Sotorasib and EGFR antibodies for treating cancers containing the KRAS G12C mutation

Abstract

Provided herein is a method of treating a cancer comprising a KRAS G12C mutation in a patient, the method comprising administering to the patient sotorasib and an anti-epidermal growth factor receptor (EGFR) antibody in an amount effective to treat the cancer. Further provided is a method further comprising administering to the patient FOLFIRI (irinotecan, 5-FU and leucovorin).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 241,601, filed September 8, 2021, U.S. Provisional Patent Application No. 63 / 298,747, filed January 12, 2022, and U.S. Provisional Patent Application No. 63 / 374,012, filed August 31, 2022, each of which is incorporated by reference herein in its entirety.

[0002] Incorporation by Reference of Electronically Submitted Materials The text file containing the sequence listing is named "55328P3_Seqlisting.XML", was created on August 23, 2022, and is 13,982 bytes in size. The subject matter of the sequence listing is incorporated herein by reference in its entirety. [Background technology]

[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 three closely related genes expressing guanosine triphosphate (GTP)ases involved in regulating cell proliferation and survival. RAS proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS), can be mutationally activated at codons 12, 13, or 61 to cause human cancers. Different tumor types are associated with mutations in specific isoforms of RAS, with KRAS being the most frequently mutated isoform in the majority of cancers. The role of KRAS mutations in human cancer has been known for decades, but until recently, anticancer therapies that specifically target KRAS mutations have not been successfully developed, because the protein has generally been considered difficult to inhibit with small molecules. Summary of the Invention [Means for solving the problem]

[0004] Described herein are methods of treating cancer containing a KRAS G12C mutation in a patient, comprising administering to the patient sotorasib and an anti-epidermal growth factor receptor (EGFR) antibody in amounts effective to treat the cancer. In some embodiments, the anti-EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, an LCDR2 of SEQ ID NO: 7, and an LCDR3 of SEQ ID NO: 8. In some embodiments, the anti-EGFR antibody comprises a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region of SEQ ID NO: 9. In some embodiments, the anti-EGFR antibody comprises a heavy chain sequence of SEQ ID NO: 5 and a light chain sequence of SEQ ID NO: 10. In some embodiments, the anti-EGFR antibody is panitumumab.

[0005] In some embodiments, the method further comprises administering to the patient irinotecan, 5-fluoro-1H-pyrimidine-2,4-dione (5-fluorouracil, 5-FU), and leucovorin. In some embodiments, the method further comprises administering to the patient irinotecan, 5-FU, and levoleucovorin. In some embodiments, the method further comprises administering to the patient irinotecan and 5-FU.

[0006] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, in some cases metastatic or locally advanced. In various embodiments, the cancer is colorectal cancer. In various embodiments, the cancer is pancreatic cancer. In various embodiments, the cancer is small intestine cancer, appendix cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumors, ovarian cancer, gastrointestinal neuroendocrine tumors, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. [Brief explanation of the drawings]

[0007] [Figure 1]1 shows the mean plasma concentration-time profiles following once-daily oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1, where N indicates the number of observations across data points. [Figure 2] 1 shows the mean plasma concentration-time profiles following once-daily oral administration of 180, 360, 720, or 960 mg sotorasib on day 8, where N indicates the number of observations across data points. DETAILED DESCRIPTION OF THE INVENTION

[0008] Provided herein are methods for treating a cancer comprising a KRAS G12C mutation in a patient, the methods comprising administering to the patient sotorasib and an anti-epidermal growth factor receptor (EGFR) antibody in amounts effective to treat the cancer. In some embodiments, the methods further comprise administering to the patient irinotecan, 5-FU, and leucovorin. In some embodiments, the methods further comprise administering to the patient irinotecan, 5-FU, and levoleucovorin. In some embodiments, the methods further comprise administering to the patient irinotecan and 5-FU.

[0009] Therapeutic methods disclosed herein for administering two or more therapeutic agents (e.g., sotorasib, EGFR antibodies, irinotecan, 5-FU, leucovorin, etc.) to a patient include simultaneous administration of the therapeutic agents (e.g., within 1 hour, 45 minutes, 30 minutes, 15 minutes, or 10 minutes of each other), as well as sequential administration (e.g., administration separated by at least 1 hour, or at least 2 hours, or at least 4 hours, or at least 6 hours, or at least 8 hours, or at least 12 hours, or at least 24 hours, or at least 2 days, or at least 3 days). Unless otherwise specified herein, combination therapy of two or more therapeutic agents discussed herein includes both concomitant and sequential administration.

[0010] Sotoracive Sotorasib is a KRAS G12CSotorasib is a small molecule that irreversibly inhibits mutant proteins. Sotorasib is also known as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one, and has the following structure: [ka]

[0011] Sotorasib binds to the P2 pocket and nucleotide-binding pocket of KRAS adjacent to the mutant cysteine ​​at position 12. The inhibitor covalently modifies the cysteine ​​residue, inhibiting KRAS in the inactive guanosine diphosphate (GDP)-bound conformation. G12CIt contains a thiol-reactive moiety that blocks KRAS interaction with effectors such as rapidly progressing fibrosarcoma (RAF), thereby preventing downstream signaling, including extracellular signal-regulated kinase (ERK) phosphorylation (Cully and Downward, 2008; Ostrem et al., 2013; Simanshu et al., 2017). Inactivation of KRAS by RNA interference (RNAi) or small molecule inhibition has previously demonstrated inhibition of cell proliferation and induction of apoptosis in tumor cell lines and xenografts harboring KRAS mutations (including the KRAS G12C mutation) (Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patrice et al., 2016). Studies with sotorasib confirmed these in vitro findings, similarly demonstrating growth inhibition and regression of cells and tumors harboring the KRAS G12C mutation (Canon et al., 2019). See also LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (Amendment 5 / 2021), which is incorporated herein by reference in its entirety.

[0012] Anti-EGFR antibody In some embodiments, the method further comprises administering to the patient an anti-epidermal growth factor receptor (EGFR) antibody. In some embodiments, the anti-EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, an LCDR2 of SEQ ID NO: 7, and an LCDR3 of SEQ ID NO: 8. In some embodiments, the anti-EGFR antibody comprises a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region of SEQ ID NO: 9. In some embodiments, the anti-EGFR antibody comprises a heavy chain sequence of SEQ ID NO: 5 and a light chain sequence of SEQ ID NO: 10. In some embodiments, the anti-EGFR antibody is panitumumab.

[0013] Panitumumab is a fully human immunoglobulin (Ig) G2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). Panitumumab binds to the extracellular domain of EGFR, thus preventing its activation and intracellular signaling.

[0014] Panitumumab (VECTIBIX®) is approved for the treatment of patients with wild-type RAS (both KRAS and NRAS, as determined by a test approved by the FDA for this use) metastatic colorectal cancer (mCRC) as first-line therapy in combination with FOLFOX (leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin) and as monotherapy after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. The recommended dose is 6 mg / kg administered as an IV infusion Q2W over 60 minutes (≦1000 mg) or 90 minutes (>1000 mg). See also VECTIBIX® US Prescribing Information, Amgen Inc., Thousand Oaks, California 91320 (rev. 8 / 2021), which is incorporated herein by reference in its entirety.

[0015] FOLFIRI In some embodiments, the method further comprises administering to the patient irinotecan, 5-FU, and leucovorin. In some embodiments, the method further comprises administering to the patient irinotecan, 5-FU, and levoleucovorin.

[0016] The FOLFIRI regimen consisted of irinotecan 180 mg / m on day 1; 2 , racemic leucovorin 400 mg / m on day 1 2 , and 5-fluorouracil 400 mg / m on day 1. 2 IV bolus and 2400 mg / m over 46–48 hours starting on day 1 administered Q2W 2The FOLFIRI regimen consists of continuous IV infusion (IVCI) (National Comprehensive Cancer Network (NCCN) Colon, Rectal, and Anal Cancer Guidelines). Irinotecan in combination with 5-fluorouracil and leucovorin is approved by the FDA as first-line treatment for patients with metastatic cancer of the colon or rectum (CAMPTOSAR® US Prescribing Information, Pharmacia and Upjohn Co., Division of Pfizer, Inc., NY, NY 10017 (Amendment 1 / 2022), which is incorporated herein by reference in its entirety). In some embodiments, the leucovorin in the FOLFIRI regimen is 200 mg / m 2 may be replaced with levoleucovorin.

[0017] Dosing regimen In some embodiments, the method comprises administering sotorasib in an amount ranging from 240 mg to 960 mg. In some embodiments, the method comprises administering 960 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering 720 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering 480 mg to the patient once daily. In some embodiments, the method comprises administering 240 mg to the patient once daily. In some embodiments, the method comprises administering 480 mg to the patient twice daily. In some embodiments, the method comprises administering 240 mg to the patient twice daily.

[0018] In some embodiments, the methods include administering panitumumab to a patient once every two weeks. In some embodiments, the methods include administering panitumumab at 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, 5.0 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, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 ... In some embodiments, the method comprises administering panitumumab at 6 mg / kg. In some embodiments, the method further comprises administering panitumumab at 3 mg / kg.

[0019] In some embodiments, the methods described herein comprise administering to a patient (a) 960 mg of sotorasib daily; and (b) 6 mg / kg of panitumumab administered IV every two weeks. In some embodiments, the methods described herein comprise administering to a patient (a) 720 mg of sotorasib daily; and (b) 6 mg / kg of panitumumab administered IV every two weeks. In some embodiments, the methods described herein comprise administering to a patient (a) 480 mg of sotorasib daily; and (b) 6 mg / kg of panitumumab administered IV every two weeks. In some embodiments, the methods described herein comprise administering to a patient (a) 960 mg of sotorasib daily; and (b) 3 mg / kg of panitumumab administered IV every two weeks.

[0020] In some embodiments, the method further comprises administering to the patient irinotecan, 5-FU, and leucovorin. In some embodiments, the method comprises administering 400 mg / m IV. 2In some embodiments, the method further comprises administering irinotecan, 5-FU, and levoleucovorin to the patient. In some embodiments, the method comprises administering 200 mg / m IV of leucovorin to the patient. 2 In some embodiments, the method further comprises administering 180 mg / m levoleucovorin by IV administration to the patient. 2 In some embodiments, the method further comprises administering 400 mg / m irinotecan by IV administration to the patient. 2 The method further comprises administering to the patient 5-FU.

[0021] In some embodiments, the method comprises administering 180 mg / m 2 of irinotecan, 400 mg / m 2 of leucovorin, and 400 mg / m 2 of 5-FU administered to patients by IV bolus every 2 weeks and 2400 mg / m 2 of 5-FU administered to the patient via IV continuous infusion over 46 to 48 hours.

[0022] In some embodiments, the method comprises administering 180 mg / m 2 of irinotecan, 200 mg / m 2 of levoleucovorin, and 400 mg / m 2 IV bolus of 5-FU and 2400 mg / m 2 The method further comprises administering to the patient an IV continuous infusion of 5-FU over a period of 46 to 48 hours every two weeks.

[0023] In various embodiments, sotorasib is administered with a meal. In various embodiments, sotorasib is administered without a meal.

[0024] In various embodiments, the patient further requires treatment with an antacid. Antacids include, but are not limited to, proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and topical antacids. In some embodiments, the patient further requires treatment with a PPI or H2RA. 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 topical antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide. In some embodiments, the patient further requires treatment with an antacid is not administered a proton pump inhibitor or H2 receptor antagonist in combination with sotrasib. In some embodiments, patients who further require antacid treatment are not administered a proton pump inhibitor or an H2 receptor antagonist in combination with sotorasib, but are administered a locally acting antacid in combination with sotorasib, hi some embodiments, sotorasib is administered about 4 hours before or about 10 hours after the locally acting antacid.

[0025] In various embodiments, the patient further requires treatment with a CYP3A4 inducer. In some embodiments, the patient is not receiving 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, boceprevir.

[0026] In various embodiments, the patient further requires treatment with a CYP3A4 substrate. In some embodiments, the patient is not receiving a CYP3A4 substrate in combination with sotorasib. Exemplary CYP3A4 substrates include 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, and ciloxetine. Stazol, 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, erythropoietin Mycin, 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, nate Glinides, 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,These include, but are not limited to, 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, for example, Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), https: / / drug-interactions.medicine.iu.edu, accessed May 2021.

[0027] In various embodiments, the patient further requires treatment with a P-glycoprotein (P-gp) substrate. 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, and 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.

[0028] Patient characteristics In various embodiments, the patient has KRAS β-glucanase (KRAS β-glucanase) prior to administration of sotorasib as disclosed herein. G12C have a cancer determined to have one or more cells that express a mutant KRAS protein. G12C Determination of mutant proteins can be assessed as described elsewhere in this disclosure.

[0029] In some embodiments, the patient to whom sotorasib is administered in the methods described herein has previously been treated with a different anti-cancer therapy, e.g., at least one other systemic cancer therapy, such as one, two, or three. In some embodiments, the patient is a patient for whom sotorasib combination therapy is a second-line therapy, e.g., a KRAS G12C In some embodiments, the patient has previously been treated with one other systemic cancer therapy as a second-line therapy for treating metastatic colorectal cancer. In some embodiments, the patient is receiving the sotorasib combination therapy provided herein as a third-line therapy, e.g., a KRAS G12CThe patient has previously been treated with two other systemic cancer therapies, such as a third-line therapy for treating metastatic colorectal cancer. In some embodiments, the patient is receiving the sotorasib combination therapy as a first-line therapy, e.g., a KRAS G12C They have not been previously treated with any other systemic cancer therapy to be the first-line therapy for treating metastatic colorectal cancer.

[0030] In some embodiments, the prior systemic cancer therapy is a KRAS G12C In certain embodiments, the patient is treated with a KRAS inhibitor. G12C In some embodiments, the patient exhibits reduced sensitivity to therapy with a KRAS inhibitor. G12C In some embodiments, the KRAS G12C The inhibitor is sotorasib, adagrasib, GDC-6036, D-1553, JDQ443, LY3484356, BI1823911, JAB-21822, RMC-6291, or APG-1842. G12C In certain embodiments, the KRAS inhibitor is sotorasib. G12C In some embodiments, the therapy is a monotherapy. In some embodiments, the therapy is a KRAS inhibitor. G12C Therapies involving the administration of inhibitors, e.g., KRAS G12C In one embodiment, the combination therapy includes administration of a KRAS inhibitor and a MEK inhibitor or an SHP2 inhibitor (e.g., sotrasib and trametenib, adagrasib and trametinib, sotrasib and RMC-4630, adagrasib and RMC-4630, sotrasib and TNO-155, and adagrasib and TNO-155). G12C In another embodiment, the inhibitor therapy is sotorasib monotherapy. G12C In some embodiments, the prior systemic cancer therapy is a KRAS inhibitor monotherapy. G12CTherapy is not based on inhibitors. RMC-4630 (CAS No. 2172652-48-9, 6-(2-amino-3-chloropyridin-4-yl)sulfanyl-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl]methanol) is disclosed in WO 2021 / 142026, e.g., paragraph

[0005] . TNO-155 ((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine) is disclosed in WO 2021 / 224867, e.g., paragraph

[0014] .

[0031] As used herein, "sensitivity" refers to the manner in which a cancer responds to a drug, e.g., sotorasib. In an exemplary embodiment, "sensitivity" means "responsive to treatment," and the concepts of "sensitivity" and "responsiveness" are positively related in that a cancer or tumor that responds to drug treatment is said to be sensitive to that drug. In an exemplary case, "sensitivity" is defined as the ability of a population, individual, or tissue, compared with the ability of others, to respond qualitatively and normally to a particular drug dose, according to Pelikan, Edward, Glossary of Terms and Symbols used in Pharmacology (Pharmacology and Experimental Therapeutics Department Glossary at Boston University School of Medicine). The lower the dose required to produce an effect, the more sensitive the responsive system. "Sensitivity" may be quantitatively measured or described based on the intersection of the dose-effect curve with the abscissa axis or a line parallel to it; such a point corresponds to the exact dose required to produce a given degree of effect. Similarly, the "sensitivity" of a measurement system is defined as the minimum input (minimum amount) required to produce a given degree of output (effect). In an exemplary embodiment, "sensitivity" is the opposite of "resistance," and the concept of "resistance" is negatively related to "sensitivity." For example, a cancer that is resistant to drug treatment is neither sensitive nor responsive to the drug, or is initially sensitive to the drug and no longer sensitive upon acquiring resistance; the drug is no longer an effective treatment for the tumor or cancer cells, or is no longer an effective treatment.

[0032] Previous systemic cancer therapies include, but are not limited to, chemotherapy and immunotherapy. Particularly considered previous systemic cancer therapies include, but are not limited to, checkpoint inhibitor therapy (e.g., anti-PD1 therapy, anti-PDL1 therapy), platinum-based chemotherapy, and anti-EGFR therapy. Some examples of anti-PD1 therapy and anti-PDL1 therapy include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, tiselizumab, toripalimab, aspartalizumab, dostarlimab, retifanlimab, simtilimab, pidilizumab, atezolizumab, avelumab, durvalumab, and zelvalimab (AMG 404). Some examples of platinum-based chemotherapy include, but are not limited to, carboplatin, oxaliplatin, cisplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin, ProLindac™ (AP5346), and aroplatin. Some examples of anti-EGFR therapy include, but are not limited to, cetuximab and panitumumab.

[0033] In some embodiments, the patient has previously received a systemic cancer therapy that is a targeted therapy when the cancer has been identified as having a therapeutic oncogenic driver mutation in the epidermal growth factor receptor gene (EGFR), anaplastic lymphoma kinase gene (ALK), and / or ROS proto-oncogene 1 (ROS1). Targeted therapies for EGFR mutations include, but are not limited to, cetuximab, panitumumab, erlotinib, gefitinib, and afatinib. Targeted therapies for ALK mutations include, but are not limited to, crizotinib, entrectinib, lorlatinib, repotrectinib, brigatinib, alkotinib, alectinib, ensartinib, and ceritinib. Targeted therapies for ROS1 mutations include, but are not limited to, crizotinib, entrecetinib, ensartinib, alkotinib, brigatinib, taretrectinib, cabozantinib, repotrectinib, lorlatinib, and ceritinib.

[0034] In some embodiments, the patient has not received prior therapy for metastatic disease. G12C No prior therapy has been received for mutated cancers, such as metastatic colorectal and pancreatic cancer. In such cases, the sotorasib therapy provided herein is first-line therapy.

[0035] In some embodiments, the patient has previously been treated with chemotherapy and an anti-angiogenic agent. In some embodiments, the chemotherapy comprises therapy with a fluoropyrimidine, oxaliplatin, and irinotecan. In some embodiments, the anti-angiogenic agent is an anti-VEGF antibody (e.g., bevacizumab and ramucirumab), aflibercept, or regorafenib.

[0036] In various embodiments, the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see, e.g., Zubrod et al., 1960). In some embodiments, the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Status 0 indicates fully active and able to continue all pre-disease activities without limitation. Status 1 indicates limitations in physically strenuous activity but ambulatory and able to perform light or sedentary tasks. Status 2 indicates ambulatory and full self-care but unable to work; up and mobile more than 50% of the day. Status 3 indicates limited self-care and spending more than 50% of the day in bed or chair. Status 4 indicates complete inactivity, inability to perform any self-care, and entirely confined to bed or chair. Status 5 indicates death.

[0037] In various embodiments, the patient has a cancer that is determined not to be MSI-H. MSI-H cancer refers to cancer with high cellular instability, and stands for "microsatellite instability high." Determination of MSI-H cancer can be based on, for example, the Bethesda panel 9, or can be assessed by a clinician using well-known techniques, such as those described in U.S. Pat. Nos. 7,521,180, 7,662,595, 10,294,529, or 10,669,802.

[0038] In various cases, the patient has a cancer that is MSI-H. In some cases, the MSI-H cancer is mCRC and the patient has previously received a checkpoint inhibitor.

[0039] In some cases, the cancer is not MSI-H (e.g., non-MSI-H mCRC). In various cases, the patient has not received prior systemic therapy for KRAS G12C mutant cancer (e.g., mCRC), and the cancer is not MSI-H. That is, sotorasib combination therapy is a first-line treatment for KRAS G12C mutant cancer (e.g., mCRC) that is not MSI-H.

[0040] In various cases, the patient has colorectal cancer and the cancer does not contain a BRAF V600E mutation. Determination of the BRAF V600E mutation can be assessed from a patient sample using approved mutation tests from a number of commercial sources.

[0041] Adverse events In some embodiments, the method includes administering a reduced total daily dose of sotorasib if the patient experiences an adverse event with respect to the initial total daily dose. For example, in some embodiments, the initial daily dose is 960 mg of sotorasib and the reduced total daily dose is 480 mg of sotorasib. In some embodiments, the initial daily dose is 480 mg of sotorasib and the reduced total daily dose is 240 mg of sotorasib. In some embodiments, the method further includes administering a second reduced total daily dose of sotorasib if the patient experiences an adverse event with respect to the reduced total daily dose.

[0042] The term "adverse event" or "(AE)" as used herein refers to any unfavorable and unintended sign (including abnormal clinical laboratory findings), symptom, or disease that is temporally associated with the use of a medical treatment or procedure that can be considered related to the medical treatment or procedure.

[0043] In some embodiments, the adverse event is hepatotoxicity (eg, elevated liver enzymes), interstitial lung disease / (ILD) / pneumonitis, diarrhea, and / or nausea / vomiting.

[0044] hepatotoxicity 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 aminotransferase (AST), alanine aminotransferase (ALT), and / or total bilirubin (TBL)) when the patient had baseline levels of the liver biomarkers that were either not abnormal before administration of sotorasib or were lower than those measured after administration of sotorasib.

