovorin or a therapeutically effective amount of levoleucovorin, and (3) a therapeutically effective amount of 5-fluorouraciI (5-FU).

Description

METHODS OF TREATING CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/596,873, filed November 7, 2023, which is hereby incorporated by reference in its entirety.

SUBMISSION OF SEQUENCE LISTING

[0002] The content of the following Sequence Listing is incorporated herein by reference in its entirety: file name: 55355P_Seqlisting.txt, date created: November 7, 2023; size: 10,082 bytes.

BACKGROUND

[0003] The rat sarcoma (RAS) proto-oncogene has been identified as an oncogenic driver of tumorigenesis in cancers, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The RAS family consists of 3 closely related genes that express guanosine triphosphate (GTP)-ases responsible for regulating cellular proliferation and survival (Simanshu et al, 2017). The RAS proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS) (Hall et al, 1983; Taparowsky et al, 1983; Chang et al, 1982; Kirsten and Mayer, 1967; Harvey, 1964), can be mutationally activated at codons 12, 13, or 61, leading to human cancers. Different tumor types are associated with mutations in certain isoforms of RAS, with KRAS being the most frequently mutated isoform in most cancers (Prior et al, 2012). While the role of KRAS mutations in human cancers has been known for decades, no anti-cancer therapies specifically targeting KRAS mutations have been successfully developed, until recently, largely because the protein had been considered intractable for inhibition by small molecules (McCormick, 2016).

SUMMARY

[0004] Described herein are methods of treating cancer comprising a KRAS G12C mutation in a patient in need of treatment, the method comprising administering to the patient (a) a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of an epidermal growth factor receptor (EGFR) antibody, and (c) (1) a therapeutically effective amount of oxaliplatin, (2) a therapeutically effective amount of leucovorin or a therapeutically effective amount of levoleucovorin, and (3) a therapeutically effective amount of 5-fluorouracil (5-FU). In some embodiments, the EGFR antibody is an EGFR antagonist. In some embodiments, the EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8. In some embodiments, the EGFR antibody comprises the heavy chain variable region sequence of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 9. In some embodiments, the EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10. In some embodiments, the EGFR antibody is panitumumab. In some embodiments, the drug regimen under Item (c) above is a FOLFOX regimen. [0005] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is metastatic colorectal cancer. In some embodiments, the cancer is non-small cell lung cancer, and in some cases, the cancer is metastatic or locally advanced non-small cell lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

DETAILED DESCRIPTION

[0006] The addition of an EGFR antibody (e.g., the EGFR antagonist panitumumab) to a FOLFOX regimen, while shown to benefit subjects with KRAS wild-type colorectal cancer (ORC), was found to be detrimental to subjects with KRAS mutant ORC (Douillard et al., 2010). A similar finding was observed in the OPUS and COIN studies with cetuximab, an antibody and EGFR antagonist in combination with oxaliplatin based regimens (Maughan et al, 2011; Bokemeyer et al, 2011). Provided herein is the surprising discovery that the combination therapy of an EGFR antibody and a FOLFOX-type regimen was effective in treating a cancer having a KRAS mutation, when sotorasib was also administered. Thus, provided herein are methods of treating cancer comprising a KRAS G12C mutation in a patient in need of treatment, the method comprising administering to the patient (a) a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of an EGFR antibody, and (c) (1) a therapeutically effective amount of oxaliplatin, (2) a therapeutically effective amount of leucovorin or a therapeutically effective amount of levoleucovorin, and (3) a therapeutically effective amount of 5-fluorouracil (5-FU).

[0007] Without wishing to be bound by any particular theory, the following is noted: sotorasib at 960 mg QD was shown to be safe and effective under study conditions under Study 20170543 (https://clinicaltrials.gov/ct2/show/NCT03600883; CodeBreaK100). Since resistance to sotorasib may be mediated by upregulation of signaling through epidermal growth factor receptor (EGFR) pathway, adding an EGFR antagonist to sotorasib therapy may block bypass activation of the mitogen activated kinase (MAPK) signaling and lead to improved anti-tumor activity. 5-Fluoropyrimidine-based chemotherapy regimens (FOLFIRI and FOLFOX) are the recommended chemotherapy backbone regimens for metastatic ORC (National Comprehensive Cancer Network [NOON] Colon Cancer Guidelines, version 2, 2023; NCCN Rectal Cancer Guidelines, version 3, 2023, and the European Society for Medical Oncology [ESMO] mCRC Guidelines, Cervantes A, et al. ESMO Guidelines Committee, 2023). Both FOLFIRI and FOLFOX have been combined successfully with panitumumab in phase 3 studies of metastatic colorectal cancer (Peeters et al, 2010; Douillard et al., 2010).

[0008] The benefit for the addition of panitumumab to both FOLFIRI and FOLFOX regimens was restricted to the KRAS wildtype population. In the KRAS mutant population, studies evaluating EGFR antibody in combination with FOLFOX, have demonstrated lower progression free survival (PFS) and overall survival (OS), however, the mechanism for this effect is unknown (Maughan et al, 2011; Bokemeyer et al, 2011; Douillard et al, 2010).

[0009] While retrospective studies have shown a detrimental impact with the use of EGFR antibodies added to oxaliplatin-based regimens, such as FOLFOX, in patients with KRAS mutant metastatic colorectal cancer (mCRC), described herein is a study demonstrating whether blockade of abnormal KRAS signaling with sotorasib in patients with KRAS G12C mutant mCRC can mitigate this negative impact.

[0010] The methods of treatment disclosed herein include concomitant administration of the therapeutics (e.g., within 1 hour, within 45 minutes, within 30 minutes, within 15 minutes, or within 10 minutes of each other), and sequential administration (e.g., administration separated by at least 1 hour, or at least two hours, or at least four hours, or at least six hours, or at least eight hours, or at least twelve hours, or at least 24 hours, or at least 2 days, or at least 3 days). Unless otherwise described herein, combination therapy as discussed herein include both concomitant and sequential administration.

[0011] Sotorasib

[0012] Sotorasib is a small molecule that irreversibly inhibits the KRAS^G12C mutant protein. Sotorasib is also referred to 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(1/-/)-one and has the following structure:

[0013] Sotorasib binds to the P2 pocket of KRAS adjacent to the mutant cysteine at position 12 and the nucleotide-binding pocket. The inhibitor contains a thiol reactive portion which covalently modifies the cysteine residue and locks KRAS^G12C 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 the phosphorylation of extracellular signal regulated kinase (ERK) (Canon et al., 2019; Simanshu et al., 2017; Ostrem et al., 2013). Inactivation of KRAS through a small molecule inhibitor has previously demonstrated an 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; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016). Studies with sotorasib have confirmed these in vitro findings and have likewise demonstrated inhibition of growth and regression of cells and tumors harboring KRAS G12C mutations (Canon et al., 2019). See also, LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California 91320 (revision 4/2023), which is herein incorporated by reference in its entirety. In some embodiments, the methods disclosed herein comprise administering 960 mg sotorasib once daily to the patient. In some embodiments, the methods disclosed herein comprise administering 480 mg sotorasib once daily to the patient. In some embodiments, the methods disclosed herein comprise administering 240 mg sotorasib once daily to the patient.

[0014] In some embodiments, sotorasib is administered as a free base. In some embodiments, sotorasib is administered as a pharmaceutically acceptable salt. For clarity the term "sotorasib” as used herein refers to the free base of sotorasib unless otherwise noted. Any method described herein referencing sotorasib can also be practiced using a pharmaceutically acceptable salt of sotorasib. In some embodiments, sotorasib can be administered as a hydrochloride, phosphate, or mesylate. In some embodiments, sotorasib can be administered as a hydrochloride. In some embodiments, sotorasib can be administered as a phosphate. In some embodiments, sotorasib can be administered as a mesylate. For clarity, if a method provided herein recites, e.g., the administration of 960 mg of sotorasib or a pharmaceutically acceptable salt thereof to a subject, the method calls for the administration 960 mg of the free base of sotorasib or the amount of a pharmaceutically acceptable salt that corresponds to the administration of 960 mg of free base of sotorasib.

[0015] The term "pharmaceutically acceptable” refers to a species or component that is generally safe, nontoxic, and neither biologically nor otherwise undesirable for use in a subject, such as a human.

[0016] The term "pharmaceutically acceptable salt” refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed 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 either is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or associates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine). Additionally, the salts of the compounds described herein, can exist in either hydrated or anhydrous form or as solvates with other solvent molecules.

[0017] Epidermal Growth Factor Receptor (EGFR) antibody

[0018] In some embodiments, the methods further comprise administering an EGFR antibody to the patient. In some embodiments, the EGFR antibody is an antagonist. In some embodiments, the EGFR antibody comprises the heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8. In some embodiments, the EGFR antibody comprises the heavy chain variable region sequence of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 9. In some embodiments, the EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10. In some embodiments, the EGFR antibody is panitumumab.

[0019] Panitumumab is a fully human immunoglobulin (lg)G2 monoclonal antibody to the epidermal growth factor receptor (EGFR). Panitumumab binds to the extracellular domain of EGFR, thus preventing its activation and intracellular signaling. It was initially approved by the US Food and Drug Administration (FDA) on 27 September 2006, for the treatment of patients with EGFR expressing metastatic CRC after disease progression on, or following fluoropyrimidine-, oxaliplatin-, and irinotecan- containing chemotherapy regimens (Giusti et al, 2007) based on the results of a phase 3 randomized trial of panitumumab plus best supportive care vs best supportive care alone that demonstrated a statistically significant improvement in PFS in the panitumumab plus best supportive care arm (Van Cutsem et al, 2007). Retrospective subset analyses of metastatic CRC trials did not show a treatment benefit for panitumumab in subjects whose tumors contained a KRAS mutation in codon 12 or 13 and use of panitumumab was thus not recommended for treatment of CRC with a KRAS mutation in codon 12 or 13. On 23 May 2014, the US FDA approved panitumumab for use in combination with FOLFOX for first-line treatment in patients with wild-type RAS (exon 2) mCRC based on the results of the PRIME and ASPECCT trials

[0020] The recommended dose is 6 mg/kg, administered as an IV infusion over 60 minutes (< 1000 mg) or 90 minutes (> 1000 mg), every 14 days (Q2W). See also, VECTIBIX® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 8/2021), which is herein incorporated by reference in its entirety.

[0021] FOLFOX

[0022] In some embodiments, the methods described herein further comprise administering a modified FOLFOX regimen comprising oxaliplatin, leucovorin (or levoleucovorin), and 5-fluorouracil (5-FU) to the patient.

[0023] In some cases, the FOLFOX regimen is a modified FOLFOX6 (mFOLFOX6), which consists of oxaliplatin 85 mg/m² IV on day 1, leucovorin 400 mg/m² IV on day 1, and 5-fluorouracil 400 mg/m² IV bolus on day 1 and 2400 mg/m² IV continuous infusion (I VCI) over 46 to 48 hours beginning on day 1 given every two weeks (Q2W) (National Comprehensive Cancer Network (NCCN) Colon Cancer Guidelines version 2.2023; NCCN Rectal Cancer Guidelines version 3.2023; and Cervantes et al., EMSO mCRC Guidelines 2023). Oxaliplatin (e.g., ELOXATIN® US Prescribing Information, Sanofi-aventis U.S. LLC, Bridgewater, New Jersey 08807 (revision 4/2020), which is herein incorporated by reference in its entirety), in combination with infusional 5-FU (e.g., US Prescribing Information, Gland Pharma Limited, India (revision 9/2022), which is herein incorporated by reference in its entirety) and leucovorin (e.g., US Prescribing Information, Bedford Laboratories, Bedford, Ohio 44146 (revision 11/2011), which is herein incorporated by reference in its entirety) is FDA- approved for adjuvant treatment of stage 3 colon cancer in patients who have undergone complete resection of the primary tumor and in the treatment of advanced CRC. In some embodiments, levoleucovorin at 200 mg/m² can be used instead of 400 mg/m² leucovorin. See, e.g., Levoleucovorin Injection, US Prescribing Information, Sandoz, Inc., Princeton, New Jersey 08540, USA (revision 11/2013), which is herein incorporated by reference in its entirety.

[0024] In some embodiments, the modified FOLFOX regimen is FOLFOX4 (FOLFOX4, NOON Clinical Practice Guidelines in Oncology: Colon Cancer Version 4/2020), which consists of oxaliplatin 85 mg/m² on day 1 , leucovorin 200 mg/m² on day 1, and 5-fluorouracil 400 mg/m² IV bolus on day 1, and 600 mg/m² IV continuous infusion (IVCI) over 22 hours, then leucovorin 200 mg/m² on day 2, and 5-fluorouracil 400 mg/m² IV bolus on day 2, and 600 mg/m² IV continuous infusion (IVCI) over 22 hours, given every two weeks.

[0025] Dosing Regimens

[0026] In some embodiments, the methods comprise administering therapeutic agents (e.g., sotorasib, panitumumab, oxaliplatin, leucovorin or levoleucovorin, 5-fluorouracil, and combinations thereof) in doses at particular time points as part of a dosing regimen.

[0027] In some embodiments, the methods comprise administering sotorasib in an amount ranging from 240 mg to 960 mg. In some embodiments, the methods comprise administering 960 mg sotorasib to the patient once daily. In some embodiments, the methods comprise administering 480 to the patient once daily. In some embodiments, the methods comprise administering 240 mg to the patient once daily. In some embodiments, sotorasib is administered as a solid dosage form. In some embodiments, the solid dosage form is a tablet. In some embodiments, sotorasib is administered orally. In some embodiments, sotorasib, when given to patients with difficulties swallowing, may be given as a dispersion of one or more tablets comprising a therapeutically effective amount of sotorasib in 120 mL (4 ounces) of non-carbonated, room-temperature water without crushing. The dispersion is prepared by stirring the one or more tablets in water in a container until the tablets are dispersed into small pieces. The dispersion should be administered to the patient immediately or within 2 hours. Subsequently, the container is rinsed with an additional 120 mL (4 ounces) of water and the water used for rinsing is administered to the patient. In some embodiments, sotorasib is administered with food. In some embodiments, sotorasib is administered without food.

[0028] In some embodiments, the methods comprise administering panitumumab to the patient once every two weeks (Q2W). In some embodiments, the methods comprise administering an EGFR antibody (e.g., panitumumab) in an amount ranging from 3.0 mg/kg to 6 mg/kg {e.g., 3.0 mg/kg, 3.1 mg/kg, 3.2 mg/kg, 3.3 mg/kg, 3.4 mg/kg, 3.5 mg/kg, 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/kg, 4.0 mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg, 4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg, 5 mg/kg, 5.1 mg. kg, 5.2 mg/kg, 5.3 mg/kg, 5.4 mg/kg, 5.5 mg/kg, 5.6 mg/kg, 5.7 mg/kg, 5.8 mg/kg, 5.9 mg/kg, or 6 mg/kg) via IV administration once every two weeks. In some embodiments, the methods comprise administering 6 mg/kg panitumumab. In some embodiments, the methods comprise administering 4.8 mg/kg panitumumab. In some embodiments, the methods comprise administering 3.6 mg/kg panitumumab. In some embodiments, panitumumab will be administered as an IV infusion over 60 min (equal or less than 1000 mg) or 90 minutes (more than 1000 mg) Q2W. In some embodiments, panitumumab is administered intravenously using a low-protein binding 0.2 pm or 0.22 m in-line filter. In some embodiments, panitumumab may be administered over 30 to 60 minutes for doses of 1000 mg or less.

[0029] In some embodiments, the methods further comprise administering 85 mg/m² oxaliplatin to the patient every two weeks. In some embodiments, oxaliplatin is administered to the patient intravenously in 500 mL D5W (5% dextrose in water) over 90 minutes every two weeks.

[0030] In some embodiments, the methods further comprise administering leucovorin to the patient. In some embodiments, the methods comprise administering 400 mg/m² leucovorin to the patient every two weeks. Alternatively, in some embodiments, the methods further comprise administering levoleucovorin to the patient. In some embodiments the methods comprise administering 200 mg/m² levoleucovorin to the patient every two weeks. In some embodiments, the leucovorin or levoleucovorin is administered to the patient intravenously. In some embodiments, the leucovorin or levoleucovorin is administered to the patient in 500 mL D5W (5% dextrose in water) over 120 minutes every two weeks concurrently with oxaliplatin. Oxaliplatin and leucovorin (or levoleucovorin) can be infused at the same time, e.g., in separate bags using a Y-site connector.

[0031] In some embodiments, the methods further comprise administering 2800 mg/m²5-FU to the patient every two weeks. In some embodiments the methods comprise administering 2800 mg/m²5-FU are administered in two separate doses of 400 mg/m²5-FU and 2400 mg/m²5-FU. In some embodiments the 5-FU is administered to the patient intravenously. In some embodiments, the 5-FU is administered to the patient in a bolus intravenous push over 5 minutes (e.g., 400 mg/m²5-FU of the 2800 mg/m² total 5-FU dose), after the patient was administered oxaliplatin and leucovorin (or levoleucovorin). In some embodiments the 5-FU is administered to the patient in an intravenous continuous infusion (I VCI) in 500 mL D5W (5% dextrose in water) over 46 to 48 hours (e.g., the 2400 mg/m²5-FU of the 2800 mg/m² total 5-FU dose), via a suitable means, such as an ambulatory infusion device after the patient was administered the 5-FU bolus dose.

[0032] In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; (b) 6 mg/kg panitumumab via IV administration on day 1 of every two week cycle; and (c) (1) on day 1 of every two week cycle of 85 mg/m² oxaliplatin IV, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin, and (3) 400 mg/m²5-FU IV bolus on day 1 of every two week cycle and 2400 mg/m²5-FU IV continuous infusion over 46-48 hours beginning on day 1 of every two week cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 480 mg sotorasib daily; (b) 6 mg/kg panitumumab via IV administration on day 1 of every two week cycle; and (c) (1) on day 1 of every two week cycle of 85 mg/m² oxaliplatin IV, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin, and (3) 400 mg/m²5-FU IV bolus on day 1 of every two week cycle and 2400 mg/m²5-FU IV continuous infusion over 46-48 hours beginning on day 1 of every two week cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg sotorasib daily; (b) 6 mg/kg panitumumab via IV administration on day 1 of every two week cycle; and (c) (1) on day 1 of every two week cycle of 85 mg/m² oxaliplatin IV, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin, and (3) 400 mg/m²5-FU IV bolus on day 1 of every two week cycle and 2400 mg/m²5-FU IV continuous infusion over 46-48 hours beginning on day 1 of every two week cycle.

[0033] In some embodiments, the patient is in further need of treatment with an acid-reducing agent. Acidreducing agents include, but are not limited to, a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), and a locally acting antacid. In some embodiments, the patient, who is in further need of treatment with an acidreducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib. Exemplary PPIs include, but are not limited to, omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. Exemplary H2RAs include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine, roxatidine and lafutidine. Exemplary locally acting antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide. In some embodiments, the patient, who is in further need of treatment with an acid-reducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib, but is administered a locally acting antacid in combination with sotorasib. In some embodiments, sotorasib is administered about 4 hours before or about 10 hours after a locally acting antacid.

[0034] In some embodiments, the patient is not administered a CYP3A4 inducer in combination with sotorasib. Exemplary CYP3A4 inducers include, but are not limited to, barbiturates, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, and troglitazone. See, e.g., Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), www.drug-interactions.medicine.iu.edu, accessed May 2021 . In some embodiments, the patient is not administered a strong CYP3A4 inducer in combination with sotorasib. Exemplary strong CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates- inhibitors-and-inducers, accessed May 2021. In one embodiment strong CYP3A4 inhibitors include, but are not limited to ombitasvir and paritaprevir and ritonavir and dasabuvir, indinavir and ritonavir, tipranavir and ritonavir, ritonavir, cobicistat, ketoconazole, troleandomycin, telaprevir, danoprevir and ritonavir, elvitegravir and ritonavir, saquinavir and ritonavir, lopinavir and ritonavir, itraconazole, indinavir, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, lonafarnib, posaconazole, telithromycin, grapefruit juice DS3, conivaptan, tucatinib, nefazodone, ceritinib, nelfinavir, saquinavir, ribociclib, idelalisib, and boceprevir.

[0035] In some embodiments, the patient is not administered a CYP3A4 substrate in combination with sotorasib. Exemplary CYP3A4 substrates include, but are not limited to, abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib, cyclosporine, dabrafenib, daclatasvir, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, dolutegravir, domperidone, doxepin, elagolix, elbasvir/grazoprevir, eliglustat, enzalutamide, eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, imatinib, haloperidol, hydrocortisone, ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isavuconazonium, ivabradine, ivacaftor, lansoprazole, lenvatinib, lercanidipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, midazolam, naldemedine, naloxegol, nateglinide, nelfinavir, neratinib, netupitant/palonosetron, nevirapine, nifedipine, nisoldipine, nitrendipine, olaparib, omeprazole, ondansetron, osimertinib, ospemifene, palbociclib, panobinostat, pantoprazole, perampanel, pimavanserin, pimozide, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, ribociclib, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast, rolapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus, sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus(fk506), tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, vilazodone, vincristine, vorapaxar, voriconazole, zaleplon, and ziprasidone. See, e.g., Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), https://drug-interactions.medicine.iu.edu, accessed May 2021.

[0036] In some embodiments, the patient is not administered a P-gp substrate in combination with sotorasib. Exemplary P-gp substrates include, but are not limited to dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed May 2021. In some embodiments, the patient is not administered a P-gp substrate in combination with sotorasib, wherein the P-gp substrate is a P-gp substrate with a narrow therapeutic window. Exemplary P-gp substrates with a narrow therapeutic window include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, and vincristine.

[0037] In some embodiments, the patient is in further need of treatment with a QT prolonging medication. In some embodiments, the patient is not administered a QT prolonging medication. Medications known to prolong QT include, but are not limited to, amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, and vandetanib.

[0038] Patient Characteristics

[0039] In some embodiments, the patient has a cancer that was determined to have one or more cells expressing the KRAS^G12C mutant protein prior to administration of sotorasib as disclosed herein. Determination of KRAS^G12C mutant protein can be assessed as described elsewhere in this disclosure. In some embodiments, the patient does not have KRAS exon 2, exon 3, or exon 4 mutations or NRAS exon 2, exon 3, or exon 4 mutations. [0040] In some embodiments, the patient has not received treatment with a KRAS^G12C inhibitor prior to start of a sotorasib/EGFR therapy/FOLFOX therapy as disclosed herein. In some embodiments, KRAS^G12C inhibitor is sotorasib, adagrasib, divarasib (GDC-6036), garsoarsib (D-1553), opnurasib (JDQ443), glecirasib (JAB-21822), fulzerasib (IBI351, GFH925), RMC-6291, LY3484356, BI1823911, GH35, ZG1077, ASP2453, AZD4747, AZD4625, or APG-1842. In certain embodiments the KRAS^G12C inhibitor is sotorasib. In certain embodiments, the KRAS^G12C inhibitor is adagrasib. In some embodiments, the therapy is monotherapy. In some embodiments, the therapy with a KRAS^G12C inhibitor is sotorasib monotherapy. In another embodiments, the therapy with a KRAS^G12C inhibitor is adagrasib monotherapy.

[0041] In some embodiments, the patient has had at least one prior therapy for metastatic disease prior to start of a sotorasib/EGFR therapy/FOLFOX therapy as disclosed herein. Prior therapies for metastatic disease include, but are not limited to, chemotherapies and immunotherapies. Specific contemplated prior systemic cancer therapies include, but are not limited to, fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, ramucirumab, aflibercept, pembrolizumab, nivolumab, ipilimumab, trifluridine and tipiracil, and regorafenib, or any combination the foregoing.

[0042] In some embodiments, the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 (see, e.g., Zubrod et al., 1960). In some embodiments, the patient exhibits an ECOG PS of < 1 . In some embodiments, the patient exhibits an ECOG PS score of 0 or 1 . A PS of 0 indicates fully active and able to carry on all pre-disease performance without restriction. PS of 1 indicates restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. PS of 2 indicates ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours. PS of 3 indicates capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. PS of 4 indicates completely disabled, cannot carry on any selfcare and totally confined to bed or chair. PS of 5 indicates death.