[0045] Alanine transaminase (ALT), also known as serum glutamate pyruvate transaminase (SGPT) or alanine aminotransferase (ALAT), catalyzes the transfer of an amino group from alanine to α-ketoglutarate to produce pyruvate and glutamate. When the liver is damaged, the level of ALT in the blood can increase due to leakage of ALT from damaged or necrotic liver cells into the blood.

[0046] Aspartate transaminase (AST), also known as serum glutamic oxaloacetic transaminase (SGOT or GOT) or aspartate aminotransferase (ASAT), catalyzes the transfer of an amino group from aspartate to α-ketoglutarate to produce oxaloacetate and glutamate. AST can increase in response to liver injury. Elevated AST can also result from injury 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 injury.

[0047] Bilirubin is a catabolic product of heme that is eliminated from the body by the liver. Conjugation of bilirubin to glucuronic acid by hepatocytes produces direct bilirubin, a water-soluble product that is easily eliminated from the body. Indirect bilirubin is unconjugated, and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin may indicate liver dysfunction.

[0048] Alkaline phosphatase (ALP) hydrolyzes phosphate groups from various molecules and is present in cells lining the bile ducts of the liver. Plasma ALP levels can be elevated in response to liver injury and are higher in growing children and elderly patients with Paget's disease. However, elevated ALP levels usually reflect biliary tree disease.

[0049] In some embodiments, the patient is free of a disorder that results in elevated liver biomarkers. Disorders associated with elevated liver biomarkers (such as AST / ALT and / or TBL levels) include hepatobiliary disease; viral hepatitis (e.g., Hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, chickenpox, toxoplasmosis, and parvovirus); any cause of hypoxia to the liver that results in right heart failure, hypotension, or ischemia; exposure to hepatotoxic agents / drugs or hepatotoxins, including herbal and dietary supplements, plants, and mushrooms. genetic disorders causing impaired glucuronidation (e.g., Gilbert syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); alpha-1-antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson's disease and hemochromatosis; non-alcoholic fatty liver disease including steatohepatitis; and / or extrahepatic causes (e.g., rhabdomyolysis, hemolysis).

[0050] Prior to receiving sotorasib, a patient's baseline liver function can be assessed by various means known in the art, such as blood chemistry tests that measure biomarkers of liver function. In some embodiments, the methods described herein involve monitoring liver biomarkers in patients and withholding sotorasib administration in patients with abnormal liver function of >Grade 2 as measured by AST and / or ALT levels. In such embodiments, sotorasib administration is suspended until the patient's AST and / or ALT levels improve to Grade 1 or below (baseline).

[0051] Adverse effect grades related to abnormal liver function are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 1. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE), published by the National Cancer Institute on November 27, 2017, which is incorporated herein by reference in its entirety.

[0052] [Table 1]

[0053] Grade 0 levels are characterized by biomarker levels within the normal range (WNL). "Normal" liver function, as used herein, refers to Grade 0 adverse effects. "Abnormal" liver function, as used herein, refers to Grade 1 or higher adverse effects.

[0054] "Grade 1 liver function abnormality" includes an elevation in ALT or AST greater than the ULN but less than or equal to 3 times the ULN if the baseline was normal; or 1.5 to 3.0 times baseline if the baseline was abnormal. Grade 1 liver function abnormality also includes an elevation in bilirubin levels greater than the ULN but less than or equal to 1.5 times the ULN if the baseline was normal; or >1.0 to 1.5 times baseline if the baseline was abnormal. Grade 1 liver function abnormality also includes an elevation in ALP greater than the ULN but less than or equal to 2.5 times the ULN if the baseline was normal; or >2.0 to 2.5 times baseline if the baseline was abnormal.

[0055] "Grade 2 liver function abnormalities" include elevations in ALT or AST greater than 3 times but not greater than 5 times the upper limit of normal (ULN) if the baseline was normal; or >3.0-5.0 x baseline if the baseline was abnormal. Grade 2 liver function abnormalities also include elevations in bilirubin levels greater than 1.5 times but not greater than 3 times the ULN if the baseline was normal; or >1.5-3.0 x baseline if the baseline was abnormal. Grade 2 liver function abnormalities also include elevations in ALP greater than 2.5 times but not greater than 5 times the ULN if the baseline was normal; or >2.5-5.0 x baseline if the baseline was abnormal.

[0056] "Grade 3 liver function abnormalities" include elevations in ALT, AST, or ALP greater than 5 times the ULN and less than or equal to 20 times the ULN if the baseline was normal; >5.0 to 20.0 x baseline if the baseline was normal. Grade 3 liver function abnormalities also include elevations in bilirubin levels greater than 3 times the ULN and less than or equal to 10 times the ULN if the baseline was normal; >3.0 to 10 x baseline if the baseline was abnormal.

[0057] "Grade 4 liver function abnormality" includes an elevation in ALT, AST, or ALP greater than 20 times the ULN if the baseline was normal; if the baseline was abnormal, >20 x baseline. Grade 4 liver function abnormality also includes an elevation in bilirubin levels greater than 10 times the ULN if the baseline was normal; if the baseline was abnormal, >10.0 x baseline.

[0058] The ULN for various indicators of liver function depends on the assay used, the patient population, and the respective normal laboratory ranges of the values ​​for the designated biomarkers, but can be easily determined by those skilled in the art. Exemplary values ​​for the normal ranges for a healthy adult population are listed in Table 2 below. See Cecil Textbook of Medicine, pp. 2317-2341, WB Saunders & Co. (1985).

[0059] [Table 2]

[0060] 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 AST and / or ALT levels in a patient rise to, for example, Grade 2 or Grade 3 levels, and the patient's baseline AST and / or ALT levels were less than Grade 2 or less than Grade 3. 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 AST and / or ALT levels in a patient rise to Grade 1 levels, and the patient's baseline AST and / or ALT levels were less than Grade 1.

[0061] 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) the patient's AST and bilirubin levels are elevated, or (2) the patient's AST or ALP levels are elevated, or (3) the patient's ALT and bilirubin levels are elevated, or (4) the patient's ALT and ALP levels are elevated, or (5) the patient's bilirubin and ALP levels are elevated, e.g., to Grade 1, Grade 2, Grade 3, or Grade 4 levels, and the patient's baseline AST, bilirubin, ALP, and / or ALT levels were less than Grade 1, less than Grade 2, less than Grade 3, or less than Grade 4, respectively. Alternatively, in any of the methods disclosed herein, three biomarkers of liver function (e.g., ALT, AST, and bilirubin, or ALT, AST, and ALP) may be elevated to Grade 1, Grade 2, Grade 3, or Grade 4 levels in a patient, and the patient's baseline biomarker levels were less than Grade 1, less than Grade 2, less than Grade 3, or less than Grade 4, respectively.

[0062] 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 ALT and / or AST levels are greater than about 3-fold compared to the upper limit of normal (ULN). In related embodiments, the abnormal levels of ALT and / or AST are greater than about a 3-fold to about a 5-fold increase compared to the upper limit of normal (ULN) (i.e., a "Grade 2 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 2 abnormality is an abnormal level of ALT and / or AST greater than about a 3-fold to about a 5-fold increase compared to baseline. In some embodiments, the abnormal level of ALP is greater than about a 2.5-fold to about a 5-fold increase compared to the upper limit of normal (ULN) (i.e., a "Grade 2 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 2 abnormality is an abnormal level of ALP greater than about a 2.5-fold to about a 5-fold increase compared to baseline. In some embodiments, the abnormal level of bilirubin is greater than about a 1.5-fold to about a 3-fold increase compared to the upper limit of normal (ULN) (i.e., a "Grade 2 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 2 abnormality is an abnormal level of bilirubin greater than about a 1.5-fold to about a 3-fold increase compared to baseline.

[0063] 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 ALT and / or AST levels are greater than about 5-fold compared to the upper limit of normal (ULN). In some embodiments, the total daily dose is reduced when ALT, AST, or ALP levels are greater than about a 5-fold to about a 20-fold increase compared to the upper limit of normal (ULN) (i.e., "Grade 3 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 3 abnormality is an abnormal level of ALT and / or AST greater than about a 5-fold to about a 20-fold increase compared to baseline. In some embodiments, an abnormal level of ALP is greater than about a 5-fold to about a 20-fold increase compared to the upper limit of normal (ULN) (i.e., "Grade 3 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 3 abnormality is an abnormal level of ALP greater than about a 5-fold to about a 20-fold increase compared to baseline. In some embodiments, the total daily dose is reduced when the bilirubin level is greater than about a 3-fold to about a 10-fold increase compared to the upper limit of normal (ULN) (i.e., a "Grade 3 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 3 abnormality is an abnormal level of bilirubin greater than about a 3-fold to about a 10-fold increase compared to baseline.

[0064] 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 ALT and / or AST levels are greater than about 20-fold compared to the upper limit of normal (ULN) (i.e., "Grade 4 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 4 abnormality is an abnormal level of ALT and / or AST greater than about a 20-fold increase compared to baseline. In some embodiments, an abnormal level of ALP is greater than about a 20-fold increase compared to the upper limit of normal (ULN) (i.e., "Grade 4 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 4 abnormality is an abnormal level of ALP greater than about a 20-fold increase compared to baseline. In some embodiments, the total daily dose is reduced when bilirubin levels are greater than about a 10-fold increase compared to the upper limit of normal (ULN) (i.e., "Grade 4 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 4 abnormality is an abnormal level of bilirubin that is greater than about a 10-fold increase compared to baseline.

[0065] In some embodiments, the methods described herein further include increasing the total dose of sotorasib (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg) when liver biomarkers in the patient improve to Grade 1 or less (e.g., baseline).

[0066] Nausea / vomiting In some embodiments, the adverse event is nausea or vomiting. In some embodiments, the nausea / vomiting is present despite adequate supportive therapy (e.g., antiemetic therapy). "Nausea," as used herein, refers to a disorder characterized by a nauseous sensation and / or an urge to vomit.

[0067] Adverse effect grades for nausea and vomiting are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 3. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE), published by the National Cancer Institute on November 27, 2017, which is incorporated herein by reference in its entirety.

[0068] [Table 3]

[0069] In some embodiments, the methods described herein include withholding sotorasib administration in patients with nausea ≧ Grade 3 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 include administering a reduced total daily dose of sotorasib to the patient (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg).

[0070] In some embodiments, the methods described herein involve withholding sotorasib administration in patients with ≧Grade 3 emesis until the emesis has improved to ≦Grade 1 or baseline. In some embodiments, once the patient has improved to ≦Grade 1 or baseline, the methods involve administering a reduced total daily dose of sotorasib to the patient (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg).

[0071] In some embodiments, the methods described herein further include increasing the total dose of sotorasib (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg) when the nausea in the patient has improved to Grade 1 or less (e.g., baseline).

[0072] diarrhea In some embodiments, the adverse event is diarrhea, hi some embodiments, the diarrhea is present despite adequate supportive therapy (e.g., antidiarrheal therapy).

[0073] Adverse effect grades for diarrhea are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 4. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE), published by the National Cancer Institute on November 27, 2017, which is incorporated herein by reference in its entirety.

[0074] [Table 4]

[0075] In some embodiments, the methods described herein include withholding sotorasib administration in patients with diarrhea ≧ Grade 3 until the patient improves to ≦ Grade 1 or baseline. In some embodiments, once the patient improves to ≦ Grade 1 or baseline, the methods include administering a reduced total daily dose of sotorasib to the patient (e.g., 240 mg to 480 mg, or 480 mg to 960 mg).

[0076] In some embodiments, the methods described herein further include increasing the total dose of sotorasib (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg) when diarrhea in the patient improves to Grade 1 or less (e.g., baseline).

[0077] Interstitial lung disease In some embodiments, the adverse event is interstitial lung disease (ILD) or pneumonitis. If ILD or pneumonitis is suspected at any grade level, sotorasib is held. If ILD or pneumonitis is confirmed and no other cause of ILD or pneumonitis is identified, sotorasib is permanently discontinued.

[0078] Response to sotorasib combination therapy The response rate or outcome for patients administered sotorasib in the methods disclosed herein can be measured in several ways after the patient has been administered sotorasib for a suitable period of time. In various embodiments, the patient is administered sotorasib 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., 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 various embodiments, the patient is administered sotorasib for at least 1 month. In various embodiments, the patient is administered sotorasib for at least 3 months. In various embodiments, the patient is administered sotorasib for at least 6 months.

[0079] Patients can respond to sotorasib combination therapy as measured by at least stable disease (SD) as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). At least stable disease is stable disease, or has demonstrated a partial response (PR), or has demonstrated a complete response (CR) (i.e., "at least SD" = SD + PR + CR, often referred to as disease control). In various embodiments, stable disease does not shrink sufficiently to qualify as a partial response (PR) or expand sufficiently to qualify as progressive disease (PD). In various embodiments, patients demonstrate at least a partial response (i.e., "at least PR" = PR + CR, often referred to as an objective response).

[0080] Response may be measured by one or more of: a decrease in tumor size, an inhibition or reduction in tumor growth, a decrease in target or tumor lesions, a delay in time to progression, no new tumors or lesions, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastasis. In various embodiments, a patient's disease progression may be assessed by measuring tumor size, tumor lesions, or the formation of new tumors or lesions, by evaluating the patient using a computed tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, X-rays, ultrasound, or some combination thereof.

[0081] Progression-free survival (PFS) can be evaluated as described in RECIST 1.1 protocol. In various embodiments, patients exhibit a PFS of at least 1 month. In various embodiments, patients exhibit a PFS of at least 3 months. In some embodiments, patients exhibit a PFS of at least 6 months.

[0082] Additional means for assessing response are described in detail in the Examples below and may be applied generally to the methods disclosed herein.

[0083] KRAS G12C cancer Without wishing to be bound by any particular theory, the following is noted: sotorasib inhibits KRAS G12C Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS (Hong et al., 2020). Hong et al. report that "[p]re-clinical studies demonstrated that sotorasib inhibited nearly all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, and led to durable and complete tumor regression in mice bearing KRAS p.G12C tumors" (ibid.; see also Canon et al., 2019, and Lanman et al., 2020).

[0084] Sotorasib was evaluated in a phase 1 dose-escalation and expansion study in 129 patients with locally advanced or metastatic cancer harboring a histologically confirmed KRAS G12C mutation identified by local molecular testing of tumor tissue, including 59 patients with non-small cell lung cancer, 42 patients with colorectal cancer, and 28 patients with other tumor types (Hong et al., 2020, pp. 1208–1209). Hong et al. reported disease control rates (95% CI) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer, and 75.0% for other tumor types (Hong et al., 2020, at page 1213, Table 3). The cancer types showing either stable disease (SD) or partial response (PR) reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma (Hong et al., 2020, p. 1212 (Figure A), and appendix (p. 59 (Figure S5) and p. 63 (Figure S6))).

[0085] The KRAS G12C mutation occurs at the alteration frequencies shown in the table below (Cerami et al., 2012; Gao et al., 2013). For example, the table shows that 11.6% of patients with non-small cell lung cancer have cancers in which one or more cells express the KRAS G12C mutant protein. Therefore, KRAS G12C Sotorasib, which specifically and irreversibly binds to, is useful for treating patients with cancers including, but not limited to, those listed in Table 5 below.

[0086] [Table 5]

[0087] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, 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 neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In some embodiments, the cancer is small intestine cancer, appendix cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In various embodiments, the cancer is non-small cell lung cancer, and in some particular embodiments, metastatic or locally advanced non-small cell lung cancer. In various embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.

[0088] Methods for detecting KRAS, STK11, KEAP1, EGFR, ALK, and / or ROS1 mutation status The presence or absence of G12C, STK11, KEAP1, EGFR, ALK, and / or ROS1 mutations in cancers as described herein can be determined using methods known in the art. Determining whether a tumor or cancer contains a mutation can be done, for example, by evaluating the nucleotide sequence encoding the protein, by evaluating the amino acid sequence of the protein, or by evaluating the characteristics of a putative mutant protein, or by any other suitable method known in the art. Wild-type human KRAS (nucleotide sequence set forth in Genbank accession number BC010502; amino acid sequence set forth in Genbank accession number AGC09594), STK11 (Gene ID: 6794; available at www.ncbi.nlm.nih.gov / gene / 6794; accessed January 2020), KEAP1 (Gene ID: 9817; available at www.ncbi.nlm.nih.gov / gene / 9817; accessed January 2020), EGFR (Gene ID: The nucleotide and protein sequences of ALK (Gene ID: 1956; available at www.ncbi.nlm.nih.gov / gene / 1956; accessed March 2021), ALK (Gene ID: 238; available at www.ncbi.nlm.nih.gov / gene / 238; accessed March 2021), and ROS1 (Gene ID: 6098; available at www.ncbi.nlm.nih.gov / gene / 6098; accessed March 2021) are known in the art.

[0089] Methods for detecting mutations include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing and / or next-generation sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for mutations, such as KRAS G12C mutations, by real-time PCR. Real-time PCR uses a fluorescent probe specific to a particular mutation, such as the KRAS G12C mutation. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, mutations are identified using direct sequencing of specific regions in a gene. This approach identifies all possible mutations in the sequenced region. In some embodiments, the presence or absence of insertion mutations can be detected using gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and / or arrays. In some embodiments, methods include, but are not limited to, detecting mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0090] In some embodiments, multiplex PCR-based sequencing is used for mutation detection and may include several amplicons to provide improved sensitivity for detection of one or more genetic biomarkers. For example, the multiplex PCR-based sequencing may include about 60 amplicons (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 amplicons). In some embodiments, the multiplex PCR-based sequencing may include 61 amplicons. Amplicons generated using multiplex PCR-based sequencing may range from about 15 bp to about 1000 bp (e.g., about 25 bp to about 1000 bp, about 35 bp to about 1000 bp, about 50 bp to about 1000 bp, about 100 bp to about 1000 bp, about 250 bp to about 1000 bp, about 500 bp to about 1000 bp, about 750 bp to about 1000 bp, about 15 bp to about 750 bp, about 15 For example, an amplicon generated using multiplex PCR-based sequencing may contain a nucleic acid having a length of about 33 bp.

[0091] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using a sequencing technique (e.g., a next-generation sequencing technique). Various sequencing techniques are known in the art. For example, methods for detecting and characterizing circulating tumor DNA in cell-free DNA can be described elsewhere (see, e.g., Haber and Velculescu, 2014). Non-limiting examples of such techniques include SafeSeqs (see, e.g., Kinde et al., 2011), OnTarget (see, e.g., Forshew et al., 2012), and TamSeq (see, e.g., Thompson et al., 2012).

[0092] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using droplet digital PCR (ddPCR), a method known to be highly sensitive for detecting mutations. In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using other sequencing techniques, including, but not limited to, chain termination techniques, shotgun techniques, sequencing-by-synthesis methods, methods utilizing microfluidic technology, other capture techniques, or other sequencing techniques known in the art that are useful for detecting small amounts of DNA in a sample (e.g., ctDNA in a cell-free DNA sample).

[0093] In some embodiments, the presence of one or more mutations present in the sample obtained from a patient is detected using an array-based method.For example, the step of detecting genetic alterations (for example, one or more genetic alterations) in cell-free DNA is carried out using a DNA microarray.In some embodiments, the DNA microarray can detect one or more of multiple cancer cell mutations.In some embodiments, the cell-free DNA is amplified before detecting genetic alterations. Non-limiting examples of array-based methods that can be used in any of the methods described herein include complementary DNA (cDNA) microarrays (see, e.g., Kumar et al. 2012; Laere et al. 2009; Mackay et al. 2003; Alizadeh et al. 1996), oligonucleotide microarrays (see, e.g., Kim et al. 2006; Lodes et al. 2009), bacterial artificial chromosome (BAC) clone chips (see, e.g., Chung et al. 2004; Thomas et al. 2005), single nucleotide polymorphism (SNP) microarrays (see, e.g., Mao et al. 2007; Jasmine et al. 2012), microarray-based comparative genomic hybridization arrays (array-CGH) (see, e.g., Beers and Nederlof, 2006; Pinkel et al. 2005; Michels et al. 2012). al. 2007), molecular inversion probe (MIP) assays (see, e.g., Wang et al. 2012; Lin et al. 2010). In some embodiments, the cDNA microarray is an Affymetrix microarray (see, e.g., Irizarry 2003; Dalma-Weiszhausz et al. 2006), a NimbleGen microarray (see, e.g., Wei et al. 2008; Albert et al. 2007), an Agilent microarray (see, e.g., Hughes et al. 2001), or a BeadArray array (see, e.g., Liu et al. 2017).In some embodiments, the oligonucleotide microarray is a DNA tiling array (see, e.g., Mockler and Ecker, 2005; Bertone et al. 2006). Other suitable array-based methods are known in the art.

[0094] The methods for determining whether a tumor or cancer contains a mutation can use a variety of samples. In some embodiments, the sample is taken from a patient with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded (FFPE) sample. In some embodiments, the sample is a circulating cell-free DNA and / or circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In certain embodiments, the sample is obtained by excision, core needle biopsy (CNB), fine needle aspiration (FNA), urine collection, or hair follicle collection. In some embodiments, liquid cytology using whole blood or cerebrospinal fluid may be used to assess mutation status.