[0043] Adverse Events

[0044] In some embodiments, the methods comprise administering a reduced total daily dose of sotorasib when the patient experiences an adverse event to the initial total daily dose. For example, in some embodiments, the initial daily dose is 960 mg sotorasib and the reduced total daily dose is 480 mg sotorasib. In some embodiments, the initial daily dose is 480 mg sotorasib and the reduced total daily dose is 240 mg sotorasib. In some embodiments, the methods further comprise administering a second reduced total daily dose of sotorasib when the patient experiences an adverse event to the reduced total daily dose.

[0045] The term "adverse event” or “(AE)” as used herein refers to any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may be considered related to the medical treatment or procedure.

[0046] In some embodiments, the adverse event is hepatotoxicity {e.g., elevation of liver enzymes), interstitial lung disease (ILD)/pneumonitis, diarrhea, and/or nausea/vomiting. [0047] Hepatotoxicity

[0048] In some embodiments, the adverse event is hepatotoxicity. The term "hepatotoxicity” as used herein refers to a patient having abnormal laboratory values of liver biomarkers (e.g., alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine aminotransferase (ALT), and/or total bilirubin (TBL)), when the patient had baseline levels of the liver biomarker(s) prior to sotorasib administration that were not abnormal laboratory values or were lower than those measured after administration of sotorasib.

[0049] Alanine transaminase (ALT), also called serum glutamic pyruvate transaminase (SGPT) or alanine aminotransferase (ALAT), catalyzes the transfer of an amino group from alanine to o-ketoglutarate to produce pyruvate and glutamate. When the liver is damaged, levels of ALT in the blood can rise due to the leaking of ALT into the blood from damaged or necrosed hepatocytes.

[0050] Aspartate transaminase (AST) also called serum glutamic oxaloacetic transaminase (SGOT or GOT) or aspartate aminotransferase (ASAT), catalyzes the transfer of an amino group from aspartate to o-ketoglutarate to produce oxaloacetate and glutamate. AST can increase in response to liver damage. Elevated AST also can result from damage to other sources, including red blood cells, cardiac muscle, skeletal muscle, kidney tissue, and brain tissue. The ratio of AST to ALT can be used as a biomarker of liver damage.

[0051] Bilirubin is a catabolite of heme that is cleared from the body by the liver. Conjugation of bilirubin to glucuronic acid by hepatocytes produces direct bilirubin, a water-soluble product that is readily cleared from the body. Indirect bilirubin is unconjugated, and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin can be indicative of liver impairment.

[0052] Alkaline phosphatase (ALP) hydrolyzes phosphate groups from various molecules and is present in the cells lining the biliary ducts of the liver. ALP levels in plasma can rise in response to liver damage and are higher in growing children and elderly patients with Paget's disease. However, elevated ALP levels usually reflect biliary tree disease.

[0053] In some embodiments, the patient is not suffering from a disorder that results in elevated liver biomarkers. Disorders associated with elevated liver biomarkers (such as AST/ALT and/or TBL values) include, but are not limited to, hepatobiliary tract disease; viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; heritable disorders causing impaired glucuronidation (e.g, Gilbert's syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g, indinavir, atazanavir); alpha-one antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson's disease and hemochromatosis; nonalcoholic fatty liver disease including steatohepatitis; and/or non-hepatic causes (e.g, rhabdomyolysis, hemolysis). [0054] Prior to receiving sotorasib, the baseline liver function of the patient can be assessed by various means known in the art, such as blood chemistry tests measuring biomarkers of liver function. In some embodiments, the methods described herein comprise monitoring liver biomarkers in the patient and withholding sotorasib administration in patients having > Grade 2 abnormal liver function, as assessed by levels of AST and/or ALT. In such embodiments, sotorasib administration is paused until the AST and/or ALT levels in the patient improve(s) to Grade 1 or better (baseline).

[0055] Adverse effect Grades for abnormal liver function are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 1. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.

[0056] Table 1.

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal; WNL= within normal limits

[0057] Grade 0 levels are characterized by biomarker levels within normal limits (WNL). "Normal" liver function, as used herein, refers to Grade 0 adverse effects. "Abnormal" liver function, as used herein, refers to Grade 1 and above adverse effects.

[0058] "Grade 1 liver function abnormalities" include elevations in ALT or AST greater than the ULN and less than or equal to 3-times the ULN if baseline was normal; 1 .5 - 3.0 x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of bilirubin levels greater than the ULN and less than or equal to 1 ,5-times the ULN if baseline was normal; > 1 .0 - 1 .5 x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of ALP greater than the ULN and less than or equal to 2.5-times the ULN if baseline was normal; > 2.0 - 2.5 x baseline if baseline was abnormal.

[0059] "Grade 2 liver function abnormalities" include elevations in ALT or AST greater than 3-times and less than or equal to 5-times the upper limit of normal (ULN) if baseline was normal; >3.0 - 5.0 x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than 1 ,5- times and less than or equal to 3-times the ULN if baseline was normal; > 1 .5 - 3.0 x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of ALP greater than 2.5-times and less than or equal to 5-times the ULN if baseline was normal; > 2.5 - 5.0 x baseline if baseline was abnormal.

[0060] "Grade 3 liver function abnormalities" include elevations in ALT, AST, or ALP greater than 5-times and less than or equal to 20-times the ULN if baseline was normal; >5.0 - 20.0 x baseline if baseline was abnormal. Grade 3 liver function abnormalities also include elevations of bilirubin levels greater than 3-times and less than or equal to 10-times the ULN if baseline was normal; > 3.0 - 10 x baseline if baseline was abnormal.

[0061] "Grade 4 liver function abnormalities" include elevations in ALT, AST, or ALP greater than 20-times the ULN if baseline was normal; > 20 x baseline if baseline was abnormal. Grade 4 liver function abnormalities also include elevations of bilirubin levels greater than 10 times the ULN if baseline was normal; > 10.0 x baseline if baseline was abnormal.

[0062] The ULN for various indicators of liver function depends on the assay used, the patient population, and each laboratory's normal range of values for the specified biomarker, but can readily be determined by the skilled practitioner. Exemplary values for normal ranges for a healthy adult population are set forth in Table 2 below. See Cecil Textbook of Medicine, pp. 2317-2341, W.B. Saunders & Co. (1985). [0063] Table 2. - Upper Limit of Normal (ULN) Values

[0064] In any of the methods described herein, the total daily dose of sotorasib is reduced {e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the AST and/or ALT level (s) in the patient is/are elevated, e.g. to a Grade 2 or Grade 3 level, where the baseline AST and/or ALT levels of the patient were below Grade 2 or Grade 3 levels. In some embodiments, the total daily dose of sotorasib is reduced {e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg), when the AST and/or ALT level(s) in the patient is/are elevated is to a Grade 1 level, wherein the baseline AST and/or ALT levels of the patient were below Grade 1 levels.

[0065] Alternatively, in any of the methods disclosed herein, the total daily dose of sotorasib is reduced {e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when (1) AST and bilirubin levels in the patient are elevated, or (2) when AST or ALP levels in the patient are elevated, or (3) when ALT and bilirubin levels in the patient are elevated, or (4) when ALT and ALP levels in the patient are elevated, or (5) when bilirubin and ALP levels in the patient are elevated, e.g., to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline AST, bilirubin, ALP, and/or ALT levels of the patient were below Grade 1 , Grade 2, Grade 3 or Grade 4 levels, respectively. Alternatively, in any of the methods disclosed herein, three biomarkers of liver function may be elevated in the patient {e.g, ALT and AST and bilirubin, or ALT and AST and ALP) to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline biomarker levels of the patient were below Grade 1 , Grade 2, Grade 3 or Grade 4 levels, respectively.

[0066] In some embodiments, the total daily dose of sotorasib is reduced {e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 3 times compared to the upper limit of normal (ULN). In a related embodiment, the abnormal level of ALT and/or AST is greater than about 3- to about 5-fold increase compared to the upper limit of normal (ULN), i.e. a "Grade 2 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 2 abnormality is an abnormal level of ALT and/or AST greater than about 3-fold to about 5-fold increase compared to baseline. In some embodiments, the abnormal level of ALP is greater than about 2.5- to about 5-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 2 abnormality is an abnormal level of ALP greater than about 2.5-fold to about 5-fold increase compared to baseline. In some embodiments, the abnormal level of bilirubin is greater than about 1.5- to about 3-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 2 abnormality is an abnormal level of bilirubin greater than about 1.5-fold to about 3-fold increase compared to baseline.

[0067] In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 5 times compared to the upper limit of normal (ULN). In some embodiments, the total daily dose is reduced when the level of ALT, AST, or ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e. a "Grade 3 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 3 abnormality is an abnormal level of ALT and/or AST greater than about 5-fold to about 20-fold increase compared to baseline. In some embodiments, the abnormal level of ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 3 abnormality is an abnormal level of ALP greater than about 5-fold to about 20- fold increase compared to baseline. In some embodiments, the total daily dose is reduced when the level of bilirubin is greater than about 3- to about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 3 abnormality is an abnormal level of bilirubin greater than about 3-fold to about 10-fold increase compared to baseline.

[0068] In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 20 times compared to the upper limit of normal (ULN) (i.e., a "Grade 4 abnormality”). In some embodiments, where the patient has an abnormal baseline, the Grade 4 abnormality is an abnormal level of ALT and/or AST greater than about 20-fold increase compared to baseline. In some embodiments, the abnormal level of ALP is greater than about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 4 abnormality is an abnormal level of ALP greater than about 20- fold increase compared to baseline. In some embodiments, the total daily dose is reduced when the level of bilirubin is greater than about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality". In some embodiments, where the patient has an abnormal baseline, the Grade 4 abnormality is an abnormal level of bilirubin greater than about 10-fold increase compared to baseline.

[0069] In some embodiments, the methods described herein further comprise increasing the total dose of sotorasib (e.g, from 240 mg to 480mg, or from 480 mg to 960 mg) when liver biomarker(s) in the patient has improved to a Grade 1 or better (e.g, baseline).

[0070] Nausea/Vomiting

[0071] In some embodiments, the adverse event is nausea or vomiting. In some embodiments, the nausea/vomiting is present despite appropriate supportive care (e.g, anti-emetic therapy). "Nausea” as used herein refers to a disorder characterized by a queasy sensation and/or the urge to vomit. [0072] Adverse effect Grades for nausea and vomiting are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 3. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.

[0073] Table 3.

[0074] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having > Grade 3 nausea until the patient has improved to < Grade 1 or baseline. In some embodiments, once the patient has improved to < Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.

[0075] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having > Grade 3 vomiting until the vomiting improves to < Grade 1 or baseline. In some embodiments, once the patient has improved to < Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.

[0076] In some embodiments, the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when nausea in the patient has improved to a Grade 1 or better (e.g., baseline).

[0077] Diarrhea

[0078] In some embodiments, the adverse event is diarrhea. In some embodiments, the diarrhea is present despite appropriate supportive care (e.g., anti-diarrheal therapy). [0079] Adverse effect Grades for diarrhea are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 4. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.

[0080] Table 4.

[0081] In some embodiments, the methods described herein comprise withholding sotorasib administration in a patient having > Grade 3 diarrhea until the patient has improved to < Grade 1 or baseline. In some embodiments, once the patient has improved to < Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g, from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.

[0082] In some embodiments, the methods described herein further comprise increasing the total dose of sotorasib (e.g, from 240 mg to 480mg, or from 480 mg to 960 mg) when diarrhea in the patient has improved to a Grade 1 or better (e.g., baseline).

[0083] Interstitial Lung Disease

[0084] In some embodiments, the adverse event is interstitial lung disease (ILD) or pneumonitis. In cases where ILD or pneumonitis is suspected at any grade level, sotorasib is withheld. In cases where ILD or pneumonitis is confirmed, and no other causes of the ILD or pneumonitis is identified, sotorasib is permanently discontinued.