[0095] In various embodiments, a test approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA), is used to determine whether a patient has a mutation, e.g., a KRASG12C-mutated cancer, or whether a tumor or tissue sample obtained from such a patient contains cells with the mutation. In some embodiments, the test for KRAS mutation used is the therascreen® KRAS RGQ PCR Kit (Qiagen). The therascreen® KRAS RGQ PCR Kit is a real-time quantitative PCR assay for the detection of seven somatic mutations (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) in codons 12 and 13 of the human KRAS oncogene using a Rotor-Gene Q MDx 5plex HRM instrument. The kit is intended for use with DNA extracted from FFPE samples of NSCLC or CRC obtained by resection, CNB, or FNA. Mutation testing for STK11, KEAP1, EGFR, ALK, and / or ROS1 can be performed using commercially available tests such as the Resolution Bioscience Resolution ctDx Lung™ assay, which includes 24 genes (including those therapeutic in NSCLC). Tissue samples can be tested using the Tempus xT 648 panel.

[0096] In some embodiments, the cancer is identified as having a KRAS G12C mutation. In some embodiments, the cancer is identified as having a mutation, e.g., a loss-of-function mutation, of STK11. In some embodiments, the cancer is identified as having a mutation, e.g., a loss-of-function mutation, of KEAP1. In some embodiments, the cancer is identified as having wild-type STK11. In some embodiments, the cancer is identified as having wild-type KEAP1.

[0097] In various embodiments, the cancer is identified as having a loss-of-function mutation in STK11 and wild-type KEAP1. In some embodiments, the cancer is identified as having a loss-of-function mutation in STK11 and a loss-of-function mutation in KEAP1. In some embodiments, the cancer is identified as having wild-type STK11 and wild-type KEAP1. In some embodiments, the cancer is identified as having wild-type STK11 and a loss-of-function mutation in KEAP1.

[0098] The term "loss-of-function mutation," as used herein, refers to a mutation (e.g., a substitution, deletion, truncation, or frameshift mutation) that results in the expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological or enzymatic activity), results in the expression of only a fragment of a protein that no longer exhibits wild-type activity, or does not result in the expression of a wild-type protein. For example, a loss-of-function mutation affecting the STK11 gene in a cell can result in reduced expression of the STK11 protein, expression of only a fragment of the STK11 protein, or expression of an STK11 protein that exhibits reduced or no enzymatic activity in a cancerous cell (e.g., no serine / threonine kinase enzymatic activity). Similarly, a loss-of-function mutation affecting the KEAP1 gene in a cell can result in reduced expression of the KEAP1 protein, expression of only a fragment of the KEAP1 protein, or expression of a KEAP1 protein that exhibits reduced or no activity in a cell (e.g., unable to interact with or activate erythroid transcription factor 2-related transcription factor 2 (NRF2)).

[0099] Methods for detecting PD-L1 protein expression PD-L1 expression can be determined by methods known in the art. For example, PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with pembrolizumab. This is a quantitative assay that uses a monoclonal mouse anti-PD-L1, clone 22C3 PD-L1, and the EnVision FLEX visualization system on the Lin 48 automated stainer to detect PD-L1 in FFPE samples, such as human non-small cell lung cancer tissue. Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells that show partial or complete membrane staining at a given intensity. Staining can range from 0% to 100% to indicate PD-L1 expression.

[0100] PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Meyers Squibb as a companion test for treatment with nivolumab. This quantitative assay uses monoclonal rabbit anti-PD-L1, clone 28-8, and the EnVision FLEX visualization system on the Lin 48 automated stainer to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissues.

[0101] Other commercially available tests for PD-L1 detection include the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca), which utilizes a monoclonal rabbit anti-PD-L1, clone SP263, and the Ventana SP142 assay (developed by Ventana in collaboration with Genentech / Roche), which uses a rabbit monoclonal anti-PD-L1 clone SP142.

[0102] In some embodiments, a test approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA), is used to determine the PD-L1 TPS of a cancer as disclosed herein. In various embodiments, the PD-L1 TPS is determined using an immunohistochemistry (IHC) test. In some embodiments, the IHC test is the PD-L1 IHC 22C3 pharmDx test. In various embodiments, the IHC test was performed using a sample obtained, for example, by resection, CNB, or FNA.

[0103] In various embodiments, patients have a PD-L1 TPS of less than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In various embodiments, patients have a PD-L1 TPS of less than 50% or less than 1%. In various embodiments, patients have a PD-L1 TPS of 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% or greater. In various embodiments, patients have a PD-L1 TPS of 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% or less. In various embodiments, the patient has a PD-L1 TPS of 50% or less, or 1% or less. In various embodiments, the patient has a PD-L1 TPS of greater than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In various embodiments, the patient has a PD-L1 TPS score in a range bounded by any of the values ​​recited in the preceding embodiments. For example, the patient has a PD-L1 TPS score in the range of less than 50% and greater than 1%, less than 50% and greater than 1%, less than 50% and greater than 1%, or less than 50% and greater than 1%.

[0104] In various embodiments, the patient has a PD-L1 TPS score ranging from less than 50% to greater than or equal to 1%. In some embodiments, the patient has a PD-L1 TPS score ranging from greater than or equal to 0% to less than 1%. In some embodiments, the patient has a PD-L1 TPS score ranging from greater than 50% to less than or equal to 100%. In some embodiments, the patient has a PD-L1 TPS score less than 1%. In some embodiments, the patient has a PD-L1 TPS score between 1 and 49%. In some embodiments, the patient has a PD-L1 TPS score of greater than 50% (i.e., between 50% and 100%).

[0105] Embodiment 1. A method of treating a cancer containing a KRAS G12C mutation in a patient, comprising administering to the patient sotorasib and an anti-epidermal growth factor receptor (EGFR) antibody in amounts effective to treat the cancer. 2. The method of embodiment 1, comprising administering to the patient 960 mg of sotorasib daily. 3. The method of embodiment 1, comprising administering to the patient 720 mg of sotorasib daily. 4. The method of embodiment 1, comprising administering to the patient 480 mg of sotorasib daily. 5. The method of embodiment 1, comprising administering to the patient 240 mg of sotorasib daily. 6. The method of any one of embodiments 1-5, comprising administering sotorasib to the patient once daily. 7. The method of any one of embodiments 1-5, comprising administering sotorasib to the patient twice daily. 8. The method of any one of embodiments 1-5, comprising administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient every two weeks. 9. The method of embodiment 8, wherein the anti-EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, an LCDR2 of SEQ ID NO: 7, and an LCDR3 of SEQ ID NO: 8. 10. The method of embodiment 9, wherein the anti-EGFR antibody comprises a heavy chain variable region sequence of SEQ ID NO:4 and a light chain variable region sequence of SEQ ID NO:9. 11. The method of embodiment 10, wherein the anti-EGFR antibody comprises the heavy chain sequence of SEQ ID NO:5 and the light chain sequence of SEQ ID NO:10. 12. The method of embodiment 8, wherein the anti-EGFR antibody is panitumumab. 13. The method of any one of embodiments 1-12, comprising administering 13.6 mg / kg of panitumumab to the patient. 13. The method of any one of embodiments 1-12, comprising administering 14.3 mg / kg of panitumumab to the patient. 15.(a) 960 mg of sotorasib daily; and (b) panitumumab 6 mg / kg administered intravenously every 2 weeks 13. The method of any one of embodiments 1-12, comprising administering to the patient 16.(a) 720 mg of sotorasib daily; and (b) panitumumab 6 mg / kg administered intravenously every 2 weeks 13. The method of any one of embodiments 1-12, comprising administering to the patient 17.(a) 480 mg of sotorasib daily; and (b) panitumumab 6 mg / kg administered intravenously every 2 weeks 13. The method of any one of embodiments 1-12, comprising administering to the patient 18.(a) 960 mg of sotorasib daily; and (b) panitumumab 3 mg / kg administered intravenously every 2 weeks 13. The method of any one of embodiments 1-12, comprising administering to the patient 19. The method of any one of embodiments 1-18, further comprising administering to the patient irinotecan, 5-FU, and leucovorin. 20. IV administration: 400 mg / m 2 20. The method of embodiment 19, comprising administering to the patient a leucovorin of 21. The method of any one of embodiments 1-18, further comprising administering to the patient irinotecan, 5-FU, and levoleucovorin. 22. 200 mg / m IV 2 22. The method of embodiment 21, comprising administering to the patient levoleucovorin in an amount of 23. 180 mg / m IV 2 23. The method of any one of embodiments 1-22, comprising administering to the patient irinotecan of 24. IV administration: 400 mg / m 2 23. The method of any one of embodiments 1-22, comprising administering to the patient 5-FU of 25. IV administration: 180 mg / m 2 of irinotecan, 400 mg / m 2 of leucovorin, and 400 mg / m 2 of 5-FU administered to patients by IV bolus every 2 weeks, and 2400 mg / m 2 25. The method of any one of embodiments 1-20, and 23-24, comprising administering to the patient 5-FU of 26. IV administration: 180 mg / m 2 of irinotecan, 200 mg / m 2 of levoleucovorin, and 400 mg / m 2 IV bolus of 5-FU and 2400 mg / m 2 25. The method of any one of embodiments 1-18, and 21-24, comprising administering to the patient an IV continuous infusion of 5-FU of 5-FU over 46-48 hours every two weeks. 27. The method of any one of embodiments 1-18, further comprising administering irinotecan and 5-FU to the patient. 28. 180 mg / m IV 2 28. The method of embodiment 27, comprising administering to the patient 29. 150 mg / m by IV administration 2 28. The method of embodiment 27, comprising administering to the patient 30. IV administration: 180 mg / m 2 of irinotecan, and 400 mg / m 2 IV bolus of 5-FU and 2400 mg / m 2 29. The method of any one of embodiments 1-18 and 28, comprising administering to the patient an IV continuous infusion of 5-FU over 46-48 hours every two weeks. 31. IV administration: 150 mg / m 2 of irinotecan, and 400 mg / m 2 IV bolus of 5-FU and 2400 mg / m 2 28. The method of any one of embodiments 1-18 and 27, comprising administering to the patient an IV continuous infusion of 5-FU over 46-48 hours every two weeks. 32. The method of any one of embodiments 1-31, wherein the cancer is a solid tumor. 33. The method of any one of embodiments 1-32, wherein the cancer is small intestine cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumors, ovarian cancer, gastrointestinal neuroendocrine tumors, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. 34. The method of any one of embodiments 1-33, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer (CRC). 35. The method of any one of embodiments 1-33, wherein the cancer is non-small cell lung cancer (NSCLC). 36. The method of any one of embodiments 1-33, wherein the cancer is metastatic pancreatic cancer. 37. The method of any one of embodiments 1-36, wherein the patient has previously received at least one other systemic cancer therapy. 38. At least one systemic cancer therapy targets KRAS G12C 38. The method of embodiment 37, wherein the therapy is selected from inhibitor therapy, anti-PD-1 therapy, anti-PD-L1 therapy, and platinum-based chemotherapy. 39. At least one systemic cancer therapy targets KRAS G12C 38. The method of embodiment 37, which is not inhibitor therapy. 40. The method of any one of embodiments 1-39, wherein the cancer is colorectal cancer (CRC). 41. The method of any one of embodiments 1-34 and 39, wherein the patient has previously received therapy with a fluoropyrimidine, oxaliplatin, irinotecan, and an anti-angiogenic agent. 42. The method of embodiment 40 or 41, wherein the patient has previously received treatment with a checkpoint inhibitor. 43. The patient has KRASG12C The method of any one of embodiments 1-34 and 40-42, wherein the patient is resistant to therapy with an inhibitor. 44. The method of any one of embodiments 1-34, 36, and 40-43, wherein the patient has previously received at least one other therapy for metastatic disease. 45. The method of any one of embodiments 1-34, 36, and 40-43, wherein the patient has previously received one other therapy for metastatic disease. 46. ​​The method of any one of embodiments 1-34 and 40, wherein the patient has not received prior therapy for metastatic disease. 47. The method of any one of embodiments 1-46, wherein the patient does not have active brain metastases from non-brain tumors or leptomeningeal disease. 48. The method of any one of embodiments 1-47, wherein the patient has not had a myocardial infarction in the 6 months prior to the start of treatment. 49. The method of any one of embodiments 1-48, wherein the patient exhibits at least stable disease (SD) after 1, 3, or 6 months of sotorasib and panitumumab therapy as measured by RECIST 1.1 protocol. 50. The method of any one of embodiments 1-49, wherein the patient exhibits at least a partial response (PR) after 1, 3, or 6 months of sotorasib and panitumumab therapy as measured by a RECIST 1.1 protocol. 51. The method of any one of embodiments 1-50, wherein the patient exhibits a progression-free survival (PFS) of at least 3 months. 52. The method of any one of embodiments 1-51, wherein the patient does not have a Hepatitis A infection, a Hepatitis B infection, or a Hepatitis C infection. 53. The method of any one of embodiments 1-52, wherein the patient does not suffer from interstitial pneumonia or pulmonary fibrosis. 54. The method of any one of embodiments 1-53, wherein the patient further requires treatment with an antacid. 55. The method of embodiment 54, wherein the antacid is a proton pump inhibitor (PPI), an H2 receptor antagonist (H2RA), or a locally acting antacid. 56. The method of embodiment 54 or embodiment 55, wherein the antacid is a topically acting antacid, and sotorasib is administered about 4 hours before or about 10 hours after the topically acting antacid. 57. The method of embodiment 55 or embodiment 56, wherein the topically acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide. 58. The method of any one of embodiments 1-57, wherein the patient further requires treatment with a proton pump inhibitor (PPI) or an H2 receptor antagonist (H2RA). 59. The method of embodiment 58, wherein the patient is not administered a PPI or H2RA in combination with sotorasib. 60. The method of any one of embodiments 55, 58, or 59, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. 61. The method of any one of embodiments 55, 58 or 59, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine. 62. The method of any one of embodiments 1-61, wherein the patient further requires treatment with a CYP3A4 inducer. 63. The method of embodiment 62, wherein the patient is not administered a CYP3A4 inducer in combination with sotorasib. 64. The method of embodiment 62 or 63, wherein the CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoid, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, and troglitazone. 65. The method of embodiment 62 or embodiment 63, wherein the patient is not administered a strong CYP3A4 inducer in combination with sotorasib. 66. The method of embodiment 65, wherein the strong CYP3A4 inducer is phenytoin or rifampin. 67. The method of any one of embodiments 1-66, wherein the patient further requires treatment with a CYP3A4 substrate. 68. The method of embodiment 67, wherein the patient is not administered a CYP3A4 substrate in combination with sotorasib. 69. CYP3A4 substrates include abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, caffergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, and clarithromycin. Isin, 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, fluticasone 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,The method of embodiment 67 or 68, wherein the agent is 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, or ziprasidone. 70. The method of any one of embodiments 1-69, wherein the patient further requires treatment with a P-glycoprotein (P-gp) substrate. 71. The method of embodiment 70, wherein the patient is not administered a P-gp substrate in combination with sotorasib. 72. The method of embodiment 70 or embodiment 71, wherein the P-gp substrate is etexilate, digoxin, or fexofenadine. 73. The method of any one of embodiments 1-72, wherein the cancer exhibits a PD-L1 Tumor Proportion Score (TPS) of 1-49%. 74. The method of any one of embodiments 1-73, wherein the cancer exhibits a PD-L1 Tumor Proportion Score (TPS) of less than 1%. 75. The method of any one of embodiments 1-74, wherein the cancer exhibits a PD-L1 Tumor Proportion Score (TPS) of 50-100%. 76. The method of any one of embodiments 1-75, wherein the cancer further comprises an STK11 mutation. 77. The method of any one of embodiments 1-76, wherein the cancer further comprises a KEAP1 mutation. 78. The method of embodiment 76 or embodiment 77, wherein the mutation is a loss-of-function mutation.

[0106] First Set of Alternative Embodiments 1. A method of treating a cancer containing a KRAS G12C mutation in a patient, comprising administering to the patient sotorasib and an anti-epidermal growth factor receptor (EGFR) antibody in amounts effective to treat the cancer. 2. The method of embodiment 1, comprising administering to the patient 960 mg of sotorasib daily. 3. The method of embodiment 1, comprising administering to the patient 240 mg of sotorasib daily. 4. The method of any one of embodiments 1-3, comprising administering sotorasib to the patient once daily. 5. The method of any one of embodiments 1-3, comprising administering sotorasib to the patient twice daily. 6. The method of any one of embodiments 1-5, comprising administering an anti-epidermal growth factor receptor (EGFR) antibody to the patient every two weeks. 7. The method of embodiment 6, wherein the anti-EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, an LCDR2 of SEQ ID NO: 7, and an LCDR3 of SEQ ID NO: 8. 8. The method of embodiment 7, wherein the anti-EGFR antibody comprises a heavy chain variable region sequence of SEQ ID NO:4 and a light chain variable region sequence of SEQ ID NO:9. 9. The method of embodiment 7, wherein the anti-EGFR antibody comprises a heavy chain sequence of SEQ ID NO:5 and a light chain sequence of SEQ ID NO:10. 10. The method of embodiment 7, wherein the anti-EGFR antibody is panitumumab. 11. The method of any one of embodiments 1-10, comprising administering 11.6 mg / kg of panitumumab to the patient. 12.(a) 960 mg of sotorasib daily; and (b) panitumumab 6 mg / kg administered intravenously every 2 weeks 11. The method of any one of embodiments 1-10, comprising administering to the patient 13.(a) 240 mg of sotorasib daily; and (b) panitumumab 6 mg / kg administered intravenously every 2 weeks 11. The method of any one of embodiments 1-10, comprising administering to the patient 14. The method of any one of embodiments 1-13, further comprising administering to the patient irinotecan, 5-FU and leucovorin. 15. IV administration: 400 mg / m 215. The method of embodiment 14, comprising administering to the patient a leucovorin of 16. The method of any one of embodiments 1-13, further comprising administering to the patient irinotecan, 5-FU, and levoleucovorin. 17. 200 mg / m IV 2 17. The method of embodiment 16, comprising administering to the patient levoleucovorin in an amount of 18. 180 mg / m IV 2 18. The method of any one of embodiments 1-17, comprising administering to the patient irinotecan of 19. IV administration: 400 mg / m 2 19. The method of any one of embodiments 1-18, comprising administering to the patient 5-FU of 20. IV administration: 180 mg / m 2 of irinotecan, 400 mg / m 2 of leucovorin, and 400 mg / m 2 of 5-FU administered to patients by IV bolus every 2 weeks, and 2400 mg / m 2 20. The method of any one of embodiments 1-15, and 18-19, comprising administering to the patient 5-FU of the formula (I) over 46-48 hours by IV continuous infusion. 21. IV administration: 180 mg / m 2 of irinotecan, 200 mg / m 2 of levoleucovorin, and 400 mg / m 2 IV bolus of 5-FU and 2400 mg / m 2 18. The method of any one of embodiments 1-13, 16 and 17, comprising administering to the patient an IV continuous infusion of 5-FU of 5-FU over 46-48 hours every two weeks. 22. The method of any one of embodiments 1-13, further comprising administering irinotecan and 5-FU to the patient. 23. 180 mg / m IV 2 23. The method of embodiment 22, comprising administering to the patient a dose of irinotecan of 24. 150 mg / m by IV administration 2 23. The method of embodiment 22, comprising administering to the patient a dose of irinotecan of 25. IV administration: 180 mg / m 2 of irinotecan, and 400 mg / m 2 IV bolus of 5-FU and 2400 mg / m 2 24. The method of any one of embodiments 1-13 and 23, comprising administering to the patient an IV continuous infusion of 5-FU over 46-48 hours every two weeks. 26. IV administration: 150 mg / m 2 of irinotecan, and 400 mg / m 2 IV bolus of 5-FU and 2400 mg / m 2 25. The method of any one of embodiments 1-13 and 24, comprising administering to the patient an IV continuous infusion of 5-FU over 46-48 hours every two weeks. 27. The method of any one of embodiments 1-26, wherein the cancer is a solid tumor. 28. The method of any one of embodiments 1-27, wherein the cancer is small intestine cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, pancreatic cancer, germ cell tumors, ovarian cancer, gastrointestinal neuroendocrine tumors, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. 29. The method of any one of embodiments 1-28, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer (CRC). 30. The method of any one of embodiments 1-29, wherein the cancer is non-small cell lung cancer (NSCLC). 31. The method of any one of embodiments 1-28, wherein the cancer is metastatic pancreatic cancer. 32. The method of any one of embodiments 1-28, wherein the cancer is colorectal cancer. 33. The method of any one of embodiments 1-32, wherein the patient has previously received at least one other systemic cancer therapy. 34. At least one systemic cancer therapy targets KRAS G12C 34. The method of embodiment 33, wherein the therapy is selected from inhibitor therapy, anti-PD-1 therapy, anti-PD-L1 therapy, and platinum-based chemotherapy. 35. At least one systemic cancer therapy targets KRAS G12C 34. The method of embodiment 33, which is not inhibitor therapy. 36. The method of any one of embodiments 1-28, wherein the cancer is metastatic colorectal cancer (mCRC). 37. The method of any one of embodiments 1-36, wherein the patient has previously received at least one other systemic cancer therapy. 38. The method of any one of embodiments 1-36, wherein the patient has previously received at least two other systemic cancer therapies. 39. The method of embodiment 37 and embodiment 38, wherein the systemic cancer therapy is a therapy comprising administering to the patient a fluoropyrimidine, irinotecan, and oxaliplatin. 40. The method of any one of embodiments 36-39, wherein the mCRC is determined to be MSI-H and the systemic cancer therapy is a therapy comprising administering to the patient a checkpoint inhibitor. 41. The method of any one of embodiments 36-40, wherein the mCRC comprises a BRAF V600E mutation and the systemic cancer therapy is a therapy comprising administering to the patient encorafenib and cetuximab. 42. The method of any one of embodiments 36-41, wherein the systemic cancer therapy is adjuvant therapy and the cancer progresses within 6 months after completion of the adjuvant therapy. 43. The method of any one of embodiments 36-42, wherein the systemic cancer therapy is adjuvant therapy after resection of mCRC. 44. The method of any one of embodiments 36-43, wherein the patient exhibits an ECOG performance status of 2 or less. 45. The method of any one of embodiments 36-44, wherein the patient does not have active brain metastases. 46. ​​The method of any one of embodiments 36-45, wherein the patient does not have leptomeningeal disease. 47. The method of any one of embodiments 36-46, wherein the patient does not have a human immunodeficiency virus (HIV) infection. 48. The method of any one of embodiments 36-47, wherein the patient does not have a hepatitis B or hepatitis C infection. 49. The method of any one of embodiments 37-48, wherein the systemic cancer therapy is a therapy comprising administering to the patient (i) trifluridine and tipiracil, and (ii) regorafenib. 50. Systemic therapy is effective against KRAS G12C 50. The method of any one of embodiments 37-49, wherein the therapy does not comprise administering an inhibitor to the patient. 51. KRAS G12C The method of embodiment 50, wherein the inhibitor is sotorasib. 52. KRAS G12C The method of embodiment 50, wherein the inhibitor is adagrasib. 53. The method of any one of embodiments 37-52, wherein the systemic therapy is not a therapy comprising administering trifluridine and tipiracil to the patient. 54. The method of any one of embodiments 37-53, wherein the systemic therapy is not a therapy comprising administering regorafenib to the patient. 55. The method of any one of embodiments 1-36, wherein the patient has not previously received another systemic cancer therapy. 56. The method of embodiment 55, wherein the patient does not have active brain metastases. 57. The method of embodiments 55 and 56, wherein the patient does not have leptomeningeal disease. 58. The method of any one of embodiments 55-57, wherein the mCRC does not comprise a BRAF V600E mutation. 59. The method of any one of embodiments 55-58, wherein the mCRC is determined to not be MSI-H. 60. Systemic therapy is effective against KRAS G12C 60. The method of any one of embodiments 55-59, wherein the therapy comprises administering an inhibitor to a patient. 61. KRAS G12C The method of embodiment 60, wherein the inhibitor is sotorasib. 62. KRAS G12C The method of embodiment 60, wherein the inhibitor is adagrasib. 63. The method of any one of embodiments 55-62, wherein the patient does not have dihydropyrimidine dehydrogenase deficiency. 64. The method of any one of embodiments 55-63, wherein the patient does not have UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease. 65. The method of any one of embodiments 55-64, wherein the patient does not have a hepatitis B or hepatitis C infection. 66. The method of any one of embodiments 55-64, wherein the patient does not have New York Heart Association class II or higher cardiac disease, myocardial infarction less than 6 months prior to treatment, unstable arrhythmia, or unstable angina. 67. The method of any one of embodiments 55-64, wherein the patient exhibits an ECOG performance status of 1 or less. 68. The method of any one of embodiments 1-36, wherein the patient has previously received one other systemic cancer therapy. 69. The method of embodiment 68, wherein the cancer is determined to be MSI-H and one other systemic cancer therapy is a checkpoint inhibitor. 70. The method of embodiment 68 or embodiment 69, wherein the patient has received one other systemic cancer therapy and has progressed during or after said therapy. 71. The method of any one of embodiments 68-70, wherein one other systemic cancer therapy is adjuvant therapy and the mCRC has progressed within 6 months after completion of the adjuvant therapy. 72. The method of any one of embodiments 68-70, wherein the mCRC is determined to be MSI-H and one other systemic cancer therapy is a therapy comprising administering a checkpoint inhibitor. 73. One other systemic therapy is G12C The method of any one of embodiments 68-70, wherein the therapy does not include administering an inhibitor to the patient. 74. KRAS G12C 74. The method of embodiment 73, wherein the inhibitor is sotorasib. 75. KRAS G12C The method of embodiment 73, wherein the inhibitor is adagrasib. 76. The method of any one of embodiments 68-70, wherein the one other systemic therapy is not a therapy comprising administering irinotecan. 77. The method of any one of embodiments 68-76, wherein the patient exhibits an ECOG performance status of 1 or less. 78. The method of any one of embodiments 68-77, wherein the patient does not have active brain metastases. 79. The method of any one of embodiments 68-78, wherein the patient does not have leptomeningeal disease. 80. The method of any one of embodiments 68-79, wherein the mCRC does not contain a BRAF V600E mutation. 81. The method of any one of embodiments 68-80, wherein the patient does not have dihydropyrimidine dehydrogenase deficiency. 82. The method of any one of embodiments 68-81, wherein the patient does not have UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease. 83. The method of any one of embodiments 68-82, wherein the patient does not have a hepatitis B or hepatitis C infection. 84. The method of any one of embodiments 68-83, wherein the patient does not have New York Heart Association class II or higher cardiac disease, myocardial infarction less than 6 months prior to treatment, unstable arrhythmia, or unstable angina. 85. The method of any one of embodiments 1-84, wherein the patient exhibits at least stable disease (SD) after 1, 3, or 6 months of sotorasib and panitumumab therapy as measured by a RECIST 1.1 protocol. 86. The method of any one of embodiments 1-85, wherein the patient exhibits at least a partial response (PR) after 1, 3, or 6 months of sotorasib and panitumumab therapy as measured by a RECIST 1.1 protocol. 87. The method of any one of embodiments 1-86, wherein the patient exhibits a progression-free survival (PFS) of at least 3 months. 88. The method of any one of embodiments 1-87, wherein the patient further requires treatment with an antacid. 89. The method of embodiment 88, wherein the antacid is a proton pump inhibitor (PPI), an H2 receptor antagonist (H2RA), or a locally acting antacid. 90. The method of embodiment 88 or embodiment 89, wherein the antacid is a topically acting antacid, and sotorasib is administered about 4 hours before or about 10 hours after the topically acting antacid. 91. The method of embodiment 89 or embodiment 90, wherein the topically acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide. 92. The method of any one of embodiments 1-91, wherein the patient further requires treatment with a proton pump inhibitor (PPI) or an H2 receptor antagonist (H2RA). 93. The method of embodiment 92, wherein the patient is not administered a PPI or H2RA in combination with sotorasib. 94. The method of any one of embodiments 89, 92, or 93, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. 95. The method of any one of embodiments 89, 92, or 93, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine. 96. The method of any one of embodiments 1-95, wherein the patient further requires treatment with a CYP3A4 inducer. 97. The method of embodiment 96, wherein the patient is not administered a CYP3A4 inducer in combination with sotorasib. 98. The method of embodiment 96 or 97, wherein the CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoid, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, or troglitazone. 99. The method of embodiment 96 or embodiment 97, wherein the patient is not administered a strong CYP3A4 inducer in combination with sotorasib. 100. The method of embodiment 99, wherein the strong CYP3A4 inducer is phenytoin or rifampin. 101. The method of any one of embodiments 1-100, wherein the patient further requires treatment with a CYP3A4 substrate. 102. The method of embodiment 101, wherein the patient is not administered a CYP3A4 substrate in combination with sotorasib. 103. CYP3A4 substrates include abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, caffergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, and clarithromycin. mycin, 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,The method of embodiment 101 or 102, wherein the agent is 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, or ziprasidone. 104. The method of any one of embodiments 1-103, wherein the patient further requires treatment with a P-glycoprotein (P-gp) substrate. 105. The method of embodiment 104, wherein the patient is not administered a P-gp substrate in combination with sotorasib. 106. The method of embodiment 104 or embodiment 105, wherein the P-gp substrate is etexilate, digoxin, or fexofenadine. 107. The method of any one of embodiments 1-106, wherein the cancer exhibits a PD-L1 Tumor Proportion Score (TPS) of 1-49%. 108. The method of any one of embodiments 1-107, wherein the cancer exhibits a PD-L1 Tumor Proportion Score (TPS) of less than 1%. 109. The method of any one of embodiments 1-108, wherein the cancer exhibits a PD-L1 Tumor Proportion Score (TPS) of 50-100%. 110. The method of any one of embodiments 1-109, wherein the cancer further comprises an STK11 mutation. 111. The method of any one of embodiments 1-110, wherein the cancer further comprises a KEAP1 mutation. 112. The method of embodiment 110 or embodiment 111, wherein the mutation is a loss-of-function mutation.

[0107] Second Set of Alternative Embodiments 1. A method for treating a cancer containing a KRAS G12C mutation in a patient, comprising administering to the patient (a) sotorasib and (b) an anti-epidermal growth factor receptor (EGFR) antibody in amounts effective to treat the cancer. 2. The method of embodiment 1, comprising administering to the patient 960 mg of sotorasib daily. 3. The method of embodiment 1, comprising administering to the patient 240 mg of sotorasib daily. 4. The method of any one of embodiments 1-3, comprising administering sotorasib to the patient once daily. 5. The method of any one of embodiments 1-3, comprising administering sotorasib to the patient twice daily. 6. The method of any one of embodiments 1-5, wherein the anti-EGFR antibody is panitumumab. The method of embodiment 6, comprising administering 7.6 mg / kg of panitumumab to the patient. 8.(a) 960 mg of sotorasib daily; and (b) panitumumab 6 mg / kg administered intravenously every 2 weeks 8. The method of embodiment 6 or embodiment 7, comprising administering to the patient 9.(a) 240 mg of sotorasib daily; and (b) panitumumab 6 mg / kg administered intravenously every 2 weeks 8. The method of embodiment 6 or embodiment 7, comprising administering to the patient 10. The method of any one of embodiments 1-13, further comprising administering to the patient: (c) irinotecan, (d) 5-FU, and (e) leucovorin or levoleucovorin. 11. 400 mg / m IV 2 11. The method of embodiment 10, comprising administering to the patient a dose of leucovorin of 12. 200 mg / m IV 2 11. The method of embodiment 10, comprising administering to the patient a dose of levoleucovorin of 13. 180 mg / m IV 2 13. The method of any one of embodiments 10-12, comprising administering to the patient irinotecan of 14. 400 mg / m IV 2 14. The method of any one of embodiments 10-13, comprising administering to the patient 5-FU of 15. IV administration: 180 mg / m 2of irinotecan, 400 mg / m 2 of leucovorin, and 400 mg / m 2 of 5-FU administered to patients by IV bolus every 2 weeks, and 2400 mg / m 2 11. The method of embodiment 10, comprising administering to the patient by IV continuous infusion over 46 to 48 hours. 16. IV administration: 180 mg / m 2 of irinotecan, 200 mg / m 2 of levoleucovorin, and 400 mg / m 2 IV bolus of 5-FU and 2400 mg / m 2 11. The method of embodiment 10, comprising administering to the patient an IV continuous infusion of 5-FU of 5-FU over 46-48 hours every two weeks. 17. The method of any one of embodiments 1-16, wherein the cancer is a solid tumor. 18. The method of any one of embodiments 1-17, wherein the cancer is non-small cell lung cancer (NSCLC). 19. The method of any one of embodiments 1-17, wherein the cancer is metastatic pancreatic cancer. 20. The method of any one of embodiments 1-17, wherein the cancer is colorectal cancer. 21. The method of any one of embodiments 1-17, wherein the cancer is metastatic colorectal cancer (mCRC). 22. The method of any one of embodiments 1-36, wherein the patient has received at least one prior systemic cancer therapy. 23. The method of any one of embodiments 1-36, wherein the patient has received at least two prior systemic cancer therapies. 24. The method of embodiment 22 and embodiment 23, wherein the systemic cancer therapy is a therapy comprising administering to the patient a fluoropyrimidine, irinotecan, and oxaliplatin. 25. The method of any one of embodiments 21-24, wherein the mCRC is determined to be MSI-H and the systemic cancer therapy is a therapy comprising administering to the patient a checkpoint inhibitor. 26. The method of any one of embodiments 21-25, wherein the mCRC comprises a BRAF V600E mutation and the systemic cancer therapy is a therapy comprising administering to the patient encorafenib and cetuximab. 27. The method of any one of embodiments 21-26, wherein the patient exhibits an ECOG performance status of 2 or less. 28. The method of any one of embodiments 21-27, wherein the patient does not have active brain metastases. 29. Systemic therapy is effective against KRAS G12C The method of any one of embodiments 22-28, wherein the therapy does not include administering an inhibitor to the patient. 30. The method of any one of embodiments 1-21, wherein the patient has not received prior systemic cancer therapy. 31. The method of embodiment 30, wherein the patient does not have active brain metastases. 32. The method of any one of embodiment 30 or embodiment 31, wherein the mCRC does not comprise a BRAF V600E mutation. 33. The method of any one of embodiments 30-32, wherein the mCRC is determined to be not MSI-H. 34. Systemic therapy is effective against KRAS G12C The method of any one of embodiments 30-33, wherein the therapy comprises administering an inhibitor to a patient. 35. The method of any one of embodiments 30-34, wherein the patient exhibits an ECOG performance status of 1 or less. 36. The method of any one of embodiments 1-21, wherein the patient has received one prior systemic cancer therapy. 37. The method of embodiment 36, wherein if the cancer is determined to be MSI-H, the systemic cancer therapy is a checkpoint inhibitor. 38. The method of embodiment 36 or embodiment 37, wherein the patient has received systemic cancer therapy and has progressed during or after said therapy. 39. Systemic therapy is effective against KRAS G12C The method of any one of embodiments 36-38, wherein the therapy does not include administering an inhibitor to the patient. 40. The method of any one of embodiments 36-38, wherein the systemic therapy is not a therapy comprising administering irinotecan. 41. The method of any one of embodiments 36-40, wherein the patient exhibits an ECOG performance status of 1 or less. 42. The method of any one of embodiments 36-41, wherein the patient does not have active brain metastases. 43. The method of any one of embodiments 36-42, wherein the mCRC does not comprise a BRAF V600E mutation. 44. The method of any one of embodiments 1-43, wherein the patient exhibits at least stable disease (SD) after 1, 3, or 6 months of sotorasib and panitumumab therapy as measured by a RECIST 1.1 protocol. 45. The method of any one of embodiments 1-43, wherein the patient exhibits at least a partial response (PR) after 1, 3, or 6 months of sotorasib and panitumumab therapy as measured by a RECIST 1.1 protocol. 46. ​​The method of any one of embodiments 1-45, wherein the patient further requires treatment with an antacid. 47. The method of embodiment 46, wherein the antacid is a proton pump inhibitor (PPI), an H2 receptor antagonist (H2RA), or a locally acting antacid. 48. The method of embodiment 46 or embodiment 47, wherein the antacid is a topically acting antacid, and sotorasib is administered about 4 hours before or about 10 hours after the topically acting antacid. 49. The method of any one of embodiments 1-48, wherein the patient further requires treatment with a proton pump inhibitor (PPI) or an H2 receptor antagonist (H2RA). 50. The method of embodiment 49, wherein the patient is not administered a PPI or H2RA in combination with sotorasib. [Example]

[0108] The term "subject" is used interchangeably throughout the examples with "patient" in need of treatment with one or more of the methods described herein.

[0109] Example 1 - Sotorasib in combination with panitumumab and optionally FOLFIRI While not wishing to be bound by any particular theory, the following is noteworthy: 960 mg QD sotorasib was shown to be safe and effective under the test conditions in Study 20170543 (https: / / clinicaltrials.gov / ct2 / show / NCT03600883; CodeBreaK100). Because resistance to sotorasib may be mediated by upregulation of signaling through the epidermal growth factor receptor (EGFR) pathway, adding an EGFR inhibitor to sotorasib therapy may block bypass activation of mitogen-activated kinase (MAPK) signaling, leading to improved antitumor activity. FOLFIRI has been selected as the chemotherapy backbone because it has been successfully combined with panitumumab in a phase 3 trial for metastatic colorectal cancer (Peeters et al., 2010). Therefore, this study, Study 20190135 (https: / / clinicaltrials.gov / ct2 / show / NCT04185883; CodeBreaK 101, subprotocol H), is investigating sotorasib in combination with panitumumab (an EGFR-targeted monoclonal antibody) and optionally FOLFIRI.

[0110] Overall design: A multicenter, open-label study will be designed to evaluate the safety, tolerability, pharmacokinetics (PK), PD, and efficacy of sotorasib in combination with panitumumab (or panitumumab + FOLFIRI) in subjects with KRAS G12C-mutated advanced CRC, NSCLC, and advanced solid tumors.

[0111] On the days that PK samples are collected in Cycle 1, and after a dose hold for sotorasib, treatments will be administered in the following order: sotorasib, panitumumab, and, if applicable, FOLFIRI. Sotorasib will be administered orally once daily (QD). Alternatively, twice-daily dosing may be used, resulting in the same total daily dose. Panitumumab 6 mg / kg will be administered as a 60-minute (≤1000 mg) or 90-minute (>1000 mg) intravenous (IV) infusion every 2 weeks (Q2W). FOLFIRI will be administered at 180 mg / m IV infusion on Day 1. 2Irinotecan and 400 mg / m 2 Racemic leucovorin and 5-fluorouracil (5-FU) 400 mg / m on day 1 2 IV bolus, then 2400 mg / m over 46–48 hours starting on day 1 Q2W 2 Instead of racemic leucovorin, 2 Levoleucovorin may also be used.

[0112] The first dose of panitumumab will be administered 2 hours after the sotorasib dose. Subsequent panitumumab doses may be administered immediately after the sotorasib dose. In Part 1 Cohort B, panitumumab will be administered followed by FOLFIRI.

[0113] This study includes a dose-finding phase (Part 1) and an expansion phase (Part 2). Part 1 Cohort A is a dose-finding period to investigate the safety of combining sotorasib with panitumumab. Sotorasib doses will start at a total daily dose of 960 mg. If necessary, two lower dose levels of sotorasib and one lower dose level of panitumumab may be considered. Part 1 Cohort B will consist of dose-finding of sotorasib, panitumumab, and FOLFIRI and will begin once the recommended phase 2 doses (RP2Ds) of sotorasib and panitumumab have been defined in Part 1 Cohort A. Part 2, consisting of eight separate cohorts, will begin once the dose of the sotorasib and panitumumab combination is defined in Part 1 Cohort A, while specific cohorts will begin once the dose of sotorasib in combination with panitumumab plus FOLFIRI is defined in Part 1 Cohort B. The eight cohorts in Part 2 (i.e., Cohorts A-H) are as follows:

[0114] Sotorasib + panitumumab dose expansion cohort Cohort A: KRAS patients previously treated with fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenic agents, and in the case of microsatellite instability high (MSI H), checkpoint inhibitors (CPIs) if approved in their region. G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer (n=max 40).

[0115] Cohort B: KRAS G12C Any KRAS G12C mutant solid tumor resistant to inhibitor therapy (n=max 20).

[0116] Cohort C: KRAS, previously treated with at least one systemic therapy G12C Inhibitor-naive KRAS G12C mutant NSCLC (n=max 40).

[0117] Cohort D: KRAS, previously treated with one prior line of therapy for metastatic disease G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer (n=max 20). Initiation of this cohort is contingent on the activity of this combination in other cohorts in this study and emerging sotorasib combination data.

[0118] Cohort E: (Twice daily [BID] cohort): KRAS patients previously treated with a fluoropyrimidine, oxaliplatin, irinotecan, and an antiangiogenic agent, and if MSI-H, a CPI if approved in that region. G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer (n=max 40). Initiation of this cohort is contingent on the activity of sotorasib and panitumumab in other cohorts of this study and emerging sotorasib monotherapy and combination data.

[0119] Cohort H: KRAS patients who have received at least one prior therapy for metastatic disease or who refuse or are ineligible for standard of care chemotherapy G12C Inhibitor-naive KRAS G12C mutant pancreatic cancer (n=max 40).

[0120] Dose expansion cohort of sotorasib + panitumumab + FOLFIRI Cohort F: No prior therapy for metastatic disease, KRAS G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer (n=max 40).

[0121] Cohort G: KRAS, received at least one prior therapy for metastatic disease G12C Inhibitor-naive KRAS G12C mutant metastatic colorectal cancer.

[0122] At least two responses must be observed in the first 20 subjects in Cohorts A, C, E, F, G, or H of Part 2 to continue enrollment in the respective cohort. Part 2 will confirm the safety and evaluate preliminary antitumor activity of sotorasib in combination with panitumumab and sotorasib in combination with panitumumab and FOLFIRI.

[0123] Overall, approximately 310 subjects will be enrolled in the study in both Part 1 and Part 2.

[0124] Part 1: Dose finding The primary objective of Part 1 is to evaluate the safety and tolerability of sotorasib in combination with panitumumab and panitumumab plus FOLFIRI. Therefore, primary endpoints include assessment of dose-limiting toxicities, treatment-emergent adverse events, and treatment-related adverse events.

[0125] Part 1, Cohort A Dose Level 1: Sotorasib oral total daily dose of 960 mg + panitumumab IV at 6 mg / kg Q2W on day 1 Dose Level-1: Sotorasib oral total daily dose of 720 mg + panitumumab IV at 6 mg / kg Q2W on day 1 Dose Level-2: Sotorasib oral total daily dose of 480 mg + panitumumab IV at 6 mg / kg Q2W on day 1 If dose level 1 is not tolerated and is thought to be primarily due to panitumumab toxicity (e.g., rash, paronychia), a dose of panitumumab 3 mg / kg IV day 1 Q2W with or without a dose reduction of sotorasib may be considered.