[0085] Response to Therapy As Disclosed Herein

[0086] Response rates or results for patients administered the therapeutics in the methods disclosed herein can be measured in a number of ways, after the patient has been taking the therapy for a suitable length of time. In some embodiments, response is measured after a patient is administered the therapy for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, e.g., for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months. In some embodiments, response is measured after the patient is administered the therapy for at least 1 month. In some embodiments, response is measured after the patient is administered the therapy for at least 3 months. In some embodiments, response is measured after the patient is administered the therapy for at least 6 months.

[0087] The patient can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). An at least stable disease is one that is a stable disease, has shown a partial response (PR) or has shown a complete response (CR) (i.e., "at least SD” = SD+PR+CR, often referred to as disease control). In some embodiments, the stable disease is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD). In some embodiments, the patient exhibits at least a partial response (i.e., "at least PR” = PR+CR, often referred to as objective response).

[0088] Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases. In some embodiments, the progression of a patient's disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof.

[0089] Progression free survival (PFS) can be assessed as described in the RECIST 1.1 protocol. In some embodiments, the patient exhibits a PFS of at least 1 month. In some embodiments, the patient exhibits a PFS of at least 3 months. In some embodiments, the patient exhibits a PFS of at least 6 months.

[0090] Additional means for assessing response are described in detail in the examples below and can generally be applied to the methods disclosed herein.

[0091] KRAS G12C Cancers

[0092] Without wishing to be bound by any particular theory, the following is noted: sotorasib is a small molecule that specifically and irreversibly inhibits KRAS^G12C (Hong et al., 2020). Hong et al. report that “ [p] reclinical studies showed that [sotorasib] inhibited nearly all detectable phosphorylation of extracellular signal- regulated kinase (ERK), a key down-stream effector of KRAS, leading to durable complete tumor regression in mice bearing KRAS p.G12C tumors.” (id., see also Canon et al., 2019, and Lanman et al., 2020).

[0093] Sotorasib was evaluated in a Phase 1 dose escalation and expansion trial with 129 patients having histologically confirmed, locally advanced or metastatic cancer with the KRAS p.G12C mutation identified by local molecular testing on tumor tissues, 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, at page 1208-1209). Hong et al. report a disease control rate (95% Cl) 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, at page 1213, Table 3). The cancer types showing either stable disease (SD) or partial response (PR) as reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma (Hong et al., 2020, at page 1212 (Figure A), and Supplementary Appendix (page 59 (Figure S5) and page 63 (Figure S6)).

[0094] KRAS G12C mutations occur with the alteration frequencies shown in the table below (Gerami et al., 2012; Gao et al., 2013). For example, the table shows that 11.6% of patients with non-small cell lung cancer have a cancer, wherein one or more cells express KRAS G12C mutant protein. Accordingly, sotorasib, which specifically and irreversibly bind to KRAS^G12C is useful for treatment of patients having a cancer, including, but not limited to the cancers listed in Table 5 below.

Table 5

[0095] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In some embodiments, the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In some embodiments, the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In some embodiments, the cancer is non-small cell lung cancer, and in some specific embodiments, metastatic or locally advanced non-small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is metastatic colorectal cancer. In some embodiments, the cancer is pancreatic cancer.

[0096] Embodiments

[0097] 1 . A method of treating cancer comprising a KRAS G12C mutation in a patient in need of treatment, the method comprising administering to the patient (a) a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of an epidermal growth factor receptor (EGFR) antibody and (c) (1) a therapeutically effective amount of oxaliplatin, (2) a therapeutically effective amount of leucovorin or a therapeutically effective amount of levoleucovorin, and (3) a therapeutically effective amount of 5-fluorouraci I (5-FU).

[0098] 2. The method of embodiment 1 , wherein the therapeutically effective amount of sotorasib or salt thereof is 960 mg daily. [0099] 3. The method of embodiment 1 , wherein the therapeutically effective amount of sotorasib or salt thereof is 480 mg daily.

[00100] 4. The method of embodiment 1, wherein the therapeutically effective amount of sotorasib or salt thereof is 240 mg daily.

[00101 ] 5. The method of any one of embodiments 1 -4, wherein the therapeutically effective amount of sotorasib or salt thereof is administered to the patient once daily.

[00102] 6. The method of any one of embodiments 1 -5, wherein the sotorasib or salt thereof is administered as a tablet.

[00103] 7. The method of any one of embodiments 1 -6, wherein the sotorasib or salt thereof is administered as a free base.

[00104] 8. The method of any one of embodiments 1 -7, wherein the EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.

[00105] 9. The method of embodiment 8, wherein the EGFR antibody comprises the heavy chain variable region sequence of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 9.

[00106] 10. The method of embodiment 8 or embodiment 9, wherein the EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10.

[00107] 11 . The method of any one of embodiments 1-10, wherein the EGFR antibody is panitumumab.

[00108] 12. The method of any one of embodiments 1-11, wherein the therapeutically effective amount of the EGFR antibody is 6 mg/kg.

[00109] 13. The method of any one of embodiments 1-12, wherein the EGFR antibody is administered intravenously.

[00110] 14. The method of any one of embodiments 1-13, wherein the EGFR antibody is administered every two weeks.

[00111] 15. The method of any one of embodiments 1-14, wherein the therapeutically effective amount of oxaliplatin is 85 mg/m².

[00112] 16. The method of any one of embodiments 1-15, wherein the oxaliplatin is administered intravenously.

[00113] 17. The method of any one of embodiments 1-16, wherein the oxaliplatin is administered every two weeks.

[00114] 18. The method of any one of embodiments 1-17, wherein the method comprises administering a therapeutically effective amount of leucovorin. [00115] 19. The method of any one of embodiments 1-18, wherein the therapeutically effective amount of leucovorin is 400 mg/m² leucovorin.

[00116] 20. The method of any one of embodiments 1-19, wherein the leucovorin is administered intravenously.

[00117] 21. The method of any one of embodiment 1-20, wherein the leucovorin is administered every two weeks.

[00118] 22. The method of any one of embodiments 1-17, wherein the method comprises administering a therapeutically effective amount of levoleucovorin.

[00119] 23. The method of any one of embodiments 1-17 and 22, wherein the therapeutically effective amount of levoleucovorin is 200 mg/m² levoleucovorin.

[00120] 24. The method of any one of embodiments 1-17, 22, and 23, wherein the levoleucovorin is administered intravenously.

[00121] 25. The method of any one of embodiments 1-17 and 22-24, wherein the levoleucovorin is administered every two weeks.

[00122] 26. The method of any one of embodiments 1-25, wherein the therapeutically effective amount of 5-FU is 2800 mg/m² 5-FU.

[00123] 27. The method of embodiment 26, wherein the 2800 mg/m² 5-FU are administered in two separate doses of 400 mg/m² 5-FU and 2400 mg/m² 5-FU.

[00124] 28. The method of any one of embodiments 1-27, wherein the 5-FU is administered intravenously.

[00125] 29. The method of any one of embodiments 1-28, wherein the 5-FU is administered every two weeks.

[00126] 30. The method of any one of embodiments 1 , 2, and 5-29, comprising administering to the patient

(a) 960 mg sotorasib or salt thereof daily;

(b) 6 mg/kg panitumumab intravenously every two weeks; and

(c) (1) 85 mg/m² oxaliplatin intravenously every two weeks, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin intravenously every two weeks, and (3) 400 mg/m²5-FU intravenously (bolus) followed by 2400 mg/m² 5-FU intravenously over 46-48 hours as a continuous infusion every two weeks.

[00127] 31. The method of any one of embodiments 1 , 3, and 5-29, comprising administering to the patient

(a) 480 mg sotorasib or salt thereof daily;

(b) 6 mg/kg panitumumab intravenously every two weeks; and

(c) (1) 85 mg/m² oxaliplatin intravenously every two weeks, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin intravenously every two weeks, and (3) 400 mg/m²5-FU intravenously (bolus) followed by 2400 mg/m² 5-FU intravenously over 46-48 hours as a continuous infusion every two weeks. [00128] 32. The method of any one of embodiments 1, 4, and 5-29, comprising administering to the patient

(a) 240 mg sotorasib or salt thereof daily;

(b) 6 mg/kg panitumumab intravenously every two weeks; and

(c) (1) 85 mg/m² oxaliplatin intravenously every two weeks, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin intravenously every two weeks, and (3) 400 mg/m²5-FU intravenously (bolus) followed by 2400 mg/m²5-FU intravenously over 46-48 hours as a continuous infusion every two weeks.

[00129] 33. The method of any one of embodiments 30-32, wherein steps (a) though (c) are initiated sequentially on the first day of a two week period.

[00130] 34. The method of embodiment 33, wherein step (a) is executed 2 hours before step (b) on the first day of the first two week period.

[00131] 35. The method of embodiment 33 or 34, wherein in step (c) (1) oxaliplatin and (2) leucovorin or levoleucovorin are administered, concurrently or subsequently, and then (3) 5-FU is administered.

[00132] 36. The method of any one of embodiments 1-35, wherein the cancer is a solid tumor.

[00133] 37. The method of any one of embodiments 1-36, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[00134] 38. The method of any one of embodiments 1-37, wherein the cancer is colorectal cancer (CRC).

[00135] 39. The method of any one of embodiments 1-37, wherein the cancer is metastatic colorectal cancer (mCRC).

[00136] 40. The method of any one of embodiments 1-39, wherein the patient has previously received at least one prior cancer therapy.

[00137] 41 . The method of embodiment 40, wherein at least one prior cancer therapy is selected from fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, ramucirumab, aflibercept, pembrolizumab, nivolumab, ipilimumab, trifluridine and tipiracil, and regorafenib, or any combination the foregoing.

[00138] 42. The method of embodiment 40 or embodiment 41, wherein the at least one prior cancer therapy is not a therapy comprising administering to the patient a KRAS^G12C inhibitor.

[00139] 43. The method of any one of embodiments 1-42, wherein the patient exhibits an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 .

[00140] 44. The method of any one of embodiments 1-43, wherein the patient has an absolute neutrophil count equal or greater than 1 .5 x 10⁹/L. [00141] 45. The method of any one of embodiments 1-44, wherein the patient has an absolute neutrophil count equal or greater than 2 x 10⁹/L.

[00142] 46. The method of any one of embodiments 1-45, wherein the patient has a glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation equal or greater than 60 ml/min/1 .73 m².

[00143] 47. The method of any one of embodiments 1-46, wherein the patient has an aspartate aminotransferase (AST) level of less than 2.5 x upper limit of normal (ULN), or equal or less than 5 x ULN if liver metastases are present.

[00144] 48. The method of any one of embodiments 1-47, wherein the patient has an alanine aminotransferase (ALT) level of less than 2.5 x ULN or equal or less than 5 x ULN if liver metastases are present.

[00145] 49. The method of any one of embodiments 1-48, wherein the patient does not have a primary brain tumor.

[00146] 50. The method of any one of embodiments 1-49, wherein the patient does not have active brain metastases, carcinomatous meningitis from non brain tumors, or both.

[00147] 51 . The method of any one of embodiments 1-50, wherein the patient does not have sensory peripheral neuropathy of greater than grade 1 at baseline.

[00148] 52. The method of any one of embodiments 1-51, wherein the patient does not have congenital long QT syndrome.

[00149] 53. The method of any one of embodiments 1-52, wherein the patient does not have a mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4 other than the KRAS G12C mutation.

[00150] 54. The method of any one of embodiments 1-53, wherein the patient is not administered a QT prolonging medication.

[00151] 55. The method of embodiment 54, wherein the QT prolonging medication is amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, or vandetanib.

[00152] 56. The method of any one of embodiments 1-55, wherein the patient does not have a dihydropyrimidine dehydrogenase deficiency.

[00153] 57. The method of any one of embodiments 1-56, wherein the patient is not administered a cytochrome P450 (GYP) 3A4 sensitive substrate.

[00154] 58. The method of embodiments 57, wherein the GYP 3A4 sensitive substrate has a narrow therapeutic window. [00155] 59. The method of embodiment 57 or embodiment 58, wherein the CYP 3A4 sensitive substrate is alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, tacrolimus, or sirolimus.

[00156] 60. The method of any one of embodiments 1-59, wherein the patient is not administered a P- glycoprotein (P-gp) sensitive substrate.

[00157] 61 . The method of embodiment 60, wherein the P-gp sensitive substrate has a narrow therapeutic index.