[0126] Part 1, Cohort B Dose Level 1: Q2W on day 1, oral total daily dose of sotorasib identified from Part 1 Cohort A + 6 mg / kg panitumumab IV (or 3 mg / kg if dose identified in Part 1 Cohort A) ± irinotecan 180 mg / m on day 1 2 , leucovorin 400 mg / m on day 1 2 , and 5-FU 400 mg / m on day 1. 2 IV bolus and 2400 mg / m over 46–48 hours starting on day 1 administered Q2W 2 IV continuous infusion (IVCI). At investigational sites using levoleucovorin instead of racemic leucovorin, the dose of levoleucovorin is 200 mg / m 2 becomes.

[0127] Dose Level -1: Q2W on day 1, oral total daily dose of sotorasib identified from Part 1 Cohort A + 6 mg / kg panitumumab IV (or 3 mg / kg if dose identified in Part 1 Cohort A) ± irinotecan 180 mg / m on day 1 2 , and 5FU 2400 mg / m over 46–48 hours starting on day 1 administered Q2W. 2 IV continuous infusion (IVCI).

[0128] Dose Level -2: Q2W on day 1, oral total daily dose of sotorasib identified from Part 1 Cohort A + 6 mg / kg panitumumab IV (or 3 mg / kg if dose identified in Part 1 Cohort A) ± irinotecan 150 mg / m on day 1 2 and 5-fluorouracil 2400 mg / m over 46–48 hours starting on day 1 administered Q2W. 2 IV continuous infusion (IVCI).

[0129] Part 2 - Dose expansion of sotorasib + panitumumab (and +FOLFIRI, Cohorts F and G only) The primary objective of Part 2 is to evaluate patients with KRAS who have received prior chemotherapy and antiangiogenic therapy and, if MSI-H, are receiving a CPI if approved in their region. G12C Inhibitor-naive KRAS G12C-mutated metastatic CRC (Cohorts A and E); KRAS G12C-mutated advanced solid tumors that had progressed after prior exposure to a KRAS G12C inhibitor (Cohort B); and KRAS G12C-mutated patients who had received at least one prior systemic therapy. G12C inhibitor-naive KRAS G12C mutant NSCLC (Cohort C); and KRAS ≤1 prior line of therapy for metastatic disease G12C inhibitor-naive KRAS G12C-mutated metastatic CRC (Cohort D); and KRAS who have received at least one prior treatment for progressive disease or who have refused or are ineligible for standard-of-care chemotherapy. G12C To evaluate the safety and preliminary antitumor activity of sotorasib in combination with panitumumab in inhibitor-naive KRAS G12C-mutated metastatic pancreatic cancer (Cohort H), panitumumab, and FOLFIRI in patients with no prior therapy for metastatic disease (Cohort F) and patients with at least one prior therapy for metastatic disease (Cohort G). G12C It will also be evaluated in inhibitor-naive KRAS G12C mutant metastatic CRC.

[0130] Objective response rate (ORR) as measured by RECIST 1.1 provided initial evidence of antitumor activity and is included as a secondary endpoint in this portion of the study. Other relevant efficacy measures, including PFS, duration of response, disease control rate, and time to response, provide additional supportive evidence of antitumor activity and are included as secondary endpoints.

[0131] Cohort A: KRAS, previously treated with fluoropyrimidine, oxaliplatin, irinotecan, and antiangiogenic agents, and in case of MSI-H, with CPIs if approved in the region G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer: Sotorasib total daily dose identified from Part 1 Cohort A of this study orally + 6 mg / kg (or 3 mg / kg for dose identified in Part 1 Cohort A) panitumumab IV on day 1 Q2W.

[0132] Cohort B: KRAS G12C Any KRAS G12C-mutated solid tumor refractory to inhibitor therapy: Sotorasib oral total daily dose identified from Part 1 Cohort A of this study + 6 mg / kg (or 3 mg / kg for dose identified in Part 1 Cohort A) panitumumab IV on day 1 Q2W.

[0133] Cohort C: KRAS, previously treated with at least one systemic therapy G12C Inhibitor-naive KRAS G12C-mutant NSCLC: Sotorasib oral total daily dose identified from Part 1 Cohort A of this study + 6 mg / kg (or 3 mg / kg for dose identified in Part 1 Cohort A) panitumumab IV on day 1 Q2W.

[0134] Cohort D: KRAS patients who have received ≤1 prior line of therapy for metastatic disease G12C Inhibitor-naive KRAS G12C-mutated metastatic CRC: Sotorasib oral total daily dose identified from Part 1 Cohort A of this study + 6 mg / kg (or 3 mg / kg if dose identified in Part 1 Cohort A) panitumumab IV Q2W on Day 1. Initiation of this cohort is contingent on activity of this combination in other cohorts of this study and emerging sotorasib combination data.

[0135] Cohort E (BID cohort): Subjects receiving sotorasib on a BID dosing schedule who have previously been treated with a fluoropyrimidine, oxaliplatin, irinotecan, and an antiangiogenic agent, and in the case of MSI-H, a CPI if approved in that region. G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer: Q2W on day 1, a total daily dose of sotorasib orally identified from Part 1 Cohort A of this study + 6 mg / kg (or 3 mg / kg if the dose identified in Part 1 Cohort A) panitumumab IV. Initiation of this cohort is contingent on the activity of sotorasib and panitumumab in other cohorts of this study and emerging sotorasib monotherapy and combination data.

[0136] Cohort H: KRAS patients who have received at least one prior therapy for metastatic disease or who have refused or are ineligible for standard of care chemotherapy G12C Inhibitor-naive KRAS G12C-mutated pancreatic cancer: Q2W on day 1, a total daily dose of sotorasib orally identified from Part 1 Cohort A of this study plus 6 mg / kg (or 3 mg / kg if the dose identified in Part 1 Cohort A) panitumumab IV.

[0137] Cohort F: No prior therapy for metastatic disease, KRAS G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer: Q2W on day 1, total daily dose of sotorasib orally identified from Part 1 Cohort B of this study + 6 mg / kg (or 3 mg / kg if dose identified in Part 1 Cohort B) panitumumab IV + FOLFIRI dose identified in Part 1 Cohort B.

[0138] Cohort G: KRAS, received at least one prior therapy for metastatic disease G12CInhibitor-naive KRAS G12C-mutated metastatic CRC. Q2W on day 1, a total daily oral dose of sotorasib identified from Part 1 Cohort B of this study + 6 mg / kg (or 3 mg / kg for the dose identified in Part 1 Cohort B) panitumumab IV + a FOLFIRI dose identified in Part 1 Cohort B.

[0139] Subjects will remain in this study for approximately 3 years. The screening period will be a maximum of 28 days. The planned treatment period for subjects will be until disease progression or unacceptable toxicity. The expected treatment period for each subject is approximately 8 months, followed by a safety follow-up (SFU) visit 30 (+3) days after the last dose of investigational product or protocol-mandated therapy. Subjects will be followed until the later of an analysis of PFS or 3 years after the last subject enrolled.

[0140] Summary of eligibility criteria: Adult subjects (18 years of age or older) with metastatic advanced solid tumors that harbor a KRAS G12C mutation, as assessed by molecular testing of a tumor biopsy specimen, and who have received at least one prior systemic therapy for their advanced disease are eligible to participate in Part 1 Cohorts A and B, and Part 2 Cohorts A-E and H. Subjects in Part 2 Cohort F must not have received prior treatment for their metastatic disease. Subjects in Part 2 Cohort G must have received at least one prior therapy for their metastatic disease. Eligibility criteria for the study cohorts are as follows:

[0141] Part 1 Cohort A: - Pathologically confirmed metastatic colorectal cancer with a KRAS G12C mutation, identified by molecular testing performed in accordance with national requirements. In the United States, this testing must be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. -KRAS in the past G12C If previously treated with a KRAS inhibitor, the subject G12CInhibitor dose reduction is required or KRAS G12C At least two subjects per dose level must have KRAS inhibitor intolerance. G12C Must be inhibitor-naive. Subject must have received at least one prior treatment for progressive disease

[0142] Part 1 Cohort B: - Pathologically confirmed metastatic colorectal cancer with a KRAS G12C mutation, identified by molecular testing performed in accordance with national requirements. In the United States, this testing must be performed in a CLIA-certified laboratory. -KRAS in the past G12C If previously treated with a KRAS inhibitor, the subject G12C Inhibitor dose reduction is required or KRAS G12C At least two subjects per dose level must have KRAS inhibitor intolerance. G12C Must be inhibitor-naive. If the subject has previously been treated with FOLFIRI, the subject must not have required a dose reduction for any component of the FOLFIRI regimen due to toxicity. - Subject must have received at least one prior treatment for progressive disease.

[0143] Part 2 Cohort A: - Pathologically confirmed metastatic colorectal cancer with a KRAS G12C mutation, identified by molecular testing performed in accordance with national requirements. In the United States, this testing must be performed in a CLIA-certified laboratory. -Target has previously been diagnosed with KRAS G12C May not have been treated with inhibitors. Subjects must have progressed after receiving fluoropyrimidines, oxaliplatin, and irinotecan and antiangiogenic agents. - For subjects with tumors known to be MSI-H, who are clinically able to receive a CPI and require prior therapy with a CPI if any of these agents are approved for that indication in that region or country.

[0144] Part 2 Cohort B: - Pathologically confirmed metastatic advanced solid tumor with a KRAS G12C mutation, identified by molecular testing performed in accordance with national requirements. In the United States, this testing must be performed in a CLIA-certified laboratory. -Target has previously been diagnosed with KRAS G12C There should be no intolerance to inhibitors. If the subject has previously required a dose reduction of sotorasib, the subject may be eligible with approval of the medical monitor if the investigator assesses that treatment may be beneficial and the previous dose reduction was due to toxicity that, in the investigator's opinion, may not be due to sotorasib. -Target is KRAS G12C Progression must have occurred at the time of the last dose of inhibitor or within 2 months of the last dose. Subjects must have received at least one prior treatment for progressive disease and at least one of the prior treatments had a KRAS G12C Inhibitors must be included.

[0145] Part 2 Cohort C: - Pathologically confirmed metastatic NSCLC with a KRAS G12C mutation, identified by molecular testing performed according to national requirements. In the United States, this testing must be performed in a CLIA-certified laboratory. -Target has previously been diagnosed with KRAS G12C May not have been treated with inhibitors. - Subject must have received at least one prior treatment for progressive disease.

[0146] Part 2 Cohort D: - Pathologically confirmed metastatic CRC with a KRAS G12C mutation, identified by molecular testing performed according to national requirements. In the United States, this testing must be performed in a CLIA-certified laboratory. -Target has previously been diagnosed with KRAS G12C May not have been treated with inhibitors. - Subjects must have received only one prior regimen for metastatic disease.

[0147] Part 2 Cohort E (BID administration): - Pathologically confirmed metastatic colorectal cancer with KRAS G12C mutation, identified by molecular testing performed according to national requirements. -Target has previously been diagnosed with KRAS G12C May not have been treated with inhibitors. Subjects must have progressed after receiving fluoropyrimidines, oxaliplatin, and irinotecan and antiangiogenic agents. - For subjects with tumors known to be MSI-H, who are clinically able to receive anti-PD1 therapy and require prior therapy with anti-PD1 therapy if any of these agents are approved for that indication in that region or country.

[0148] Part 2 Cohort H: - Pathologically confirmed metastatic pancreatic cancer with a KRAS G12C mutation, as identified by molecular testing performed in accordance with national requirements. In the United States, this testing must be performed in a CLIA-certified laboratory. -Target has previously been diagnosed with KRAS G12C May not be inhibitor-treated - Subject must have received at least one prior treatment for metastatic disease or have refused standard of care chemotherapy or have a contraindication to standard of care chemotherapy. If a subject progresses within 6 months after completion of administration of neoadjuvant or adjuvant therapy, the neoadjuvant or adjuvant therapy counts as a line of therapy for metastatic disease.

[0149] Part 2 Cohort F: - Pathologically confirmed metastatic CRC with KRAS G12C mutation, identified by molecular testing performed according to national requirements. -Target has previously been diagnosed with KRAS G12C May not have been treated with inhibitors. - Subject may not have received prior systemic therapy for metastatic disease.

[0150] Part 2 Cohort G: - Pathologically confirmed metastatic CRC with KRAS G12C mutation, identified by molecular testing performed according to national requirements. -Target has previously been diagnosed with KRAS G12C May not have been treated with inhibitors. - Subject must have received at least one prior systemic therapy for metastatic disease.

[0151] Subjects must be willing to undergo pre-treatment and on-treatment tumor biopsies, if clinically feasible. If a pre-treatment tumor biopsy is not medically feasible or the sample does not have enough tissue for testing, subjects must be willing to provide an archived tumor tissue sample (formalin-fixed, paraffin-embedded [FFPE] sample) collected within the past 5 years, if available. Subjects with a previously molecularly confirmed KRAS G12C mutation who do not have archived tissue available may be allowed to enroll without a tumor biopsy upon consent by the investigator and medical monitor if a tumor biopsy is not clinically feasible.

[0152] Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria.

[0153] Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

[0154] Life expectancy >3 months in the investigator's opinion.

[0155] Ability to take oral medications and willingness to document daily adherence to the investigational product.

[0156] Corrected QT interval (QTc) of 470 milliseconds or less for women and 450 milliseconds or less for men (based on the average of three screening electrocardiograms).

[0157] Subjects have adequate hematological, renal, and hepatic function and coagulation. Appropriate hematological laboratory evaluations include: Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 / L Platelet count ≥ 100 x 10 9 / L Hemoglobin ≥ 9 × g / dL

[0158] Adequate renal laboratory evaluation includes measured creatinine clearance or estimated glomerular filtration rate ≥ 60 mL / min / 1.73 m based on Modification of Diet in Renal Disease (MDRD) calculations. 2 Includes:

[0159] Appropriate liver laboratory evaluations include: -AST < 2.5 × upper limit of normal (ULN) (≤ 5 × ULN if liver metastases are present) -ALT < 2.5 × ULN (≤ 5 × ULN if liver metastases are present) Total bilirubin <1.5 x ULN (Part 1: Cohort A, Part 2: Cohorts A-E and Cohort H: <2.0 x ULN) Total bilirubin ≤ 1 x ULN in Part 1: Cohort B, Part 2: Cohort F and Cohort G

[0160] Appropriate coagulation laboratory assessments include: - Prothrombin time (PT) or activated partial thromboplastin time (PTT) or activated PTT < 1.5 x ULN, or international normalized ratio (INR) < 1.5 x ULN, or within target range if receiving prophylactic anticoagulation therapy.

[0161] Exclusion criteria: Disease-related Primary brain tumor. Active brain metastases and / or carcinomatous meningitis from non-brain tumors. The phrase "active brain metastases," as used herein, refers to cancer that has spread to the brain from an original (primary, non-brain) tumor. Active brain metastases can be assessed by the presence of intracranial lesions. While "metastases" is plural, it should be understood that a patient who exhibits only one intracranial lesion under the criteria set forth below is a patient with "active brain metastases." In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 5 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 5 mm but less than 10 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 10 mm. If a patient had brain metastases or completed radiation therapy at least 4 weeks prior to Study Day 1, they will not be considered to have active brain metastases and will be eligible if they meet all of the following criteria: a) residual neurological symptoms of grade ≦2; b) stable dose of dexamethasone, if applicable; and c) follow-up MRI performed within 30 days shows no new lesions. For determination of the grade of any neurological symptoms due to intracranial lesions, please refer to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE), published by the National Cancer Institute on November 27, 2017, which is incorporated herein by reference in its entirety.

[0162] Other medical conditions A history or presence of a hematologic malignancy, unless there has been no evidence of disease for more than two years and the condition has been cured by treatment.

[0163] History of other malignancies within the past 2 years with the following exceptions: - Malignant tumor treated with curative intent, with no active disease for at least 2 years prior to enrollment, and considered by the treating physician to be at low risk of recurrence; - Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease; - Adequately treated in situ cervical cancer with no evidence of disease; - Adequately treated in situ ductal carcinoma with no evidence of disease; - Prostatic intraepithelial neoplasia without evidence of prostate cancer; - Well-treated non-invasive papillary urothelial carcinoma or in situ carcinoma.

[0164] Myocardial infarction, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina, or cardiac arrhythmia requiring medical therapy within 6 months of Day 1 of the study

[0165] Gastrointestinal (GI) tract disease that makes oral medications impossible, malabsorption syndrome, need for IV nutritional support, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).

[0166] Exclusion of hepatitis infection based on the following results and / or criteria: - Positive hepatitis B surface antigen (HepBsAg) (indicating chronic hepatitis B or recent acute hepatitis B); - Negative HepBsAg positive for hepatitis B core antibody; -Hepatitis C virus antibody positivity: Hepatitis C virus RNA by polymerase chain reaction (PCR) is required. Detectable hepatitis C virus RNA is indicative of chronic hepatitis C.

[0167] Known positive test for human immunodeficiency virus (HIV).

[0168] History of or evidence of interstitial pneumonia or pulmonary fibrosis.

[0169] Aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may not be discontinued except for 5 days (8 days for long-acting medications such as piroxicam) at a dose of 1.3 g or less of aspirin per day.

[0170] Active infection requiring systemic therapy.

[0171] Prior / concomitant therapy Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormone therapy [excluding subjects with a history of breast cancer receiving adjuvant hormone therapy], or investigational drug other than sotorasib) within 28 days of Study Day 1; targeted small molecule inhibitor within 14 days of Study Day 1 unless at least five half-lives have elapsed. In Part 2 Cohort B, there is no minimum time requirement from the last sotorasib dose, as long as all sotorasib-related toxicities have resolved to Grade 1 or less.

[0172] Curative or palliative radiation therapy within 2 weeks of Study Day 1. Subjects must have recovered from all radiation therapy-related toxicities of Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1 or less.

[0173] Radiation therapy to the lungs exceeding 30 Gy within 6 months of the first dose of investigational treatment

[0174] Cumulative radiation received to >25% of bone marrow in Part 1 Cohort B and Part 2 Cohorts F and G

[0175] Part 1 Cohort B and Part 2 Cohorts F and G with known dihydropyrimidine dehydrogenase deficiency

[0176] For Part 1 Cohort B, and Part 2 Cohorts F and G, known UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease

[0177] Use of known cytochrome P450 (CYP) 3A4-sensitive substrates and P-glycoprotein (P-gp) substrates (e.g., with a narrow therapeutic window) within 14 days or within 5 half-lives of a CYP3A4 or P-gp substrate or its major active metabolite, whichever is longer, prior to initiation 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, alphadihydroergocryptine, darifenacin, lomitapide, tacrolimus, aplaviroc, darunavir, lopinavir, terfenadine, aprepitant, dasatinib, lovastatin, ticagrelor, asunaprevir, dronedarone, lumefantrine, These include tilidine, atazanavir, ebastine, lurasidone, tipranavir, atorvastatin, eletriptan, maraviroc, tolvaptan, avanafil, eliglustat (in subjects who are CYP2D6 poor metabolizers (PMs)), midazolam, triazolam, AZD1305, elvitegravir, midostaurin, ulipristal, BIRL355, entrectinib, naloxegol, vardenafil, blonanserin, eplerenone, neratinib, venetoclax, bosutinib, everolimus, nisoldipine, vicriviroc, brecanavir, felodipine, paritaprevir, viraprisan, brotizolam, ibrutinib, perospirone, voclosporin, budesonide, indinavir, and quetiapine. P-gp substrates with narrow therapeutic ranges include digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, and vincristine. P450 (CYP)3A4 sensitive substrates with narrow therapeutic ranges include alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, tacrolimus, and sirolimus.

[0178] Use of strong inducers of CYP3A4 (including herbal dietary supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to initiating 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.

[0179] Use of known CYP3A4 or UGT1A1 inhibitors at least 1 week prior to starting irinotecan therapy (for Part 1 Cohort B and Part 2 Cohorts F and G only). UGTA1 inhibitors include ketoconazole, atazanavir, gemfibrozil, and indinavir.

[0180] Unresolved toxicity attributable to prior antineoplastic therapy, defined as Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade 0 or 1, or not resolved to the level indicated in the eligibility criteria, with the exception of alopecia (or any grade is acceptable). Grade 2 or 3 toxicities attributable to prior antineoplastic therapy that are deemed irreversible (defined as present for >6 months and stable), such as oxaliplatin-induced neuropathy, may be acceptable if they are not listed in the exclusion criteria and are agreed upon by both the investigator and sponsor.

[0181] Subjects cannot receive both iodine contrast for CT scans and gadolinium contrast for MRI scans.

[0182] Pre / combination clinical trial experience Currently receiving treatment in another investigational device or investigational drug trial, or less than 28 days since your last intervention in another investigational device or investigational drug trial, except for the sotorasib trial, in which case there is no minimum time requirement since your last sotorasib dose as long as all sotorasib-related toxicities have resolved to Grade 1 or less. Other investigational procedures while participating in this study are excluded.

[0183] Other Exclusions The subject had a known sensitivity to any of the products or ingredients that would be administered during dosing.

[0184] Subject had previously required a panitumumab dose reduction or dose delay due to toxicity.

[0185] For subjects in Part 1 Cohort B, and Part 2 Cohorts F and G, subjects must have, to the investigator's knowledge, required a dose reduction or delay of either 5-fluorouracil or irinotecan due to toxicity in a previous chemotherapy regimen.

[0186] Subjects may not be able to complete all study visits or procedures required by the protocol and / or may not, to the best of the subject's and the investigator's knowledge, be able to comply with all necessary study procedures (e.g., clinical outcome assessments).

[0187] History or evidence of any other clinically significant disorder, condition, or disease (other than those outlined above) that would pose a risk to the subject's safety or interfere with the evaluation, procedures, or completion of the study.

[0188] Female subjects of childbearing potential with a positive pregnancy test as assessed by screening with a serum pregnancy test and / or a urine pregnancy test.

[0189] The female subject is pregnant or breastfeeding, or planning to become pregnant or breastfeeding, during treatment and for 7 days after the last dose of sotorasib.

[0190] The female subject is pregnant or lactating / breastfeeding, or planning to become pregnant or breastfeed, during treatment and for an additional 2 months after the last dose of panitumumab.

[0191] The female subject is pregnant or lactating / breastfeeding, or planning to become pregnant or breastfeed, during treatment and for an additional 6 months after the last dose of FOLFIRI.

[0192] Female subjects of childbearing potential who are unwilling to use one highly effective method of contraception during treatment and for 7 days after the last dose of sotorasib.

[0193] Female subjects of childbearing potential who are unwilling to use one highly effective method of contraception during treatment and for an additional 2 months after the last dose of panitumumab.

[0194] Female subjects of childbearing potential who are unwilling to use one highly effective method of contraception during treatment and for an additional 6 months after the last dose of FOLFIRI.

[0195] Male subjects with a female partner of childbearing potential who practice sexual abstinence (abstaining from heterosexual intercourse) during treatment and for 7 days after the last dose of sotorasib, or who do not wish to use contraception.

[0196] Male subjects with pregnant partners who are unwilling to abstain or use condoms during treatment and for 7 days after the last dose of sotorasib.

[0197] Male subjects who are willing to abstain from sperm donation during the study and for an additional 7 days after the last dose of sotorasib.

[0198] Male subjects with a female partner of childbearing potential who practice sexual abstinence (abstaining from heterosexual intercourse) or do not wish to use contraception during treatment and for an additional 6 months after the last dose of FOLFIRI.

[0199] Male subjects with a pregnant partner or a partner unwilling to abstain or use condoms during treatment and for an additional 6 months after the last dose of FOLFIRI.

[0200] Male subjects who are willing to abstain from sperm donation during the study and for an additional 6 months after their last dose of FOLFIRI.

[0201] Objectives and evaluation items

[0202] [Table 6]

[0203] FOLFIRI regimen premedication and supportive medications Prior to administration of FOLFIRI, all subjects should receive an antiemetic (e.g., oral or IV dexamethasone, 5-hydroxyyptamine 3 [5-HT3] receptor antagonist). Antiemetics should be initiated at least 30 minutes prior to irinotecan administration on the day of treatment. Alternative and additional antiemetics may be used as clinically indicated, at the investigator's discretion or in accordance with standard institutional or local practice. IV or subcutaneous administration of prophylactic or therapeutic atropine for cholinergic symptoms may be used at the investigator's discretion or in accordance with standard institutional or local practice.

[0204] Growth factor support may be used at the investigator's discretion or according to standard institutional or local practice.

[0205] Medications for diarrhea management should be used at the investigator's discretion or according to standard institutional or local practice.

[0206] Treatments, medical devices, and / or procedures excluded during the study period Anti-tumor therapy such as chemotherapy, antibody therapy, molecularly targeted therapy, retinoid therapy, or hormone therapy (excluding subjects with breast cancer receiving this as adjuvant therapy).

[0207] Strong CYP3A4 inducers (including herbal dietary supplements such as St. John's wort) unless approved by the principal investigator and medical monitor.

[0208] Known CYP3A4 and / or P-gp sensitive substrates with narrow therapeutic ranges unless approved by the principal investigator and medical monitor.

[0209] CYP3A4 and / or UGT1A1 inhibitors (Part 1 Cohort B, Part 2 Cohort F, and Cohort G only) unless approved by the principal investigator and medical monitor -Other investigational drugs Anti-EGFR targeted drugs other than panitumumab.

[0210] If a subject requires palliative radiation therapy or surgery for pain control during the study, all study medication should be withheld. The subject may be allowed to resume study medication after consultation with the principal investigator and medical monitor.

[0211] Dose-limiting toxicities: The dose-limiting toxicity (DLT) window (i.e., the DLT-evaluable period) is the first 28 days of sotorasib and panitumumab treatment (start of cycle 1, day 1). AE grading will be based on the guidelines provided in CTCAE version 5.0. A subject is DLT-evaluable if they complete the above DLT window and receive 80% or more of the planned dose of sotorasib and panitumumab within the first 28 days, or if they experience a DLT at any time during the DLT window. A DLT is defined as an adverse event attributable to sotorasib and / or panitumumab that occurs during the first treatment cycle and meets the criteria listed below.

[0212] (1) adverse events leading to permanent discontinuation of the investigational product; (2) Febrile neutropenia (3) Neutropenia infection (4) Grade 4 neutropenia of any duration (5) Grade 3 neutropenia lasting more than 7 days (6) Grade 3 thrombocytopenia for more than 7 days (7) Grade 3 thrombocytopenia accompanied by grade 2 or greater 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 or greater nausea lasting 3 days or more despite optimal medical support (13) Grade 3 elevation of ALT or AST lasting more than 5 days (only for subjects without liver metastases at baseline) (14) Grade 4 elevation of ALT or AST regardless of duration (15) Grade 3 or higher bilirubin elevation (16) Other grade 3 or higher AEs, with the following exceptions: - DLT exclusion: Grade 3 fatigue <1 week -DLT exclusion: Grade 3 panitumumab skin toxicity - DLT exclusion: Asymptomatic grade 3 electrolyte abnormalities that last less than 72 hours, are clinically uncomplicated, and resolve spontaneously or respond to medical intervention -DLT exclusion: Grade 3 amylase or lipase not associated with symptoms or clinical findings of pancreatitis -DLT exclusion: other select laboratory abnormalities that do not appear to be clinically relevant or harmful to the patient and / or that can be corrected by substitution or modification (e.g., grade 3 lymphopenia, grade 3 hypoalbuminemia, grade 3 hypomagnesemia) -DLT exclusion: Grade 3 infusion reaction (17) Subjects who meet the criteria for a Hy's Law case (i.e., severe drug-induced liver injury [DILI]) are considered DLTs. A Hy's Law case is defined as follows: AST or ALT levels ≥ 3 × ULN and serum total bilirubin (TBL) > 2 × ULN, without signs of cholestasis and with no clear alternative explanation for the observed liver-related laboratory abnormalities.

[0213] If a subject experiences a DLT during the DLT evaluation period, study treatment for that subject should be discontinued, unless the investigator believes the subject is deriving clinical benefit from therapy, in which case therapy may be resumed with consideration for dose reduction.

[0214] Sotorasib dose modification guidelines for hematologic and non-hematologic toxicities

[0215] [Table 7]

[0216] If sotorasib is withheld, panitumumab should also be withheld.

[0217] Dose reduction levels of sotorasib for individual subject toxicity management are provided in the table below.

[0218] [Table 8]

[0219] Hepatotoxicity Guidelines for Sotorasib: Guidelines for the management and monitoring of subjects with elevated AST, ALT, or alkaline phosphatase (ALP) are shown in the table below.

[0220] [Table 9]

[0221] Hepatotoxic Reactions: Subjects with abnormal liver 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 permanently discontinuing sotorasib.

[0222] The following discontinuation and / or withholding rules apply to subjects in whom an alternative cause for their changes in liver biomarkers (TBL, INR, and transaminases) is identified. Important additional causes of elevated AST / ALT and / or TBL levels include, but are not limited to, hepatobiliary disease; viral hepatitis (e.g., hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, chickenpox, toxoplasmosis, and parvovirus); any cause of hypoxia to the liver causing right heart failure, hypotension, or ischemia; exposure to hepatotoxic agents / drugs or hepatotoxins, including herbal and dietary supplements, plants, and mushrooms; genetic disorders causing impaired glucuronidation (e.g., Gilbert syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); α1-antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson's disease and hemochromatosis; non-alcoholic fatty liver disease, including steatohepatitis; and / or extrahepatic causes (e.g., rhabdomyolysis, hemolysis).

[0223] As described below, if another cause for elevated liver tests (ALT, AST, ALP) and / or TBL is discovered and / or laboratory abnormalities return to normal or baseline, rechallenge may be considered.

[0224] [Table 10]

[0225] Panitumumab dose modification: For subjects who experience toxicity during the study, one or more doses of panitumumab will be withheld, reduced, or postponed (administered more than 14 days apart). Exemplary panitumumab dose reductions are listed in the table below.

[0226] [Table 11]

[0227] Exemplary panitumumab dose modification guidelines due to skin toxicity are provided in the table below.

[0228] [Table 12]

[0229] If severe or life-threatening inflammatory or infectious complications occur, consider withholding or discontinuing panitumumab as clinically appropriate.

[0230] Because sunlight can worsen any skin reactions that may occur, patients are advised to wear sunscreen and hats and limit sun exposure during panitumumab treatment. Active skin treatment, including skin moisturizers, sunscreen (SPF > 15 UVA and UVB), and topical steroid creams (1% hydrocortisone or less), can help manage skin toxicity. Patients may be advised to apply moisturizer and sunscreen to their face, hands, feet, neck, back, and chest every morning during treatment, and to apply topical steroids to their face, hands, feet, neck, back, and chest every night. Treatment for skin reactions should be based on severity and may include moisturizers, sunscreen (SPF > 15 UVA and UVB), topical steroid creams (1% hydrocortisone or less) applied to the affected areas, and / or oral antibiotics as prescribed by a physician.

[0231] If acute onset or worsening of pulmonary symptoms occurs, consider withholding panitumumab. If interstitial lung disease is confirmed, discontinue panitumumab.

[0232] For toxicities other than cutaneous or pulmonary, the use of panitumumab should be withheld in the presence of grade 3 or 4 panitumumab-related toxicity, with the following exceptions: -Panitumumab is only withheld for symptomatic Grade 3 or 4 hypomagnesemia and / or hypocalcemia that persists despite aggressive magnesium and / or calcium supplementation. -Panitumumab will only be held for Grade 3 or 4 nausea, diarrhea, or vomiting that persists despite maximal supportive care.

[0233] For non-cutaneous toxicities: If panitumumab is withheld, it may be resumed if adverse events improve to Grade 1 or less or return to baseline.

[0234] Infusion Reactions: Infusion reactions may manifest as fever, chills, dyspnea, bronchospasm, hypotension, or anaphylaxis.

[0235] In patients experiencing a mild or moderate (grade 1 or 2) infusion reaction, the infusion rate is reduced by 50% for the duration of that infusion.

[0236] Discontinue the infusion in patients experiencing a severe infusion reaction. Depending on the severity and / or persistence of the reaction, permanently discontinue panitumumab.

[0237] FOLFIRI dose reduction

[0238] [Table 13]

[0239] Doses of irinotecan, 5-fluorouracil, and leucovorin will be calculated based on height and weight on Day 1 of Cycle 1 and should be recalculated using current weight at each dose. If institutional policy permits, FOLFIRI doses do not require recalculation if the subject's weight changes less than 10%. The reason for FOLFIRI dose changes will be recorded on each subject's CRF.

[0240] FOLFIRI dose modification guidelines

[0241] [Table 14]

[0242] [Table 15]

[0243] Radiological image evaluation The extent of disease will be assessed by contrast-enhanced MRI / CT according to RECIST v1.1. The lowest possible dose should be utilized to reduce radiation exposure to the subject.

[0244] The screening scan must be performed within 28 days prior to enrollment and will be used as the baseline. Imaging performed as part of standard of care within the screening window for scans may be used for the baseline scan as long as it meets the screening scan requirements. All subsequent scans will be performed in the same manner as at screening, preferably on the same scanner, using the same contrast agent. Radiological evaluation should include a CT of the chest, contrast-enhanced CT or MRI of the abdomen and pelvis, and evaluation of all other known sites of disease, as detailed in the institutional imaging manual.

[0245] The same imaging modality, MRI field strength, and IV and oral contrast agents used at screening should be used for all subsequent evaluations. Liver-specific MRI contrast agents should not be used. To mitigate potential safety concerns, macrocyclic gadolinium contrast agents are recommended to follow National Health Institute guidelines or, if more stringent, local standards.

[0246] During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, and all other known sites of disease will be performed every 6 ± 1 weeks, regardless of treatment cycle, until the first four response assessments. After the four (6-week) response assessments, radiological imaging and tumor assessments will be performed every 12 ± 1 weeks. Radiological imaging and tumor assessments will be performed until disease progression, initiation of new anticancer therapy, death, withdrawal of consent, or study termination. Imaging may also be performed more frequently if clinically indicated at the discretion of the managing physician. Radiographic response (CR, PR) requires confirmation by repeat serial scans at least 4 weeks after initial documentation of response and may be delayed until the next scheduled scan to avoid unnecessary procedures.

[0247] All NSCLC subjects, subjects with a history of brain metastases, or subjects with signs and symptoms suggestive of brain metastases must have a brain MRI performed within 28 days prior to the first dose of sotorasib. Thereafter, brain scans may be performed at any time if necessary at the discretion of the managing physician. All brain scans per protocol must be MRI unless MRI is contraindicated, followed by CT with contrast is permitted.

[0248] Radiographic evaluation at the end of study or during the end of treatment (EOT) visit should only be performed for subjects who discontinue treatment for reasons other than disease progression per RECIST v1.1 guidelines.

[0249] Determination of disease response for subject clinical management will be assessed at the clinical site according to RECIST v1.1. Scans may be submitted to the central imaging core laboratory for archival and (if necessary) independent response assessment utilizing RECIST v1.1 criteria. Exploratory imaging analyses will be performed at the center and may include tumor volume measurements, viable tumor measurements, tissue necrosis rates, and diseased tissue analysis (radiomics).

[0250] Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) definition Measurable lesions Measurable tumor lesion - a non-lymph node lesion with well-defined borders that can be accurately measured in at least one dimension and a longest diameter ≥ 10 mm on a CT / MRI scan with a slice thickness of 5 mm or less. When the slice thickness is greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness.

[0251] Lymph node involvement - To be considered pathologically enlarged and measurable, lymph nodes must be ≥15 mm in the short axis when assessed by CT / MRI (recommended scan slice thickness of ≤5 mm). At baseline and follow-up, only the short axis is measured and tracked. Node size is usually reported as two dimensions in the axial plane. The smaller of these measurements is the short axis (perpendicular to the long axis).

[0252] Irradiated Lesions - Tumor lesions located in areas previously irradiated or subjected to other locoregional therapy are not measurable unless progression of the lesion has been documented prior to enrollment.

[0253] Non-measurable lesions: All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with a short axis ≥10 mm but <15 mm and a CT scan slice thickness of 5 mm or less), are considered non-measurable and are characterized as non-target lesions.

[0254] Other examples of non-measurable lesions include lesions with previous local treatment: tumor lesions located in areas previously irradiated or subjected to other locoregional therapy should not be considered measurable unless progression of the disease has been documented; biopsied lesions; and categorically, small lesions, bone lesions, inflammatory breast disease, and clusters of leptomeningeal disease are non-targetable.

[0255] Measurement method Lesion Measurements - The longest diameter of the selected lesion should be measured in the plane in which the image was acquired (axial plane). All measurements should be taken and recorded in metric notation. All baseline assessments should be performed as close to the start of treatment as possible and no later than 4 weeks prior to Study Day 1.

[0256] Methods of Assessment—The same methods of assessment and the same techniques should be used to characterize each identified and reported lesion throughout the trial.

[0257] CT / MRI - Contrast-enhanced CT or MRI should be used to evaluate all lesions. Optimal visualization and measurement of metastases in solid tumors requires consistent IV contrast administration (dose and rate) and timing of scans. CT and MRI should be performed with contiguous slices ≤5 mm thick.

[0258] Baseline documentation of "target" and "non-target" lesions Target Lesions - All measurable lesions, up to a maximum of two lesions per organ and five lesions total, representing all involved organs, should be identified, recorded, and measured as target lesions at baseline. -Target lesions should be selected based on their size (lesions with the longest diameter) and amenability to accurate repeated measurements. -Pathological lymph nodes (with a short axis of ≥15 mm) may be identified as target lesions. All other pathological lymph nodes (those ≥10 mm but with a short axis of <15 mm) should be considered non-target lesions. - For all target lesions, the sum of the diameters (longest diameter for non-lymph node lesions and short axis for lymph node lesions) will be calculated and reported as the baseline sum of the diameters. The baseline sum of the diameters will be used as the criterion to characterize objective tumor response.

[0259] Non-target Lesions - All other lesions (or sites of disease), including diseased lymph nodes, should be identified as non-target lesions and should also be recorded at baseline. Measurement of these lesions is not required, and these lesions should be tracked throughout the study as "present," "absent," or "overt progression." In addition, multiple non-target lesions involving the same organ may be recorded as one item on the case report form (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases").

[0260] Response criteria

[0261] [Table 16]

[0262] [Table 17]

[0263] Overall response assessment Best overall response is the best response recorded from the start of study treatment until the end of treatment or disease progression / relapse (taking the lowest measurement recorded since treatment began as the criterion for PD).

[0264] In general, the assignment of a subject's best response will depend on the findings of both target and non-target disease, and will also take into account the appearance of new lesions.

[0265] [Table 18]

[0266] [Table 19]

[0267] [Table 20]

[0268] Special notes for response evaluation Lymph node lesions - For lymph nodes identified as target lesions, the actual short axis measurement should always be recorded, even if the lymph node regresses to less than 10 mm on examination. To qualify for CR, each lymph node must achieve a short axis of <10 mm rather than complete disappearance. The short axis measurement of the lymph node target lesion is added along with the longest diameter measurement of the target lesion to create a total target lesion diameter for a particular assessment (time point).

[0269] "Too Small to Measurable" Target Lesions - All lesions (lymph node and non-lymph node) recorded at baseline should have their measurements recorded at each subsequent assessment during the study. When lesions become smaller than 5 mm, the accuracy of measurements decreases. Therefore, lesions smaller than 5 mm are considered "too small to measurable" and are not measured. With this designation, they are assigned a default measurement of 5 mm. Lesion measurements smaller than 5 mm do not need to be recorded unless the lesion has completely resolved and a "0" can be recorded for the measurement.

[0270] New Lesion - The term "new lesion" always refers to the presence of a new finding that is clearly a neoplasm. New findings that could only be neoplastic but may also be benign (infection, inflammation, etc.) are not selected as new lesions until review confirms that they are neoplastic. -If a new lesion is uncertain, for example, due to small size, continued therapy and follow-up evaluation will clarify whether it actually represents new disease. If repeat scans confirm the definite presence of new lesions, progression should be declared using the date of the initial scan. -Lesions identified on follow-up examination in an anatomical location not scanned at baseline will be considered new lesions and will represent disease progression, notwithstanding any response that may be observed in target or non-target lesions present from baseline.

[0271] Subjects with a global deterioration in health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having "worsening symptoms." Even after cessation of treatment, every attempt should be made to document objective progression with additional imaging evaluations.

[0272] In some situations, it may be difficult to distinguish residual disease from scar or normal tissue. When assessment of complete response (CR) depends on this determination, it is recommended that residual disease be further investigated by fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET / computed tomography (PET / CT), or possibly fine-needle aspiration / biopsy, to confirm CR status.

[0273] Confirmatory measurement / duration of response Confirmed response - In nonrandomized trials where response is the primary endpoint, confirmation of PRs and CRs is required to ensure that the identified responses are not the result of measurement error.

[0274] Duration of Overall Response - Duration of overall response is measured from the first fulfillment of the metrics for CR / PR (whichever is first documented) to the first date of objectively documented recurrence or progressive disease or death, whichever occurs first.

[0275] Duration of stable disease - SD is measured from the start of treatment until criteria for disease progression are met and is taken as the lowest measurement recorded since treatment began or death, whichever occurs first.

[0276] ECOG Performance and NYHA Classification

[0277] [Table 21]

[0278] New York Heart Association Functional Classification Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, or shortness of breath. Class II: Mild limitation of physical activity. Comfortable at rest, but ordinary physical activity causes fatigue, palpitations, or dyspnea. Class III: Significant limitation of physical activity. Comfortable at rest, but less than usual activity causes fatigue, palpitations, or dyspnea. Class IV: No physical activity can be performed without discomfort. Symptoms of heart failure may occur even at rest. Any physical activity increases discomfort.

[0279] Preliminary results (data cut April 23, 2021): Eight patients (five women, three men; median age: 60.5 years [range: 31-79 years]) were enrolled in a dose-finding study with sotorasib 960 mg QD and 6 mg / kg IV Q2W panitumumab. The median number of lines of therapy for metastatic disease was 3.5 (range: 1-10); five patients had previously received sotorasib. The median treatment duration (tx) was 4.4 months (range: 1.4, 8.8). No dose-limiting toxicities (DLTs) were observed during the DLT evaluation period (first 28 days). Tx-related adverse events (TRAEs) of any grade related to sotorasib or panitumumab were reported in four and eight patients, respectively. No grade 4 or fatal TRAEs occurred. Two patients had panitumumab TRAEs that led to a panitumumab dose modification (one with acneiform dermatitis and one with dry skin, rash, hypokalemia, and hypomagnesemia), and one patient had a sotorasib TRAE that led to a sotorasib dose modification (diarrhea). One patient had a confirmed partial response, five with stable disease (SD), one with progressive disease (PD), and one with clinical PD but not evaluated. Of the patients previously treated with sotorasib, four had a reduction in total target lesions; four had SD, and one with PD developed a new lesion despite a reduction in target lesion size. Sotorasib exposure was similar to that observed in the monotherapy study.