[00158] 62. The method of embodiment 60 or embodiment 61, wherein the P-gp sensitive substrate is digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, or vincristine.

[00159] 63. The method of any one of embodiments 1-62, wherein the patient is not administered an inducer of CYP 3A4.

[00160] 64. The method of embodiment 63, wherein the inducer of CYP3A4 is rifampin, phenytoin, mitotane, carbamazepine, avasimibe, enzalutamide, rifapentine, St John's Wort extract, apalutamide, lumacaftor, or ivosidenib.

[00161] 65. The method of any one of embodiments 1-64, wherein the patient exhibits at least a stable disease (SD) after 1, 3, or 6 months of sotorasib, panitumumab, oxaliplatin, leucovorin or levoleucovorin, and 5- FU administration, as measured by RECIST 1.1 protocol.

[00162] 66. The method of any one of embodiments 1-64, wherein the patient exhibits at least a partial response (PR) after 1, 3, or 6 months of sotorasib, panitumumab, oxaliplatin, leucovorin or levoleucovorin, and 5- FU administration, as measured by RECIST 1.1 protocol.

[00163] 67. The method of any one of embodiments 1-66, wherein the method further comprises a step of determining whether the patient has a cancer comprising a KRAS G12C mutation.

Example

[00164] The term "subject” is used throughout the disclosure interchangeably with "patient”, who is in need of treatment with one or more methods described herein. The terms "subject” and "patient” refer to a human subject and a human patient, respectively.

Example 1 - Sotorasib in combination with panitumumab and mFOLFOX6

[00165] In this study, sotorasib in combination with panitumumab and FOLFOX will not be administered to subjects enrolled in Part 1 Cohort C and Part 2 Cohort J with known mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4, other than the KRAS G12C mutation. In the primary analysis of a phase 3 study (n=1 , 183; 655 patients with wild-type KRAS [exon 2] and 440 patients with mutant KRAS mCRC) evaluating panitumumab in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared with FOLFOX alone as first-line therapy for mCRC, a significant shortening of PFS was observed in patients with mutant KRAS mCRC who received panitumumab and FOLFOX (n=221 ) versus FOLFOX alone (n=219). A trend toward shortened OS time was also observed in the mutant KRAS mCRC population. A predefined retrospective subset analysis of 641 patients of the 656 patients with wild-type KRAS (exon 2) mCRC from the phase 3 study identified additional RAS (KRAS [exons 3 and 4] or NRAS [exons 2, 3, or 4]) mutations in 17% (n=108) of patients. A shortening of PFS and OS was observed in patients with mutant RAS mCRC who received panitumumab and FOLFOX (n=51 ) versus FOLFOX alone (n=57).

[00166] Objectives and Endpoints

[00167] Overall Design:

[00168] A phase 1b multicenter, open label study is set up to evaluate the safety, tolerability, pharmacokinetic (PK) behavior, pharmacodynamic (PD) behavior, and efficacy of sotorasib in combination with panitumumab and mFOLFOX6 in subjects with KRAS G12C mutant metastatic colorectal cancer.

[00169] On days when PK samples are drawn in cycle 1, and after any dose hold of sotorasib, the treatments will be administered in the following sequence: sotorasib, panitumumab, and mFOLFOX6. Sotorasib will be administered orally once daily (QD). Alternatively, twice daily dosing may be used but the total daily dose will be the same. Panitumumab 6 mg/kg will be administered as 60-minute (< 1000 mg) or 90-minute (> 1000 mg) intravenous (IV) infusion every 2 weeks (Q2W). The mFOLFOX6 regimen consists of oxaliplatin 85 mg/m² IV on day 1, leucovorin 400 mg/m² IV on day 1 and 5-fluorouracil 400 mg/m² IV bolus on day 1 and 2400 mg/m² IV continuous infusion (I VCI) over 46 to 48 hours beginning on day 1 given Q2W (National Comprehensive Cancer Network [NCCN] Colon Cancer Guidelines version 2. 2023 and NCCN Rectal Cancer Guidelines version 3. 2023). Levoleucovorin at 200 mg/m² may be used instead of leucovorin.

[00170] The first dose of panitumumab will be administered 2 hours after sotorasib administration. Subsequent panitumumab doses may be administered before or immediately following sotorasib administration. In Part 1, Cohort C and Part 2 Cohort J mFOLFOX6 will be administered after panitumumab.

[00171] The study will include a dose exploration phase (Part 1) and expansion phase (Part 2). Part 1 Cohort C will consist of dose exploration of sotorasib, panitumumab, and mFOLFOX6. The dose expansion in Part 2 Cohort J is based on the dose identified as recommended phase 2 dose (RP2D) in Part 1 Cohort C.

[00172] Part i Cohort C

[00173] Dose level 1 : sotorasib 960 mg orally total daily dose + 6 mg/kg panitumumab IV on day 1 Q2W + oxaliplatin 85 mg/m² IV on day 1, leucovorin 400 mg/m² IV on day 1 and 5-FU 400 mg/m² IV bolus on day 1 and 2400 mg/m² IV continuous infusion (IVCI) over 46 to 48 hours beginning on day 1 given Q2W. For investigative sites that use levoleucovorin instead of leucovorin, the levoleucovorin dose will be 200 mg/m².

[00174] Dose level -1 : sotorasib 480 mg orally total daily dose + 6 mg/kg panitumumab IV on day 1 Q2W + oxaliplatin 85 mg/m² IV on day 1, leucovorin 400 mg/m² IV on day 1 and 5-FU 400 mg/m² IV bolus on day 1 and 2400 mg/m² IV continuous infusion (IVCI) over 46 to 48 hours beginning on day 1 given Q2W. For investigative sites that use levoleucovorin instead of leucovorin, the levoleucovorin dose will be 200 mg/m².

[00175] Dose level -2: sotorasib 240 mg orally total daily dose + 6 mg/kg panitumumab IV on day 1 Q2W + oxaliplatin 85 mg/m² IV on day 1, leucovorin 400 mg/m² IV on day 1 and 5-FU 400 mg/m² IV bolus on day 1 and 2400 mg/m² IV continuous infusion (IVCI) over 46 to 48 hours beginning on day 1 given Q2W. For investigative sites that use levoleucovorin instead of leucovorin, the levoleucovorin dose will be 200 mg/m².

[00176] Part 2 Cohort J: sotorasib total daily dose identified from Part 1 Cohort C, panitumumab, mFOLFOX6 in KRAS^G12C inhibitor naive KRAS G12C mutated metastatic colorectal cancer with at least 1 prior therapy for metastatic disease.

[00177] Study Population:

[00178] Inclusion Criteria:

[00179] Subjects are eligible to be included in the study only if the following criteria apply:

[00180] Age 18 years or older (adult)

[00181] For Part 1 Cohort C:

-Pathologically documented, metastatic colorectal cancer with KRAS G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.

-Subject's tumor must have been tested for KRAS and NRAS mutations through molecular testing according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory. Note: Subjects may not have known mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4, other than the KRAS G12C mutation.

-Subjects must not have required dose reduction or been intolerant of a KRAS^G12C inhibitor if they have received treatment with a KRAS^G12C inhibitor in the past. A minimum of 2 subjects must be KRAS^G12C inhibitor naive per dose level.

-Subjects must have had at least 1 prior treatment for advanced disease.

-If subject had received prior treatment with 5-FU or oxaliplatin, subjects must not have required a dose reduction or dose delay of 5-FU or oxaliplatin because of toxicity.

-Subject must have normal electrolytes (calcium, magnesium, phosphorus, and sodium) prior to enrollment in Part 1, Cohort C. Correct electrolyte abnormalities prior to enrollment. [00182] For Part 2 Cohort J

- Pathologically documented, metastatic CRC with KRAS G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory.

-Subjects tumor must have been tested for KRAS and NRAS mutations through molecular testing. In the United States, this test must be performed in a CLIA-certified laboratory. Subjects may not have known mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4, other than the KRAS G12C mutation.

- Subjects may not have received treatment with a KRAS^G12C inhibitor in the past.

- Subjects must have received at least one prior systemic therapy for metastatic disease.

- Subject must have normal electrolytes (calcium, magnesium, phosphorus, and sodium) prior to enrolment into Part 2 Cohort J. Correct electrolyte abnormalities prior to enrolment.

[00183] Subjects must be willing to undergo pretreatment tumor biopsy and tumor biopsy on treatment, if clinically feasible. If a tumor biopsy prior to treatment is not medically feasible, or if the sample has insufficient tissue for testing, subjects must be willing to provide archived tumor tissue samples (formalin-fixed, paraffin- embedded [FFPE] sample) collected within the past 5 years, if available. Subjects with prior molecularly confirmed KRAS G12C mutation who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator and the Medical Monitor if a tumor biopsy is not clinically feasible.

[00184] Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1 .1) criteria.

[00185] Eastern Cooperative Oncology Group (ECOG) Performance Status of < 1 for subjects in Part 1 Cohort C and Part 2 Cohort J.

[00186] Life expectancy of > 3 months, in the opinion of the investigator.

[00187] Ability to take oral medications and willing to record daily adherence to investigational product.

[00188] Corrected QT interval (QTc) < 470 msec for females and < 450 msec for males (based on average of screening electrocardiogram triplicates).

[00189] Subjects have adequate hematological, renal and hepatic function and coagulation. Adequate hematological laboratory assessments, are as follows:

- Absolute neutrophil count > 1.5 x 10⁹/L for non-EU/UK subjects in Part 1 Cohort C and Part 2 Cohort J.

-Absolute neutrophil count > 2 x 10⁹/L for EU/UK subjects in Part 1 Cohort C and Part 2 Cohort J.

-Platelet count > 100 x 10⁹/L without transfusion within 2 weeks of lab assessment.

-Hemoglobin > 9 x g/dL without growth factor support or transfusion within 2 weeks of lab assessment. [00190] Adequate renal laboratory assessments include measured creatinine clearance or estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation > 60 mL/min/1.73 m².

[00191] Adequate hepatic laboratory assessments are as follows:

-AST < 2.5 x upper limit of normal (ULN) (if liver metastases are present, < 5 x ULN) -ALT < 2.5 x ULN (if liver metastases are present, < 5 x ULN) -Total bilirubin < 1 .5 x ULN for Part 1 Cohort C and Part 2 Cohort J

[00192] Adequate coagulation laboratory assessments are as follows:

- Prothrombin time (PT) or activated partial thromboplastin time (aPTT) or activated PTT < 1.5 x ULN, OR International normalized ratio (I NR) < 1.5 x ULN or within target range if on prophylactic anticoagulation therapy.

[00193] Exclusion criteria:

[00194] Subjects are excluded from the study if any of the following criteria apply:

[00195] Disease Related

[00196] Primary brain tumor.

[00197] Active brain metastases and/or carcinomatous meningitis from non-brain tumors. The phrase "active brain metastases” as used herein refers to a cancer that has spread from the original (primary, non-brain) tumor to the brain. Active brain metastases can be assessed by the presence of intracranial lesions. It is to be understood that while "metastases” is plural, patients exhibiting only one intracranial lesion under the criteria noted below is a patient who has "active brain metastases.” In some embodiments, a patient having active brain metastases has at least one measurable intracranial lesion > 5 mm. In some embodiments, a patient having active brain metastases has at least one measurable intracranial lesion >5 mm but < 10 mm. In some embodiments, a patient having active brain metastases has at least one measurable intracranial lesion > 10 mm. A patient is not considered a patient with active brain metastases if the patient has had brain metastases or have received radiation therapy ending at least 4 weeks prior to study day 1 and are eligible if they meet all of the following criteria: a) residual neurological symptoms grade < 2; b) on stable doses of dexamethasone, if applicable; and c) follow-up MRI performed within 28 days shows no new lesions appearing. For determining the grade of any neurological symptom attributable to an intracranial lesion, see National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.

[00198] Other Medical Conditions

[00199] History or presence of hematological malignancies unless curatively treated with no evidence of disease for > 2 years. [00200] History of other malignancy within the past 2 years, with the following exceptions:

- Malignancy treated with curative intent and with no known active disease present for > 2 years before enrollment and felt to be at low risk for recurrence by the treating physician;

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;

- Adequately treated cervical carcinoma in situ without evidence of disease;

- Adequately treated breast ductal carcinoma in situ without evidence of disease;

- Prostatic intraepithelial neoplasia without evidence of prostate cancer;

- Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ.

[00201] Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication.

[00202] Gastrointestinal (Gl) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for IV alimentation, uncontrolled inflammatory Gl disease (e.g., Crohn's disease, ulcerative colitis).

[00203] Exclusion of hepatitis infection based on the following results and/or criteria:

- Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute hepatitis B);

- Negative HepBsAg with a positive for hepatitis B core antibody;

- Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. Detectable Hepatitis C virus RNA suggests chronic hepatitis C.

[00204] Known positive test for human immunodeficiency virus (HIV).

[00205] History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis.

[00206] Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose < 1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).

[00207] Has an active infection requiring systemic therapy.

[00208] Sensory peripheral neuropathy of > grade 1 at baseline for subjects in Part 1 Cohort C and Part 2 Cohort J.

[00209] Prior history of posterior reversible encephalopathy syndrome (PRES), unless approved by the principal investigator and Medical Monitor.

[00210] Congenital long QT syndrome for subjects in Part 1 Cohort C and Part 2 Cohort J.

[00211] For Part 1 Cohort C and Part 2 Cohort J: Known mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4 other than KRAS G12C mutation.

[00212] Prior/Concomitant Therapy [00213] Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with history of breast cancer receiving adjuvant hormonal therapy], or investigational agent except for sotorasib) within 28 days of study Day 1 ; targeted small molecule inhibitors, within 14 days of study Day 1 , unless at least 5 half-lives have passed.

[00214] For Part 1 Cohort C and Part 2 Cohort J concomitant use of drugs which can prolong QT interval should be avoided, if possible. Exemplary medications known to prolong QT interval include, but are not limited to, amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, and vandetanib If concomitant use is required, approval of the principal investigator and a Medical Monitor is required. Subject must have normal electrolytes (calcium, magnesium, phosphorus, and sodium) prior to enrolment into Part 1 Cohort C and Part 2 Cohort J. Correct electrolyte abnormalities prior to enrollment.

[00215] Therapeutic or palliative radiation therapy within 2 weeks of study day 1 . Subjects must have recovered from all radiotherapy related toxicity to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1 or less.

[00216] Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment.

[00217] Received cumulative radiation to > 25% of bone marrow for Part 1 Cohort C and Part 2 Cohort J.

[00218] Known dihydropyrimidine dehydrogenase deficiency for Part 1 Cohort C and Part 2 Cohort J.

[00219] Use of known cytochrome P450 (CYP) 3A4 sensitive substrates or P-glycoprotein (P-gp) substrates (e.g., with a narrow therapeutic window), within 14 days or 5 half-lives of the CYP3A4 or P-gp substrate or its major active metabolite, whichever is longer, prior to start of therapy. CYP3A4 sensitive substrates include abemaciclib, buspirone, isavuconazole, ridaforolimus, ABT-384, capravirine, itacitinib, saquinavir, acalabrutinib, casopitant, ivabradine, sildenafil, alfentanil, cobimetinib, ivacaftor, simeprevir, alisporivir, conivaptan, L-771,688, simvastatin, almorexant, danoprevir, levomethadyl (LAAM), sirolimus, alpha dihydroergocryptine, darifenacin, lomitapide, tacrolimus, aplaviroc, darunavir, lopinavir, terfenadine, aprepitant, dasatinib, lovastatin, ticagrelor, asunaprevir, dronedarone, lumefantrine, tilidine, atazanavir, ebastine, lurasidone, tipranavir, atorvastatin, eletriptan, maraviroc, tolvaptan, avanafil, eliglustat (in subjects CYP2D6 poor metabolizers (PMs)), midazolam, triazolam, AZD1305, elvitegravir, midostaurin, ulipristal, BIRL 355, entrectinib, naloxegol, vardenafil, blonanserin, eplerenone, neratinib, venetoclax, bosutinib, everolimus, nisoldipine, vicriviroc, brecanavir, felodipine, paritaprevir, vilaprisan, brotizolam, ibrutinib, perospirone, voclosporin, budesonide, indinavir, and quetiapine. P- gp substrates with a narrow therapeutic window include digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, and vincristine. P450 (CYP) 3A4 sensitive substrates with a narrow therapeutic window include alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, tacrolimus, and sirolimus.

[00220] Use of strong inducers of CYP3A4 (including herbal supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to start of therapy. Strong inducers of CYP3A4 include ombitasvir and paritaprevir and ritonavir and dasabuvir, indinavir and ritonavir, tipranavir and ritonavir, ritonavir, cobicistat, ketoconazole, troleandomycin, telaprevir, danoprevir and ritonavir, elvitegravir and ritonavir, saquinavir and ritonavir, lopinavir and ritonavir, itraconazole, indinavir, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, lonafarnib, posaconazole, telithromycin, grapefruit juice DS3, conivaptan, tucatinib, nefazodone, ceritinib, nelfinavir, saquinavir, ribociclib, idelalisib, and boceprevir.

[00221] Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia (or any grade allowed). Grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible [defined as having been present and stable for >6 months], such as oxaliplatin induced neuropathy, may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor.

[00222] Subject unable to receive both iodinated contrast for CT scans and gadolinium contrast for MRI scans.

[00223] Prior/Concurrent Clinical Study Experience

[00224] Currently receiving treatment in another investigational device or drug study, or less than 28 days since last intervention on another investigational device or drug study(ies), with the exception of sotorasib studies, in which case, there is no requirement for minimum time from last sotorasib dose provided all sotorasib related toxicities have resolved to grade 1 or less. Other investigational procedures while participating in this study are excluded.

[00225] Other Exclusions

[00226] Subject has known sensitivity to any of the products or components to be administered during dosing.

[00227] Subject required dose reduction or dose delay of panitumumab in the past for toxicity.

[00228] For subjects in Part 1 Cohort C and Part 2 Cohort J, subject has required dose reduction or dose delay of 5 FU or oxaliplatin in any prior chemotherapy regimen in the past for toxicity to the investigator's knowledge. For subjects in Part 1 Cohort C and Part 2 Cohort J, subject has required dosed reduction or dose delay of 5-FU or oxaliplatin in any prior chemotherapy regimen in the past for toxicity to the investigator's knowledge.

[00229] Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (e.g., Clinical Outcome Assessments) to the best of the subject and investigator's knowledge. [00230] History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.

[00231] Female subjects of childbearing potential with a positive pregnancy test assessed at Screening by a serum pregnancy test and/or urine pregnancy test.

[00232] Female subjects who are breastfeeding or planning to breastfeed during treatment and for an additional:

-7 days after the last dose of sotorasib;

-2 months after the last dose of panitumumab;

-9 months after the last dose of mFOLFOX6.

[00233] Female subjects planning to become pregnant or donate eggs during treatment and for an additional: -7 days after the last dose of sotorasib;

-2 months after the last dose of panitumumab;

-9 months after the last dose of mFOLFOX6.

[00234] Female subjects of childbearing potential unwilling to use protocol-specified method of contraception during treatment and for an additional:

-7 days after the last dose of sotorasib;

-2 months after the last dose of panitumumab;

-9 months after the last dose of mFOLFOX6.

[00235] Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional:

-7 days after the last dose of sotorasib;

-6 months after the last dose of mFOLFOX6.

[00236] Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional:

-7 days after the last dose of sotorasib;

-6 months after the last dose of mFOLFOX6.

[00237] Male subjects unwilling to abstain from donating sperm during treatment and for an additional:

-7 days after the last dose of sotorasib;

-6 months after the last dose of mFOLFOX6.

[00238] Excluded Treatments, Medical Devices, and/or Procedures During Study Period

[00239] Anti-tumor therapy such as chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, or hormonal therapy (except for subjects with breast cancer receiving it as adjuvant therapy). [00240] Strong CYP3A4 inducers (including herbal supplements such as St. John's wort) unless approved by the principal investigator and medical monitor.

[00241] Known CYP3A4 and/or P-gp sensitive substrates with narrow therapeutic window, unless approved by the principal investigator and medical monitor.

[00242] Other investigational agents

[00243] EGFR targeting agents other than panitumumab.

[00244] If a subject needs palliative radiotherapy or surgery for pain control during the course of the study, all study drugs should be withheld. A subject may be allowed to resume study drug after discussion with the principal investigator and medical monitor.

[00245] Dose Modification:

[00246] Dose Limiting Toxicities:

[00247] The dose limiting toxicity (DLT) window (i.e., DLT-evaluable period) will be the first 28 days of sotorasib and panitumumab treatment (starting cycle 1, day 1). The grading of adverse events (AEs) will be based on the guidelines provided in the CTCAE version 5.0. A subject will be DLT evaluable if the subject has completed the DLT window as described above and received > 80% of the planned dose of sotorasib and panitumumab and at least 1 treatment/dose of mFOLFOX6 within the first 28 days. DLT is defined as any adverse event meeting the criteria listed below occurring during the first treatment cycle and attributable to sotorasib and/or panitumumab.

[00248] (1) An adverse event that results in permanent discontinuation of any investigational product (with the exception of oxaliplatin hypersensitivity reaction);

(2) Febrile neutropenia

(3) Neutropenic infection

(4) Grade 4 neutropenia of any duration

(5) Grade 3 neutropenia lasting > 7 days

(6) Grade 3 thrombocytopenia for > 7 days

(7) Grade 3 thrombocytopenia with grade > 2 bleeding

(8) Grade 4 thrombocytopenia

(9) Grade 4 anemia

(10) Grade 4, vomiting or diarrhea

(11) Grade 3 vomiting or grade 3 diarrhea lasting more than 3 days despite optimal medical support

(12) Grade > 3 nausea lasting 3 days or more despite optimal medical support

(13) Grade 3 ALT or AST elevations lasting more than 5 days (only for subjects without liver metastasis at baseline)

(14) Grade 4 elevations of ALT or AST of any duration (15) Grade > 3 bilirubin elevation

(16) Any other grade > 3 AE with the following exceptions:

- DLT Exemption: grade 3 fatigue < 1 week

- DLT Exemption: grade 3 panitumumab skin toxicity

-DLT Exemption: Asymptomatic grade 3 electrolyte abnormalities that last < 72 hours, are not clinically complicated, and resolve spontaneously or respond to medical interventions

-DLT Exemption: grade 3 amylase or lipase that is not associated with clinical manifestations of pancreatitis

-DLT Exemption: Other select lab abnormalities that do not appear to be clinically relevant or harmful to the patient and/or can be corrected with replacement or modifications (e.g., grade 3 lymphopenia, grade 3 hypoalbuminemia, grade 3 hypomagnesemia)

-DLT Exemption: grade 3 infusion reaction.

[00249] Any adverse event meeting the criteria for Hy's Law case (i.e., severe drug-induced liver injury [DILI]) will be considered a DLT. A Hy's Law case is defined as: AST or ALT values of > 3 x ULN AND with serum total bilirubin level (TBL) of > 2 x ULN without signs of cholestasis and with no other clear alternative reason to explain the observed liver related laboratory abnormalities.

[00250] If a subject experiences a DLT during the DLT evaluation period, study treatment should be discontinued for that subject. However, if the investigator believes that the subject is benefiting clinically from the therapy, therapy may be resumed with the consideration of a dose reduction.

[00251] Dosage Adjustments, Delays, Rules for Withholding or Restarting, Permanent Discontinuation

[00252] Sotorasib Dose Modifications:

[00253] Dose reduction levels of sotorasib for toxicity management of individual subjects are provided in the tables below.

[00254] Sotorasib dose modification guidelines for hematologic and non-hematologic toxicities.

³ Subjects may be resumed at a dose lower than the recommended restarting dose after discussion with the Medical Monitor ^bFor subjects with hepatotoxicity, see below

[00255] If sotorasib is held, panitumumab should be held as well.

[00256] Dose reduction levels of sotorasib for toxicity management of individual subjects is provided in the following table.

[00257] Hepatotoxicity Guidelines for Sotorasib: Guidelines for management and monitoring of subjects with increased AST, ALT, or alkaline phosphatase (ALP) are presented in the table below.