[0280] Results showed that the combination of sotorasib (960 mg QD) and panitumumab (6 mg / kg IV Q2W) was safe and tolerable, with promising efficacy in heavily pretreated patients with KRAS G12C-mutated CRC. Adverse events were consistent with known adverse events of sotorasib and panitumumab. See also Fakih et al., 2021 (Abstract #3245).

[0281] Additional preliminary results (data cut August 6, 2021): Thirty-one patients (21 women, 10 men; median age 58 years, range 31-79 years) were enrolled in a dose-finding study with sotorasib 960 mg QD and panitumumab 6 mg / kg IV Q2W (Part 1 and Part 2 Combined Cohort A). The median number of lines of therapy for metastatic disease was two; five patients (16.1%) had previously received sotorasib therapy. The median treatment duration at data cutoff was 10.3 weeks (range 2.1-48.1 weeks). No dose-limiting toxicities (DLTs) were observed during the DLT evaluation period (first 28 days). Treatment-related adverse events (TRAEs) of any grade were reported in 23 patients (74.2%): sotorasib-related in 14 patients (45.2%) and panitumumab-related in 23 patients (74.2%). No grade 4 or fatal TRAEs occurred. Four patients (12.9%) experienced grade 3 TRAEs. Of these grade 3 TRAEs, one patient experienced grade 3 hypokalemia, hypomagnesemia, dry skin, and rash (panitumumab-related), resulting in a panitumumab dose modification; one patient experienced grade 3 dermatitis acneiform and myalgia (panitumumab-related), resulting in a panitumumab dose modification for dermatitis acneiform only; one patient experienced grade 3 diarrhea (sotorasib-related), resulting in a sotorasib dose modification; and one patient experienced grade 3 cellulitis, peripheral edema, and dermatitis acneiform (panitumumab-related), resulting in no dose modification for either sotorasib or panitumumab. Of the TRAEs that led to dose modifications, 3 patients (9.7%) experienced TRAEs (diarrhea, fatigue, and hypokalemia) that led to a change in the sotorasib dose; 2 patients (6.5%) experienced TRAEs (acneiform dermatitis and dry skin / rash / hypokalemia / hypomagnesemia) that led to a change in the panitumumab dose. Sotorasib in combination with panitumumab was well tolerated and was not associated with fatal TRAEs.

[0282] The tumor responses observed are provided in the table below.

[0283] [Table 22]

[0284] Overall, 27% (7 of 26) of patients achieved a response (including unconfirmed responses awaiting confirmation), and 81% (21 of 26) of patients achieved disease control. In Part 1 Cohort A, 5 of 8 dose-finding patients had previously received KRAS G12C Despite having received KRAS inhibitor therapy, the majority of all patients (75%, 6 of 8 patients) experienced a reduction in target lesion size (-14.5% to -100.0%). G12C The majority of patients exposed to inhibitors (80%, 4 of 5 patients) had a best response of stable disease. G12C Four of the five patients with inhibitor treatment showed a reduction in target lesion size of 14.5% to 30.3%. One patient (KRAS G12C Patients in this cohort (inhibitor-naive) achieved a partial response within 2 months of treatment and remained on treatment at the time of data cutoff. A 100% reduction in target lesion size was observed for responders in this cohort.

[0285] In Part 2, Cohort A (n=18), overall, 83% of patients remain on treatment, with two patients remaining on treatment at 6 months. A reduction in target lesion size (-2.4% to -61.8%) was observed in the majority (83%, 15 of 18 patients) of the chemotherapy-resistant metastatic colorectal cancer (mCRC) population treated with dose expansion (Part 2, Cohort A, n=18). This reduction appears to be sustained. Median progression-free survival cannot yet be determined.

[0286] Sotorasib exposure in patients receiving both sotorasib and panitumumab was similar to that in patients receiving sotorasib alone (in the CodeBreaK 100 trial NCT03600883). Day 1: In combination therapy max (hours) 1.0, 1.9 for monotherapy; C in combination therapy max (μg / mL) 8.01, 9.71 for monotherapy; For combination therapy, AUC 0-24h (time*μg / mL) 77.2 vs. 103 for monotherapy Day 8: In combination therapy max (time) 1.0, 2.0 for monotherapy; C in combination therapy max (μg / mL) 7.50, 6.50 for monotherapy; For combination therapy, AUC 0-24h (time*μg / mL) 51.7 vs. 50.3 for monotherapy

[0287] Overall, the results demonstrated that the combination of sotorasib (960 mg QD) and panitumumab (6 mg / kg IV Q2W) was safe and tolerable, with promising efficacy in chemotherapy-resistant patients with KRAS G12C-mutant CRC. Adverse events were consistent with known adverse events of sotorasib and panitumumab. The response rate for the combination of sotorasib and panitumumab was 15.4% confirmed ORR and 26.9% ORR (including unconfirmed responses awaiting confirmation). These ORRs were numerically higher than sotorasib monotherapy in KRAS G12C-mutant CRC (7.1% ORR) (Hong et al., 2020). Sotorasib exposure was similar to that observed in monotherapy trials. Sotorasib in combination with panitumumab is associated with promising early efficacy signals in patients with KRAS.G12C-mutated CRC. See also Fakih et al., 2021 (ePoster #3245).

[0288] Additional preliminary results (data cutoff June 24, 2022): Forty patients (30 women, 10 men; median age: 58 years) were enrolled in a dose-finding study with sotorasib 960 mg QD and panitumumab 6 mg / kg IV Q2W (Part 2 Cohort A). Preliminary safety data for 23 of these patients and efficacy data for 18 of these patients were included in the August 6, 2021, data cut reported above. The median number of lines of therapy for metastatic disease was two; seven patients (18%) had previously received regorafenib, and seven patients (18%) had previously received trifluridine / tipiracil. (One patient had received both regorafenib in the third line and trifluridine / tipiracil in the fourth line.)

[0289] Safety and Tolerability Treatment-related adverse events (TRAEs) of any grade were reported in 37 (93%) patients (26 [65%] related to sotorasib and 37 [93%] related to panitumumab). No grade 4 or fatal TRAEs occurred. Nine patients (23%) experienced grade 3 TRAEs. Grade 3 TRAEs included rash (n = 2, 5%), anemia, fatigue, peripheral edema, cellulitis, pustular rash, salmonellosis, skin infection, hypomagnesemia, malignant neoplasm progression, pulmonary embolism, dermatitis acneiform, and pruritus (n = 1 patient each, 3%). Of the TRAEs that led to dose modifications, 6 patients (15%) experienced TRAEs (pruritus, rash, anemia, diarrhea, hypokalemia) that led to a change in the sotorasib dose; 10 patients (25%) experienced TRAEs (acneiform dermatitis, rash, dry skin, conjunctivitis, diarrhea, hypomagnesemia, paronychia, pruritus, pustular rash, blurred vision) that led to a change in the panitumumab dose. Sotorasib in combination with panitumumab was well tolerated and was not associated with fatal or grade 4 TRAEs. No discontinuation of either drug was required.

[0290] Pharmacokinetics Sotorasib exposure in patients receiving both sotorasib and panitumumab (n=35) was similar to that in patients receiving sotorasib alone (n=32) (in the CodeBreaK 100 trial NCT03600883). t max (h), median (range): 1.0 (1.0–6.0) for combination therapy and 2.0 (0.3–6.0) for monotherapy. C max (μg / mL), mean (CV%): 9.64 (55%) for combination therapy and 7.50 (98%) for monotherapy. AUC 0-24h (time*μg / mL), mean (CV%): 65.8 (56%) for combination therapy and 65.3 (82%) for monotherapy The value is t max and CV%, which are reported to three significant figures and expressed to the nearest integer. 0-24h , area under the concentration-time curve from 0 to 24 hours after administration; Cmax, maximum observed drug concentration; t max , C max time to reach ;CV, coefficient of variation.

[0291] Efficacy:

[0292] [Table 23]

[0293] The confirmed objective response rate (ORR) of sotorasib plus panitumumab in patients with chemotherapy-resistant mCRC was 30%, and the disease control rate (DCR) was 93%. Subgroup analysis of ORR by primary tumor location (left vs. right) was performed. No clear difference in response based on tumor location was observed (left (n=27, 30% ORR); right (n=13, 31% ORR)).

[0294] RECIST target lesion reduction was observed in 88% of patients. The median treatment duration (range) was 5.9 (0.5, 11.3) months, and 25% of patients remained on treatment at the time of data cutoff. The median response duration was 4.4 months (range, 2.8-7.4).

[0295] The median follow-up was 11.0 months, and the median PFS was 5.7 months (see table below).

[0296] [Table 24]

[0297] With a median follow-up of 8.8 months, median OS had not yet been reached (95% CI: 10.4, NE) (see table below).

[0298] [Table 25]

[0299] Overall, the results demonstrated that the combination of sotorasib (960 mg QD) and panitumumab (6 mg / kg IV Q2W) was safe and tolerable, with promising efficacy in chemotherapy-resistant patients with KRAS G12C-mutant CRC. Adverse events were consistent with known adverse events of sotorasib and panitumumab. The confirmed ORR of 30% was threefold higher than that previously reported for sotorasib monotherapy in KRAS G12C-mutant CRC (7.1% ORR) (Hong et al., 2020), with a DCR of 93%. No clear differences were observed based on tumor location. Sotorasib exposure was similar to that observed in monotherapy trials. The median PFS of 5.7 months was clinically meaningful and longer than that reported for sotorasib monotherapy (median PFS: 4.0 months, Hong et al., 2020), and the OS data appear promising. See also Kuboki et al., 2022.

[0300] Additional preliminary results for triple combination therapy (sotorasib, panitumumab, and FOLFIRI) (data cutoff June 9, 2022): As previously mentioned, Study 20190135 is a sotorasib protocol investigating sotorasib in combination with other anticancer therapies. Subprotocol H of this protocol investigates the combination of sotorasib and panitumumab, and the combination of sotorasib, panitumumab, and FOLFIRI. Part 1 Cohort B of Subprotocol H is a dose-finding cohort for the combination of sotorasib, panitumumab, and FOLFIRI. A data snapshot was obtained on June 9, 2022. Six subjects in this cohort were enrolled in dose level 1 (storasib 960 mg orally daily, panitumumab 6 mg / kg intravenously every 2 weeks, and FOLFIRI chemotherapy every 2 weeks), and no dose-limiting toxicity (DLT) events were identified during the 28-day DLT evaluation period. These six subjects had received a median of three lines of prior anticancer therapy (range 1-5), five had received irinotecan chemotherapy, and all six had received fluoropyrimidine chemotherapy. The objective response rate was 50% (three of six subjects had a confirmed partial response), and the disease control rate was 100% (subjects with complete response, partial response, or stable disease as best response). Although the number of subjects was small, in a heavily pretreated population who had received a median of three lines of therapy, a 50% objective response rate is highly encouraging and compares favorably with the 10% observed with sotorasib monotherapy in the CRC cohort of Study 20170543, phase 2, and the 30% observed with the combination of sotorasib and panitumumab in Study 20190135, subprotocol H, part 2, cohort A. Dose level 1 has been declared the recommended dose for Phase 2, and enrollment into the Part 2 expansion cohort is ongoing, with enrollment of subjects into Part 2 Cohort F (treatment-naive patients with metastatic colorectal cancer harboring a KRAS G12C mutation) and Part 2 Cohort G (previously treated patients with metastatic colorectal cancer harboring a KRAS G12C mutation).

[0301] Example 2 - Panitumumab vs. Sotorasib in combination with trifluridine and tipiracil or regorafenib This is a phase 3, multicenter, randomized, open-label, active-controlled study evaluating the efficacy and safety of two different doses of sotorasib and panitumumab versus (1) trifluridine and tipiracil or (2) regorafenib in previously treated subjects with metastatic CRC harboring a KRAS G12C mutation. The study will be conducted at approximately 100 centers. The study will consist of a screening period, a treatment period, safety follow-up, and a long-term follow-up period. Approximately 153 previously treated subjects with metastatic CRC harboring a KRAS G12C mutation will be enrolled and randomized 1:1:1 to receive sotorasib 240 mg QD and panitumumab, sotorasib 960 mg QD and panitumumab, or investigator's choice ((1) trifluridine and tipiracil, or (2) regorafenib). Investigator preference must be declared prior to randomization. This trial is currently enrolling (Study 20190172, https: / / clinicaltrials.gov / ct2 / show / NCT05198934; CodeBreaK 300).

[0302] Subjects will be stratified by prior antiangiogenic therapy (Y vs. N), time from initial diagnosis of metastatic disease to randomization (≥18 months vs. <18 months), and ECOG status (0 or 1 vs. 2).

[0303] Day 1 of Cycle 1 is defined as the first day a subject receives study drug; tumor assessments will be performed (by MRI and / or CT) at baseline and at 8-week (±7-day) intervals until progression as assessed by blinded independent central review (BICR), initiation of alternative anticancer therapy, withdrawal of consent, loss to follow-up, or death, whichever occurs first. Safety follow-up CT / MRI should only be performed for subjects who discontinue treatment for reasons other than disease progression per RECIST 1.1 and have not undergone radiological imaging within 8 weeks (±7 days of visit). For subjects without progression as assessed by BICR, radiological imaging should continue every 8 weeks (±7 days) at LTFU until progression as assessed by BICR, initiation of alternative anticancer therapy, withdrawal of consent, loss to follow-up, or death, whichever occurs first. Tumor assessments and response will be determined by BICR using RECIST 1.1. Subjects at the investigator's choice will be permitted to cross over to sotorasib and panitumumab after the primary analysis of PFS only if PFS shows a clinically and statistically significant improvement in PFS in the sotorasib and panitumumab arm compared to the investigator's choice arm and safety and efficacy data strongly support the sotorasib and panitumumab arm. Subjects who previously discontinued investigator's choice due to progressive disease as determined by BICR may be offered crossover to sotorasib or panitumumab if crossover is determined appropriate after the primary analysis. Subjects who discontinued before progressive disease as determined by BICR will not be permitted to cross over unless they subsequently have progressive disease as determined by BICR before initiating another systemic therapy. Subjects who withdraw consent will not be permitted to cross over. Subjects may discontinue treatment due to disease progression, intolerance to treatment leading to treatment interruption, initiation of another anticancer therapy, or consent withdrawal. Continuation of study treatment after radiological progression may be permitted if, in the opinion of the investigator, the subject is experiencing clinical benefit, is clinically stable, has no unacceptable toxicity from the study drug, consents to biopsy, and has medical monitor approval. For subjects who continue treatment after progression, tumor assessments will continue according to schedule until the subject has discontinued all study drug.

[0304] For subjects who continue treatment after progression or crossover, the date of progression as assessed by the first BICR will be used for the primary PFS analysis, and the subject's tumor assessment after the first progression will not be used in the primary analysis to evaluate objective response endpoints.

[0305] For all subjects, information will be collected regarding the type and duration of subsequent therapy after disease progression, response to subsequent therapy, date of progression on subsequent therapy, and survival data. Subjects who discontinue treatment before RECIST 1.1 disease progression (e.g., due to unacceptable toxicity) will be followed radiographically until disease progression, withdrawal of consent, or initiation of another anticancer therapy, after which subjects who have not withdrawn consent will undergo further long-term follow-up by telephone or clinic visits to assess survival and document anticancer treatment. Subjects will be followed for one year from the last subject enrolled, or until withdrawal of consent, loss to follow-up, or death of the subject, whichever occurs first.

[0306] Interim safety analyses will be performed by an independent Data Monitoring Committee (DMC) after approximately 75 subjects have enrolled and had the opportunity to complete at least 8 weeks of study treatment, then at approximately 6-month intervals until the last subject is discontinued from treatment, and annually thereafter until the end of the study.

[0307] The evaluations performed in this study are described below and will occur at the times specified in the Schedule of Evaluations (SOA).

[0308] Disease progression will be assessed using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) as assessed by BICR.

[0309] Safety will be monitored by assessing serious and non-serious adverse events (AEs), safety laboratory tests, vital signs, and electrocardiograms (ECGs). The incidence, nature, and severity of all AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0).

[0310] Clinical safety tests will include hematology, blood chemistry, urinalysis, thyroid function, cholesterol, and triglycerides. Vital sign assessment will include blood pressure and pulse rate; additional vital signs will be collected only if clinically warranted.

[0311] PRO / QOL assessments will be assessed using PRO instruments EORTC QLQ-C30, BPI, BFI, and questions from the PRO CTCAE, a single question about symptom bother (GP5 from FACTG), and EQ-5-D-5L. PRO scores will be determined for all patients for whom PRO instruments are available in the patient's language at baseline and specified time points at SOA and compared between treatment groups. To facilitate interpretation of data from the BFI and BPI, Patient Global Impression of Severity and Patient Global Impression of Change for fatigue and pain will be collected.

[0312] Samples will be collected for sotorasib and panitumumab PK analysis.

[0313] Samples for tumor markers are collected.

[0314] Additional plasma / blood / tissue biopsy samples will be collected as exploratory biomarkers for primary and secondary resistance mechanisms. -All subjects with lesions amenable to biopsy (core needle or fine needle aspiration (FNA)) at the time of progression are encouraged to undergo biopsy at the time of progression. -All subjects treated with sotorasib and panitumumab who have biopsyable disease and wish to continue treatment past progression should undergo a biopsy at the time of progression, if medically feasible, before continuing treatment past progression.

[0315] The trial will have an independent Data Monitoring Committee (DMC) that will review safety data in accordance with the DMC Charter. Interim safety analyses will be performed by the DMC after approximately 75 subjects have enrolled and had an opportunity to complete at least 8 weeks of study treatment, then at approximately 6-month intervals until the last subject is off treatment, and approximately annually thereafter until the end of the trial.

[0316] One primary PFS analysis is planned for superiority of PFS between the sotorasib and panitumumab arm and the investigator's choice arm. The PFS progression average will occur when approximately 60 PFS events are observed in the sotorasib 960 mg and panitumumab arm and the investigator's choice arm.

[0317] Test Products Oral sotorasib 240 mg or 960 mg daily.

[0318] Panitumumab 6mg / kg IV Q2W Trifluridine and tipiracil 35 mg / m 2 , up to 80 mg (based on the trifluridine component) per dose, administered orally twice daily within 1 hour of the end of morning and evening meals on days 1-5 and 8-12 of each 28-day cycle. Round doses to the nearest 5 mg increment.

[0319] Oral regorafenib 160 mg daily for 21 days of each 28-day cycle. Taken after a low-fat meal.

[0320] Inclusion Criteria: Age 18 or older.

[0321] Pathologically confirmed metastatic colorectal cancer.

[0322] Have confirmed KRAS G12C mutation determined by central testing.

[0323] Subjects must have received at least one prior line of therapy for metastatic disease. Subjects must have experienced disease progression or recurrence during or after administration of fluoropyrimidines, irinotecan, and oxaliplatin administered for metastatic disease, unless, in the opinion of the investigator, the subject is not a candidate for fluoropyrimidines, irinotecan, or oxaliplatin, in which case the subject may be eligible after discussion with the medical monitor, provided that the subject has received at least one line of therapy for metastatic disease. Subjects with tumors known to be MSI-H must have previously received locally available checkpoint inhibitor therapy, unless medically contraindicated, in which case the subject may be eligible after discussion with the medical monitor.

[0324] Subjects with tumors known to harbor the BRAF V600E mutation must have previously been treated with encorafenib and cetuximab, if available for this indication in their country or region. If a subject progresses within 6 months after completion of adjuvant therapy, the adjuvant therapy will be counted as a line of therapy for metastatic disease. -Maintenance therapy is not considered a separate regimen of therapy. -Adjuvant therapy given after resection of metastatic disease counts as a line of therapy for metastatic disease. - Perioperative chemotherapy with or without chemoradiation therapy in metastatic disease counts as one line of therapy for metastatic disease if it is part of a surgical multimodality treatment plan.

[0325] Subjects must be willing to provide an archived tumor tissue sample (formalin-fixed, paraffin-embedded [FFPE] sample collected within the last 5 years) or agree to undergo a pre-treatment tumor biopsy (excision or core biopsy) prior to enrollment.

[0326] Measurable disease per RECIST 1.1 criteria. Previously irradiated lesions are not considered measurable unless they have progressed after radiation.

[0327] Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

[0328] Life expectancy >3 months in the investigator's opinion.

[0329] Adequate hematologic and end-organ function within 2 weeks prior to Day 1 of Cycle 1, as defined as follows: -ANC≧1.5×10 9 cells / L (without granulocyte colony-stimulating factor support within 2 weeks of the laboratory tests used to determine eligibility). Hemoglobin ≥ 9.0 g / dL (no transfusion within 2 weeks of the laboratory tests used to determine eligibility). Platelet count ≥ 100 x 10 9 cells / L (no transfusions within 2 weeks of the laboratory tests used to determine eligibility). - Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 times the upper limit of normal. Serum bilirubin ≤ 1.0 x ULN. For subjects with Gilbert's disease, direct bilirubin ≤ 1.0 x ULN - International normalized ratio (INR) and activated partial thromboplastin time (or partial thromboplastin time) ≤ 1.5 x ULN. In centers where the laboratory does not report the INR, a prothrombin time (PT) ≤ 1.5 x ULN may be used in place of the INR. Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculations ≥ 30 ml / min / 1.73 m 2 . Fridericia's corrected QTcF ≤ 470 msec.

[0330] Ability to take oral medications and willingness to document daily adherence to the investigational product.