^a If increase in AST/ALT is likely related to alternative agent, discontinue causative agent and await resolution to baseline or grade 1 prior to resuming sotorasib. ^b For example: prednisone 1 to 2 mg/kg/day, dexamethasone equivalent, or methylprednisone equivalent, followed by a taper. The taper may occur after restarting sotorasib. ^c Close monitoring at restart {e.g., daily LFTs x 2, then weekly x 4). Sotorasib dose may be increased after discussion with Medical Monitor. ^d There is no limit to the number of sotorasib re-challenges for isolated alkaline phosphatase elevations that resolve to baseline or grade 1 . ^e Dose decrements below 240 mg are not allowable. Subjects may restart at same dose without dose reduction.

[00258] Hepatotoxicity Response: Subjects with abnormal hepatic laboratory values (i.e. , alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBL)) and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as described below) may meet the criteria for withholding or permanent discontinuation of sotorasib.

[00259] The following stopping and/or withholding rules apply to subjects for whom another cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been identified. Important alternative causes for elevated AST/ALT and/or TBL values include, but are not limited to: Hepatobiliary tract disease; Viral hepatitis {e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); Right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; Heritable disorders causing impaired glucuronidation {e.g., Gilbert's syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation {e.g., indinavir, atazanavir); Alpha-one antitrypsin deficiency; Alcoholic hepatitis; Autoimmune hepatitis; Wilson's disease and hemochromatosis; Nonalcoholic fatty liver disease including steatohepatitis; and/or Non-hepatic causes {e.g., rhabdomyolysis, hemolysis).

[00260] Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and/or the laboratory abnormalities resolve to normal or baseline, as described in the below.

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; I NR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal

[00261] Panitumumab Dose Modifications:

[00262] For subjects who experience toxicities while on study, 1 or more doses of panitumumab are withheld, reduced, or delayed (administered at > 14 day intervals). Exemplary panitumumab dose reductions are listed in the table below.

[00263] Exemplary panitumumab dose modification guidelines due to dermatological toxicities are provided in the table below.

[00264] In the event of severe or life-threatening inflammatory or infectious complications, consider withholding or discontinuing panitumumab as clinically appropriate.

[00265] Management of Skin Toxicities

[00266] It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving panitumumab as sunlight can exacerbate any skin reactions that may occur. Proactive skin treatment including skin moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) may be useful in the management of skin toxicities. Subjects may be advised to apply moisturizer and sunscreen to face, hands, feet, neck, back and chest every morning during treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every night. Treatment of skin reactions should be based on severity and may include a moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics, as prescribed by a physician.

[00267] Pulmonary Toxicity

[00268] In the event of acute onset or worsening of pulmonary symptoms, consider withholding panitumumab. If interstitial lung disease is confirmed, discontinue panitumumab.

[00269] For Toxicities other than Dermatologic or Pulmonary

[00270] For toxicities other than dermatologic or pulmonary, withhold panitumumab for any grade 3 or 4 panitumumab-related toxicity with the following exceptions:

[00271] - Panitumumab will only be withheld for symptomatic grade 3 or 4 hypomagnesemia and/or hypocalcemia that persists despite aggressive magnesium and/or calcium replacement

[00272] - Panitumumab will only be withheld for grade 3 or 4 nausea, diarrhea, or vomiting that persists despite maximum supportive care

[00273] Infusion reactions:

[00274] Infusion reactions may manifest as fever, chills, dyspnea, bronchospasm, hypotension, or anaphylaxis.

[00275] -Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

[00276] -Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue panitumumab.

[00277] Criteria for Re-Treatment with Panitumumab

[00278] For dermatologic toxicities, see table above. [00279] For toxicities other than dermatologic: If panitumumab was withheld, administration may recommence once the adverse event has improved to < grade 1 or returned to baseline.

[00280] mFOLFOX6 Dose Modification

[00281] The table below describes the recommended dose modifications for the next dose based on the worst toxicity observed. If in the judgment of the investigator, the toxicity is primarily from 1 drug, the investigator can dose reduce only the suspected agent. If, in the opinion of the investigator, a more severe dose reduction or dose hold is needed, that is permissible.

^a There will be no leucovorin dose reduction. If the 5-fl uorouracil dose is omitted, the leucovorin is also omitted.

Levoleucovorin 200 mg/m² may be used instead of leucovorin.

5-FU = 5-fluorouracil; IV = intravenous; FOLFOX = 5 fluorouracil, leucovorin, and oxaliplatin; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events ^a There will be no leucovorin dose reduction. If the 5-FU dose is held, the leucovorin dose should be held. ^b NCI CTCAE (Version 5.0) ^c Absolute neutrophil count < 1000/mm³ and temperature > 38.5°C. ^d Despite maximum supportive care. ^e Dose modifications are based on worst toxicity observed on planned treatment days only.

[00282] mFOLFOX6 Regimen Pre-medication and Supportive Medications

[00283] Prior to the administration of mFOLFOX6 all subjects should receive antiemetic agents (e.g., oral or IV dexamethasone, 5-hydroxyyptamine3 [5-HT3] receptor antagonists). Avoid the use of the 5-HT3 receptor antagonist onandestron in subjects enrolled in Part 1 Cohort C and Part 2 Cohort J and consider use of granisetron or palanosetron. Antiemetic agents should be given on the day of treatment, starting at least 30 minutes prior to administration of oxaliplatin. Alternative and additional antiemetics may be used, where clinically indicated, at the discretion of the investigator. Prophylactic or therapeutic administration of IV or subcutaneous atropine for cholinergic symptoms may be used at the discretion of the investigator.

[00284] Growth factor support and medications for diarrhea management may be used at the discretion of the investigator.

[00285] Radiological Imaging Assessment

[00286] The extent of disease will be evaluated by contrast-enhanced MRI/CT according to RECIST v1.1. In order to reduce radiation exposure for subjects, the lowest dose possible should be utilized whenever possible. [00287] The screening scans must be performed within 28 days prior to enrollment and will be used as baseline. Imaging performed as part of standard of care that falls within the screening window given for scans may be used for the baseline scan as long as it meets the scan requirements for screening. All subsequent scans will be performed in the same manner as at screening, with the same contrast, preferably on the same scanner. Radiological assessment must include CT of the chest, and contrast-enhanced CT or MRI of the abdomen and pelvis, as well as assessment of all other known sites of disease as detailed within the Site Imaging Manual.

[00288] The same imaging modality, MRI field strength and IV and oral contrast agents used at screening should be used for all subsequent assessments. Liver specific MRI contrast agents should not be used. To reduce potential safety concerns, macrocyclic gadolinium contrast agents are recommended per National Health Institute guidelines or follow local standards if more rigorous.

[00289] During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, as well as all other known sites of disease, will be performed independent of treatment cycle every 6 ± 1 weeks for the first 4 response assessments. After 4 (6 week) response assessments, radiological imaging and tumor assessment will be performed every 12 ± 1 weeks. Radiologic imaging and tumor assessment will be performed until disease progression, start of new anti-cancer treatment, death, withdrawal of consent or until end of study. Imaging may also be performed more frequently if clinically necessitated at the discretion of the managing physician. Radiographic response (CR, PR) requires confirmation by a repeat, consecutive scan at least 4 weeks after the first documentation of response and may be delayed until the next scheduled scan to avoid unnecessary procedures.

[00290] All subjects, subjects with a history of brain metastases, and subjects with signs and symptoms suggestive of brain metastases must have MRI of the brain performed within 28 days prior to first dose of sotorasib. Subsequently, brain scans may be performed at any time if needed, in the judgement of the managing physician. All brain scans on protocol are required to be MRI unless MRI is contraindicated, and then CT with contrast is acceptable.

[00291] Radiological imaging assessment at the end of the study or during the end of treatment (EOT) visit should be performed only for subjects that discontinue treatment for a reason other than disease progression per RECIST v1 .1 guidelines.

[00292] Determination of disease response for clinical management of subjects will be assessed at the clinical sites per RECIST v1 .1 . Scans may be submitted to a central imaging core laboratory for archival and (if necessary) independent response assessment utilizing RECIST v1 .1 criteria. Exploratory imaging analyses may be performed centrally and may include tumor volumetries, viable tumor measurements, tissue necrosis ratios, and lesion texture analysis (radiomics).

[00293] Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [00294] Definitions

[00295] Measurable Lesions

[00296] Measurable Tumor Lesions - Non-nodal lesions with clear borders that can be accurately measured in at least 1 dimension with longest diameter > 10 mm in CT/MRI scan with slice thickness no greater than 5 mm. When slice thickness is greater than 5 mm, the minimum size of measurable lesion should be twice the slice thickness.

[00297] Nodal Lesions - Lymph nodes are to be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in short axis when assessed by CT/MRI (scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis is measured and followed. Nodal size is normally reported as two dimensions in the axial plane. The smaller of these measures is the short axis (perpendicular to the longest axis).

[00298] Irradiated Lesions - Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are not measurable unless there has been demonstrated progression in the lesion prior to enrollment.

[00299] Non-measurable Lesions: All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes with > 10 mm but to < 15 mm short axis with CT scan slice thickness no greater than 5 mm) are considered non-measurable and characterized as non-target lesions.

[00300] Other examples of non-measurable lesions include: Lesions with prior local treatment: tumor lesions situated in a previously irradiated area, or an area subject to other loco-regional therapy, should not be considered measurable unless there has been demonstrated progression in the lesion; Biopsied lesions; Categorically, clusters of small lesions, bone lesions, inflammatory breast disease, and leptomeningeal disease are non-measurable.

[00301] Methods of Measurement

[00302] Measurement of Lesions - The longest diameter of selected lesions should be measured in the plane in which the images were acquired (axial plane). All measurements should be taken and recorded in metric notation. All baseline evaluations should be performed as closely as possible to the beginning of treatment and not more than 4 weeks before study Day 1 .

[00303] Methods of Assessment - The same method of assessment and the same technique should be used to characterize each identified and reported lesion throughout the trial.

[00304] CT/ MRI - Contrast-enhanced CT or MRI should be used to assess all lesions. Optimal visualization and measurement of metastasis in solid tumors requires consistent administration (dose and rate) of IV contrast as well as timing of scanning. CT and MRI should be performed with < 5 mm thick contiguous slices.

[00305] Baseline documentation of "Target” and "Non-target” lesions [00306] Target Lesions - All measurable lesions up to a maximum of two (2) lesions per organ and five (5) lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline.

[00307] -Target lesions should be selected on the basis of their size (lesions with the longest diameter) and suitability for accurate repeated measurements.

[00308] -Pathologic lymph nodes (with short axis > 15 mm) may be identified as target lesions. All other pathological nodes (those with short axis > 10 mm but < 15 mm) should be considered non-target lesions.

[00309] -A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions are calculated and reported as the baseline sum of diameters. The baseline sum of diameters are used as reference by which to characterize objective tumor response.

[00310] Non-Target Lesions - All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, and these lesions should be followed as "present”, "absent”, or "unequivocal progression” throughout the study. In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case report form (e.g., "multiple enlarged pelvic lymph nodes” or "multiple liver metastases”).

[00311] Response Criteria

Evaluation of Target Lesions

Evaluation of Non-target Lesions

¹ To achieve "unequivocal progression” on the basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest "increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for unequivocal progression status.

[00312] Evaluation of Overall Response

[00313] The best overall response is the best response recorded from the start of the study treatment until the end of treatment or disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).

[00314] In general, the subject's best response assignment depends on the findings of both target and non- target disease and also take into consideration the appearance of new lesions.

Time Point response: Subjects with Target (+/- Non-target) Disease

ME = Not evaluable Time Point Response: Subjects with Non-Target Disease Only

¹ "Non-CR/non-PD” is preferred over "SD” for non-target disease since SD is increasingly used as endpoint for assessment of efficacy in some trials so as to assign this category when no lesions can be measured is not advised.

Overall Response: Confirmation of Complete Response (CR) and Partial Response (PR) required

¹ 1f a CR is truly met at first time point, then any disease at a subsequent time point, even if disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend upon whether minimum duration for SD was met. However, sometimes "CR” may be claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.

[00315] Special Notes on Response Assessment

[00316] Nodal lesions - Lymph nodes identified as target lesions should always have the actual short axis measurement recorded, even if the nodes regress to below 10 mm on study. In order to qualify for CR, each node must achieve a short axis < 10 mm, NOT total disappearance. Nodal target lesion short axis measurements are added together with target lesion' longest diameter measurements to create the sum of target lesion diameters for a particular assessment (time point).

[00317] Target lesions that become "too small to measure” - While on study, all lesions (nodal and non-nodal) recorded at baseline should have their measurements recorded at each subsequent evaluation. If a lesion becomes less than 5 mm, the accuracy of the measurement becomes reduced. Therefore, lesions less than 5 mm are considered as being "too small to measure”, and are not measured. With this designation, they are assigned a default measurement of 5 mm. No lesion measurement less than 5mm should be recorded, unless a lesion totally disappears and "0” can be recorded for the measurement.

[00318] New lesions - The term "new lesion” always refers to the presence of a new finding that is definitely tumor. New findings that only may be tumor, but may be benign (infection, inflammation, etc.) are not selected as new lesions, until that time when the review is certain they represent tumor.

[00319] -If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date of the initial scan.

[00320] -A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression, regardless of any response that may be seen in target or non-target lesions present from baseline.

[00321] Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having "symptomatic deterioration.” Every effort should be made to document the objective progression with an additional imaging assessment even after discontinuation of treatment.

[00322] In some circumstances it may be difficult to distinguish residual disease from scar or normal tissue.

When the evaluation of complete response (CR) depends on this determination, it is recommended that the residual lesion be further investigated by fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET/computed tomography (PET/CT), or possibly fine needle aspirate/biopsy, to confirm the CR status.

[00323] Confirmation Measurement I Duration of Response

[00324] Response Confirmation - In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is required to ensure responses identified are not the result of measurement error.

[00325] Duration of overall response - The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date the recurrent or progressive disease is objectively documented or death, whichever is earlier.

[00326] Duration of Stable Disease - SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started, or death, whichever is earlier.

[00327] ECOG Performance and NYHA Classification

Source: Oken et al, 1982; ECOG = Eastern Cooperative Oncology Group.

[00328] New York Heart Association Functional Classification

[00329] Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea.

[00330] Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnea.

[00331] Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation or dyspnea. [00332] Class IV Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest. If any physical activity is undertaken, discomfort is increased.

[00333] As of a July 24, 2024 data snapshot, six subjects with previously treated KRAS G12C-mutated metastatic colorectal cancer were enrolled in Dose Level 1 of Part 1 Cohort C and treated with sotorasib 960 mg daily, panitumumab 6 mg/kg intravenous every 2 weeks, and mFOLFOX6 intravenous every 2 weeks. Four of the six were evaluable for dose-limiting toxicities (DLTs). Two DLTs were noted during the DLT evaluation window; one subject had grade 3 dehydration and one subject had grade 3 diarrhea and dehydration related to study drugs during the DLT evaluation window. A lower dose of sotorasib 480 mg in combination with panitumumab and mFOLFOX6 is being explored. Of the six subjects enrolled, two had a partial response, 2 had stable disease, and two did not have imaging at the time of the data snapshot.

[00334] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.

[00335] References:

Bokemeyer et al., 2011, Ann Oncol., 22 (7): 1535- 1546

Canon et al., 2019, Nature, 575(7781): 217.

Cecil Textbook of Medicine, pp. 2317-2341, W.B. Saunders & Co. (1985)

Gerami et al., 2012, Cancer Discov., 2(5): 401.

Cervantes A, et al. ESMO Guidelines Committee. Ann Oncol. 2023 Jan;34(1): 10-32. Epub 2022 Oct 25

Chang et al., 1982, PNAS, 79:4848-4852.

Douillard et al., 2010 J Clin Oncol., 28(31 ):4697-4705.

ELOXATIN® US Prescribing Information, Sanofi-aventis U.S. LLC, Bridgewater, New Jersey 08807 (revision 4/2020).

Eisenhauer et al., 2009, Eur. J. Cancer, 45:228-247.

Fluorouracil, US Prescribing Information, Gland Pharma Limited, India (revision 9/2022).

Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), www.drug-interactions.medicine.iu.edu, accessed May 2021

Gao et al., 2013, Science Signaling, 6(269), pH .

Giusti et al., 2007, Oncologist, 12:577-583.

Hall et al., 1983, Nature, 303:396.

Harvey, 1964, Nature, 204:1104. Hong et al., 2020, N. Engl. J. Med., 383, 1207.

Janes et al., 2018, Cell., 172 (3): 578-589.

Kirsten and Mayer, 1967, J. National Cancer Inst., 39:311-335.

Lanman et al., 2020, J. Med. Chem., 63:52.

Leucovorin calcium injection, US Prescribing Information, Bedford Laboratories, Bedford, Ohio 44146 (revision 11/2011).

Levoleucovorin Injection, US Prescribing Information, Sandoz, Inc., Princeton, New Jersey 08540, USA (revision 11/2013).

LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California 91320 (revision 4/2023).

Maughan et al., 2011 The Lancet, 377(9783): 18-24.

McCormick, 2016, J. Mol. Med. (Berl)., 94:253-258.

National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2023. April 25, 2023.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 3.2023. May 26, 2023.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer Version 4/2020.

Oken et al., 1982, Am J Clin Oncol., 5(6):649-655.

Ostrem et al., 2013, Nature, 503:548-551.

Ostrem and Shokat, 2016, Nature Rev Drug D/scov., 15(11):771 -785.

Patricelli et al., 2016, Cancer Discovery, 6:316-329.

Peeters et al., 2010, J Clin Oncol., 28:4706-13

Prior et al, 2012, Cancer Res., 72:2457-2467.

Simanshu et al., 2017, Cell, 170:17-33.

Taparowsky et al., 1983, Cell, 581-586.

Van Cutsem et al, 2007, J. Clin. Oncol., 25:1658-1664. VECTIBIX® US Prescribing Information. Amgen Inc., Thousand Oaks, California, 91320, revision

8/2021). www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates- inhibitors-and-inducers, accessed May 2021.

Xie et al., 2017, Front Pharmacol., 8:823.

Zubrod et al., 1960, J Chronic Disease, 11 :7-33.

Claims

What is claimed is:

1 . A method of treating cancer comprising a KRAS G12C mutation in a patient in need of treatment, the method comprising administering to the patient (a) a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of an epidermal growth factor receptor (EGFR) antibody, and (c) (1) a therapeutically effective amount of oxaliplatin, (2) a therapeutically effective amount of leucovorin or a therapeutically effective amount of levoleucovorin, and (3) a therapeutically effective amount of 5-fluorouracil (5-FU).

2. The method of claim 1 , wherein the amount of sotorasib or salt thereof is 960 mg daily.

3. The method of claim 1 , wherein the amount of sotorasib or salt thereof is 480 mg daily.

4. The method of claim 1 , wherein the amount of sotorasib or salt thereof is 240 mg daily.

5. The method of any one of claims 1 -4, wherein the amount of sotorasib or salt thereof is administered to the patient once daily.

6. The method of any one of claims 1 -5, wherein the sotorasib or salt thereof is administered as a tablet.

7. The method of any one of claims 1 -6, wherein the sotorasib or salt thereof is administered as a free base.

8. The method of any one of claims 1-7, wherein the EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.

9. The method of claim 8, wherein the EGFR antibody comprises the heavy chain variable region sequence of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 9.

10. The method of claim 8 or claim 9, wherein the EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10.

11 . The method of any one of claims 1-10, wherein the EGFR antibody is panitumumab.

12. The method of any one of claims 1-11, wherein the amount of the EGFR antibody is 6 mg/kg.

13. The method of any one of claims 1-12, wherein the EGFR antibody is administered intravenously.

14. The method of any one of claims 1-13, wherein the EGFR antibody is administered every two weeks.

15. The method of any one of claims 1-14, wherein the amount of oxaliplatin is 85 mg/m².

16. The method of any one of claims 1-15, wherein the oxaliplatin is administered intravenously.

17. The method of any one of claims 1-16, wherein the oxaliplatin is administered every two weeks.

18. The method of any one of claims 1-17, wherein the method comprises administering leucovorin.

19. The method of any one of claims 1-18, wherein the amount of leucovorin is 400 mg/m² leucovorin.

20. The method of any one of claims 1-19, wherein the leucovorin is administered intravenously.

21 . The method of any one of claim 1 -20, wherein the leucovorin is administered every two weeks.

22. The method of any one of claims 1-17, wherein the method comprises administering levoleucovorin.

23. The method of any one of claims 1-17 and 22, wherein the amount of levoleucovorin is 200 mg/m² levoleucovorin.

24. The method of any one of claims 1-17, 22, and 23, wherein the levoleucovorin is administered intravenously.

25. The method of any one of claims 1-17 and 22-24, wherein the levoleucovorin is administered every two weeks.

26. The method of any one of claims 1-25, wherein the amount of 5-FU is 2800 mg/m² 5-FU.

27. The method of claim 26, wherein the 2800 mg/m² 5-FU are administered in two separate doses of 400 mg/m² 5-FU and 2400 mg/m² 5-FU.

28. The method of any one of claims 1-27, wherein the 5-FU is administered intravenously.

29. The method of any one of claims 1-28, wherein the 5-FU is administered every two weeks.

30. The method of any one of claims 1 , 2, and 5-29, comprising administering to the patient

(a) 960 mg sotorasib or salt thereof daily;

(b) 6 mg/kg panitumumab intravenously every two weeks; and

(c) (1) 85 mg/m² oxaliplatin intravenously every two weeks, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin intravenously every two weeks, and (3) 400 mg/m²5-FU intravenously as a bolus followed by 2400 mg/m² 5-FU intravenously over 46-48 hours as a continuous infusion every two weeks.

31 . The method of any one of claims 1 , 3, and 5-29, comprising administering to the patient

(a) 480 mg sotorasib or salt thereof daily;

(b) 6 mg/kg panitumumab intravenously every two weeks; and (c) (1) 85 mg/m² oxaliplatin intravenously every two weeks, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin intravenously every two weeks, and (3) 400 mg/m²5-FU intravenously (bolus) followed by 2400 mg/m²5-FU intravenously over 46-48 hours as a continuous infusion every two weeks.

32. The method of any one of claims 1, 4, and 5-29, comprising administering to the patient

(a) 240 mg sotorasib or salt thereof daily;

(b) 6 mg/kg panitumumab intravenously every two weeks; and

(c) (1) 85 mg/m² oxaliplatin intravenously every two weeks, (2) 400 mg/m² leucovorin or 200 mg/m² levoleucovorin intravenously every two weeks, and (3) 400 mg/m²5-FU intravenously (bolus) followed by 2400 mg/m²5-FU intravenously over 46-48 hours as a continuous infusion every two weeks.

33. The method of any one of claims 30-32, wherein steps (a) though (c) are initiated sequentially on the first day of a two week period.

34. The method of claim 33, wherein step (a) is executed 2 hours before step (b) on the first day of the first two week period.

35. The method of claim 33 or 34 , wherein in step (c) (1) oxaliplatin and (2) leucovorin or levoleucovorin are administered, concurrently or subsequently, and then (3) 5-FU is administered.

36. The method of any one of claims 1-35, wherein the cancer is a solid tumor.

37. The method of any one of claims 1-36, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

38. The method of any one of claims 1-37, wherein the cancer is colorectal cancer (CRC).

39. The method of any one of claims 1-37, wherein the cancer is metastatic colorectal cancer (mCRC).

40. The method of any one of claims 1-39, wherein the patient has previously received at least one prior cancer therapy.

41 . The method of claim 40, wherein at least one prior cancer therapy is selected from fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, ramucirumab, aflibercept, pembrolizumab, nivolumab, ipilimumab, trifluridine and tipiracil, and regorafenib, or any combination the foregoing.

42. The method of claim 40 or claim 41 , wherein the at least one prior cancer therapy is not a therapy comprising administering to the patient a KRAS^G12C inhibitor.

43. The method of any one of claims 1-42, wherein the patient exhibits an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 .

44. The method of any one of claims 1-43, wherein the method further comprises a step of determining whether the patient has a cancer comprising a KRAS G12C mutation.