[0331] Exclusion criteria: Disease-related: Active Brain Metastases. The phrase "active brain metastases," as used herein, refers to cancer that has spread to the brain from the original (primary, non-brain) tumor. Active brain metastases can be assessed by the presence of intracranial lesions. Although "metastases" is plural, it should be understood that a patient who exhibits only one intracranial lesion under the criteria set forth below is a patient with "active brain metastases." In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 5 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 5 mm but less than 10 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 10 mm. If a patient has undergone resection of brain metastases or completed radiation therapy at least 4 weeks prior to Study Day 1, they are not considered to have active brain metastases and are eligible if they meet all of the following criteria: a) residual neurological symptoms of grade ≦2; b) if applicable, receiving a stable dose of dexamethasone or equivalent for at least 2 weeks; and c) a follow-up MRI performed within 28 days of Day 1 shows no progression or appearance of new lesions. For determination of the grade of any neurological symptoms attributable to intracranial disease, please refer to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE), published by the National Cancer Institute on November 27, 2017, which is incorporated herein by reference in its entirety.

[0332] Other medical conditions: A history or presence of a hematologic malignancy, unless there has been no evidence of disease for more than two years and the condition has been cured by treatment.

[0333] History of other malignancies within the past 3 years with the following exceptions: Malignant tumors that have been treated with curative intent, have had no active disease for at least three years prior to enrollment, and are considered by their treating physician to be at low risk of recurrence. Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease. Adequately treated in situ cervical cancer with no evidence of disease. Adequately treated in situ ductal carcinoma with no evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer. Sufficiently treated urothelial papillary non-invasive carcinoma or carcinoma in situ.

[0334] Leptomeningeal disease.

[0335] Severe GI disturbances resulting in severe malabsorption, need for IV nutritional support, or inability to tolerate oral medications.

[0336] History of or evidence of interstitial pneumonia or pulmonary fibrosis

[0337] - Significant cardiovascular disease, such as New York Heart Association (Class II or higher), myocardial infarction, unstable arrhythmia, or unstable angina within 6 months prior to randomization

[0338] Any uncontrolled serious complication that, in the opinion of the investigator or medical monitor, could affect compliance with protocol procedures or interpretation of results or pose a risk to the safety of the subject.

[0339] Uncontrolled pleural, pericardial, or ascites effusion requiring repeated drainage procedures more frequently than monthly. Subjects with PleurX catheters or intraperitoneal drainage catheters may be eligible for the study with approval of the medical monitor.

[0340] Known history of human immunodeficiency virus (HIV) infection.

[0341] Exclusion of hepatitis infection based on the following results and / or criteria: - Positive hepatitis B surface antigen (HepBsAg) (indicating chronic hepatitis B or recent acute hepatitis B). -Negative HepBsAg that is positive for hepatitis B core antibody (hepatitis B core antibody testing is not necessary for screening, but if this is done and positive, hepatitis B surface antibody [anti-HBs] testing is necessary). Undetectable anti-HBs in this situation suggests the possibility of an uncertain infection, which must be ruled out). - Hepatitis C virus antibody positive: Hepatitis C virus RNA by polymerase chain reaction is required. Detectable hepatitis C virus RNA will disqualify the subject.

[0342] If the above antibody / antigen tests are not obtained, a positive hepatitis B or C viral load is obtained.

[0343] Previous concomitant therapy: Subjects who have previously received trifluridine, tipiracil, and regorafenib.

[0344] Unresolved toxicity attributable to prior antineoplastic therapy defined as CTCAE Version 5.0 Grade 0 or 1 or not resolved to the level indicated in the eligibility criteria except for alopecia (any grade is acceptable), neuropathy (up to Grade 2 is acceptable), or toxicity from prior antineoplastic therapy that is deemed irreversible [defined as present for >6 months and stable], or endocrine AEs that are maintained stable with appropriate replacement therapy.

[0345] KRAS G12C Previous treatment with inhibitors.

[0346] Prior treatment with trifluridine and tipiracil in subjects where investigator's choice would be trifluridine and tipiracil.

[0347] Prior treatment with regorafenib in subjects where investigator's choice would be regorafenib.

[0348] Curative or palliative radiation therapy within 2 weeks of Study Day 1. Subjects must have recovered from all radiation therapy-related toxicities of CTCAE version 5.0 Grade 1 or less, except for alopecia (alopecia of any grade is acceptable).

[0349] Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormone therapy [excluding subjects receiving long-term adjuvant endocrine therapy and with a history of complete resection of breast cancer without active disease for >3 years] or investigational drug) within 4 weeks of Study Day 1; note that bisphosphonates or anti-RANKL antibody therapy are permitted if needed for management of hypercalcemia or prevention of skeletal-related events. Checkpoint inhibitor therapy within 6 weeks of Study Day 1 is also excluded.

[0350] Previous panitumumab dose reductions required due to toxicity.

[0351] Use of warfarin. Other anticoagulants may also be permitted.

[0352] Use of known cytochrome P450 (CYP) 3A4 sensitive substrates and P-glycoprotein (P-gp) substrates (with a narrow therapeutic window) within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that have not been reviewed and approved by the principal investigator and medical monitor.

[0353] Use of strong inducers of CYP3A4 (including herbal dietary supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 without review and approval by the investigator and medical monitor.

[0354] If investigator's choice is regorafenib: Use of strong inhibitors of CYP3A4 (including herbal dietary supplements such as Goldenseal) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 or grapefruit juice or grapefruit-containing products within 7 days prior to study day 1, without review and approval by the investigator and medical monitor.

[0355] Oral or IV therapeutic antibiotics within 2 weeks prior to randomization. Prophylactic antibiotic use is permitted.

[0356] Pre / Combination Clinical Trial Experience: Currently receiving treatment from another investigational device or investigational drug study, or within 4 weeks of completing another investigational device or investigational drug, or within 6 weeks of receiving any other investigational drug being studied if a checkpoint inhibitor is involved.

[0357] Diagnostic evaluation: If the investigator's choice is regorafenib, the subject has uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg).

[0358] Other exclusions: Female subjects of childbearing potential who are unwilling to use protocol-specified contraceptive methods during treatment and further: - 7 days after the last dose of sotorasib. - 2 months after the last dose of panitumumab. - 6 months after the last dose of trifluridine and tipiracil. - 2 months after the last dose of regorafenib.

[0359] Women who are currently breastfeeding or plan to breastfeed during the study until: - 7 days after the last dose of sotorasib. - 2 months after the last dose of panitumumab. - 6 months after the last dose of trifluridine and tipiracil. - 2 months after the last dose of regorafenib.

[0360] Women who plan to become pregnant during the study between: - 7 days after the last dose of sotorasib. - 2 months after the last dose of panitumumab. - 6 months after the last dose of trifluridine and tipiracil. - 2 months after the last dose of regorafenib.

[0361] Female subjects of childbearing potential with a positive pregnancy test as assessed by a high-sensitivity urine or serum pregnancy test at screening or day 1.

[0362] Male subjects with female partners of childbearing potential who do not wish to practice sexual abstinence (abstain from heterosexual intercourse) or use contraception during treatment and for an additional period of: - 7 days after the last dose of sotorasib. - 6 months after the last dose of trifluridine and tipiracil. - 2 months after the last dose of regorafenib.

[0363] Male subjects with a pregnant partner who are unwilling to abstain or use condoms during treatment and for an additional period of: - 7 days after the last dose of sotorasib. - 6 months after the last dose of trifluridine and tipiracil. - 2 months after the last dose of regorafenib.

[0364] Men who are willing to abstain from sperm donation during the study and for the following additional periods: - 7 days after the last dose of sotorasib. - 6 months after the last dose of trifluridine and tipiracil. - 2 months after the last dose of regorafenib.

[0365] Major surgery within 28 days of study day 1.

[0366] The subject had a known sensitivity to any of the products or ingredients that would be administered during dosing.

[0367] Subjects may not be able to complete all study visits or procedures required by the protocol and / or may not be able to comply with all necessary study procedures to the best of the subject's and the investigator's knowledge.

[0368] History or evidence of any other clinically significant disorder, condition, or disease (other than those outlined above) that, if discussed with the investigator or physician, would pose a risk to the subject's safety or would interfere with the evaluations, procedures, or completion of the study.

[0369] Treatments, medical devices, and / or procedures excluded during the study period: (1) Chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, or hormone therapy (except for subjects with breast cancer receiving adjuvant therapy); (2) Antineoplastic therapy, such as therapeutic or palliative radiation therapy for non-target lesions, may be permitted for symptom control if discussed and agreed upon between the investigator and medical monitor prior to radiation therapy. Study drug must be withheld during radiation therapy.

[0370] For those taking sotorasib or regorafenib: Strong CYP3A4 inducers (including herbal dietary supplements such as St. John's wort) unless approved by a medical monitor.

[0371] For people taking regorafenib: Strong CYP3A4 inhibitors (including grapefruit juice, grapefruit-containing products, or herbal supplements such as Goldenseal) unless approved by a medical monitor.

[0372] For individuals taking sotorasib: Known CYP3A4 and / or P-gp sensitive substrates with narrow therapeutic index unless approved by a medical monitor.

[0373] Other investigational drugs Anti-EGFR targeted drugs other than panitumumab Objectives / Evaluation Items:

[0374] [Table 26]

[0375] [Table 27]

[0376] Rules for dose adjustment, delay, hold, or resumption of sotorasib, and permanent discontinuation The starting dose of sotorasib used in the study is 960 or 240 mg / day. Sotorasib is administered orally QD with or without food in a 28-day treatment cycle. Subjects should take their sotorasib dose (all tablets at the same time) at approximately the same time each day, with or without food. Also, sotorasib doses should not be taken more than two hours earlier than the target time based on the previous day's dose. If six hours have passed since the scheduled dose time, that day's dose should be skipped. The next day, take the next dose as prescribed. Do not take two doses at the same time to make up for a missed dose. If you vomit after taking sotorasib, do not take an extra dose. The next day, take the next dose as prescribed.

[0377] Administration for subjects who have difficulty swallowing solids: Disperse the tablet, without crushing, in 120 mL (4 oz) of room temperature non-carbonated water. Do not use any other liquid. Stir until the tablet disperses into small pieces (the tablet will not completely dissolve) and drink immediately or within 2 hours. The appearance of the mixture may range from pale yellow to bright yellow. Swallow the tablet dispersion. Do not chew tablet pieces. Rinse the container with an additional 120 mL (4 oz) of water and drink. If the mixture is not consumed immediately, stir the mixture again to ensure the tablets are dispersed.

[0378] Dose modifications of sotorasib for individual subject toxicity management are provided in the table below.

[0379] [Table 28]

[0380] Subjects receiving 240 mg sotorasib will be allowed up to two dose interruptions, but sotorasib will not be tapered upon resumption of sotorasib if deemed medically safe and appropriate according to the investigator's judgment. Subjects in the 960 mg sotorasib treatment arm who require 3 or more dose reductions due to management of sotorasib-related toxicity and subjects in the 240 mg sotorasib treatment arm who require 3 or more dose interruptions due to management of sotorasib-related toxicity should permanently discontinue sotorasib treatment.

[0381] [Table 29]

[0382] If sotorasib is withheld, panitumumab should also be withheld.

[0383] The following discontinuation and / or withholding rules apply to subjects in whom an alternative cause for their changes in liver biomarkers (TBL, INR, and transaminases) is identified. Important additional causes of elevated AST / ALT and / or TBL levels include, but are not limited to, hepatobiliary disease; viral hepatitis (e.g., hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, chickenpox, toxoplasmosis, and parvovirus); any cause of hypoxia to the liver causing right heart failure, hypotension, or ischemia; exposure to hepatotoxic agents / drugs or hepatotoxins, including herbal and dietary supplements, plants, and mushrooms; genetic disorders causing impaired glucuronidation (e.g., Gilbert syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); α1-antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson's disease and hemochromatosis; non-alcoholic fatty liver disease, including steatohepatitis; and / or extrahepatic causes (e.g., rhabdomyolysis, hemolysis).

[0384] As described below, if another cause for elevated liver tests (ALT, AST, ALP) and / or TBL is discovered and / or laboratory abnormalities return to normal or baseline, rechallenge may be considered.

[0385] [Table 30]

[0386] Hepatotoxicity Guidelines for Sotorasib: Guidelines for the management and monitoring of subjects with elevated AST, ALT, or alkaline phosphatase (ALP) are shown in the table below.

[0387] [Table 31]

[0388] Hepatotoxic Reactions: Subjects with abnormal liver 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 permanently discontinuing sotorasib.

[0389] Panitumumab dose adjustment, delay, hold, or resumption rules, and permanent discontinuation The starting dose of panitumumab used in the study is 6 mg / kg Q2W. Panitumumab will be administered as an IV infusion over 60 minutes (≤1000 mg) or 90 minutes (>1000 mg) Q2W. If the first infusion is tolerated, administer subsequent infusions over 30-60 minutes. Administer using a low protein-binding 0.2 or 0.22 μm in-line filter.

[0390] Panitumumab should be administered 2 hours (+30 minutes) after sotorasib on Day 1 of Cycle 1. Subsequent panitumumab doses do not require a 2-hour wait. Panitumumab can be administered immediately after starting sotorasib on C1D15. After Cycle 1, sotorasib does not need to be administered before panitumumab as long as it is administered as tolerated on that day. The panitumumab dose is calculated based on body weight on Day 1 of each cycle. However, if it is institutional policy, the panitumumab dose does not need to be recalculated if the subject's weight changes by less than 10%.

[0391] For subjects who experience toxicity during the study, one or more doses of panitumumab will be withheld, reduced, or postponed (administered more than 14 days apart). Exemplary panitumumab dose reductions are listed in the table below.

[0392] [Table 32]

[0393] If panitumumab is withheld, sotorasib may be continued if determined clinically safe by the investigator.

[0394] Exemplary panitumumab dose modification guidelines due to skin toxicity are provided in the table below.

[0395] [Table 33]

[0396] If severe or life-threatening inflammatory or infectious complications occur, consider withholding or discontinuing panitumumab as clinically appropriate.

[0397] Subjects initiating panitumumab should begin skin prophylaxis before the first dose of panitumumab, if feasible. Clinically indicated skin prophylaxis should include skin moisturizer, sunscreen (sun protection factor [SPF] >15 ultraviolet A [UVA] and ultraviolet B [UVB]), topical steroid cream (≤1% hydrocortisone), and oral antibiotics (doxycycline 100 mg BID or minocycline 100 mg QD) (Lacouture et al., 2010). Details of the frequency and application sites of these prophylaxis measures are provided in the panitumumab prescribing information and information leaflet.

[0398] Treatment of skin reactions should be based on severity and may include moisturizers, sunscreen (SPF > 15 UVA and UVB), topical steroid cream (1% hydrocortisone or less) applied to the affected area, and / or oral antibiotics prescribed by a physician. If these measures do not resolve the skin reaction, additional measures may be used in accordance with institutional guidelines for the management of skin toxicity.

[0399] Pulmonary toxicity If acute onset or worsening of pulmonary symptoms occurs, consider withholding panitumumab. If interstitial lung disease is confirmed, discontinue panitumumab.

[0400] ocular toxicity Patients who develop ocular toxicity while receiving panitumumab should be monitored for evidence of keratitis or ulcerative keratitis. If a diagnosis of ulcerative keratitis is confirmed, panitumumab treatment should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Signs and symptoms suggestive of acute or worsening keratitis: ocular inflammation, tearing, light sensitivity, blurred vision, eye pain, and / or redness should be immediately referred to an ophthalmologist.

[0401] Hypersensitivity reactions Permanently discontinue panitumumab depending on the severity (e.g., presence of bronchospasm, edema, angioedema, hypotension, need for parenteral medications, or anaphylaxis) and / or persistence of the hypersensitivity reaction.

[0402] Toxicity other than skin or lung In the presence of grade 3 or 4 panitumumab-related toxicity, panitumumab should be withheld, with the following exceptions: -Panitumumab is only withheld for symptomatic Grade 3 or 4 hypomagnesemia and / or hypocalcemia that persists despite aggressive magnesium and / or calcium supplementation. -Panitumumab will only be held for Grade 3 or 4 nausea, diarrhea, or vomiting that persists despite maximal supportive care.

[0403] infusion reaction Infusion reactions may manifest as fever, chills, dyspnea, bronchospasm, or hypotension. - In patients experiencing a mild or moderate (Grade 1 or 2) infusion reaction, reduce the infusion rate by 50% for the duration of that infusion. Subsequent infusions may be administered at the reduced infusion rate, if necessary. -Discontinue the infusion in patients experiencing a severe infusion reaction. Depending on the severity and / or duration of the reaction, permanently discontinue panitumumab.

[0404] Criteria for retreatment with panitumumab For non-cutaneous toxicities: If panitumumab is withheld, it may be resumed if adverse events improve to Grade 1 or less or return to baseline.

[0405] Trifluridine and tipiracil Trifluridine and tipiracil doses are calculated based on body surface area (BSA) on Day 1 of Cycle 1. At the start of subsequent cycles, if body weight changes by 10% or more, BSA should be recalculated and used for dosing.

[0406] Complete blood counts will be obtained prior to and on day 15 of each cycle.

[0407] Do not start a cycle of trifluridine and tipiracil until: -ANC is 1500 / mm 3 or greater, or recovery from febrile neutropenia - Platelet count 75,000 / mm 3 That's all - Grade 3 or 4 non-hematologic adverse reactions resolve to Grade 0 or 1

[0408] Within a treatment cycle, withhold the use of trifluridine and tipiracil if any of the following occur: -ANC 500 / mm 3 Less than or febrile neutropenia - Platelets 50,000 / mm 3 less than - Grade 3 or 4 non-hematologic adverse reaction

[0409] After recovery, increase the previous dose level to 5 mg / m if any of the following occurs: 2 After a dose reduction of 1 / 2 dose, trifluridine and tipiracil are resumed. -Fever neutropenia - Uncomplicated grade 4 neutropenia (≥1,500 / mm3) causing a delay of more than 1 week in the start of the next cycle 3or greater recovery) or thrombocytopenia (75,000 / mm 3 (Recovered more than - Non-hematologic Grade 3 or Grade 4 adverse reactions, excluding Grade 3 nausea and / or vomiting controlled by antiemetic therapy or Grade 3 diarrhea responsive to antidiarrheal medication

[0410] If, in the opinion of the investigator, a more severe dose reduction or dose maintenance is deemed necessary, it will be permitted.

[0411] Minimum dose 20mg / m twice a day 2 Do not increase the dose of trifluridine or tipiracil after a dose reduction.

[0412] Regorafenib Severe, sometimes fatal, hepatotoxicity has occurred in clinical trials (see regorafenib USPI). Monitor liver function before and during treatment. In the event of hepatotoxicity evidenced by elevated liver function tests or hepatocellular necrosis, regorafenib should be interrupted and subsequently reduced in dose or discontinued, depending on severity and duration.

[0413] If a dose change is required, the dose should be reduced by 40 mg (1 tablet) increments. If, in the opinion of the investigator, a more severe dose reduction or dose maintenance is deemed necessary, this is permitted. The minimum recommended daily dose of regorafenib is 80 mg daily.

[0414] Regorafenib should be discontinued in the following cases: Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that recurs or does not improve within 7 days despite dose reduction; for Grade 3 HFSR, discontinue therapy for at least 7 days Symptomatic grade 2 hypertension - Any grade 3 or 4 adverse reaction - Worsening infection of any grade

[0415] The dose of regorafenib is reduced to 120 mg. - First occurrence of grade 2 HFSR of any duration - After resolution of grade 3 or 4 adverse reactions, excluding infections -For Grade 3 AST / ALT elevation, resume only if the potential benefit outweighs the risk of hepatotoxicity

[0416] The dose of regorafenib is reduced to 80 mg. - If grade 2 HFSR recurs at the 120 mg dose - After resolution of grade 3 or 4 adverse reactions (excluding hepatotoxicity or infection) at the 120 mg dose

[0417] Permanently discontinue regorafenib if: -Do not tolerate the 80 mg dose - Occurrence of AST or ALT >20x ULN - AST or ALT >3x ULN and concurrent bilirubin >2x ULN Recurrence of AST or ALT >5x ULN despite dose reduction to 120mg - In case of grade 4 adverse reaction; resume only if potential benefit outweighs risk

[0418] Efficacy evaluation Disease extent will be assessed by contrast-enhanced CT / MRI according to RECIST 1.1 (discussed below). All radiological imaging will be performed as directed in the institutional imaging manual provided by the center's imaging core laboratory. Low-dose CT should be utilized whenever possible to reduce subject radiation exposure.

[0419] The screening scan must be performed within 28 days prior to Day 1 of Cycle 1. If there are multiple screening scans, the scan closest to Day 1 of Cycle 1 will be used as the baseline. Imaging performed as part of standard of care before signing informed consent may be used if it is performed within 28 days of study initiation and available for submission to the Center Imaging Core Laboratory.

[0420] The radiological evaluation must include CT / MRI of the chest, abdomen, and pelvis, as well as evaluation of all other known sites of disease, as detailed in the institutional imaging manual.

[0421] All subjects with a history of brain metastases should have a brain MRI. All brain scans for subjects with brain metastases should be MRI unless contraindicated, followed by CT with contrast is acceptable. Brain imaging (MRI or CT) should be performed if signs or symptoms suggestive of central nervous system metastases are present.

[0422] All subsequent scans should be performed with the same methodology (e.g., same contrast, MRI field strength) and preferably on the same scanner as at screening. If the imaging modality must be changed (e.g., unscheduled evaluation), it is recommended that you consult with your Amgen medical monitor.

[0423] During treatment and follow-up, radiographic imaging of the chest, abdomen, pelvis, and all other known areas of disease will be performed regardless of treatment cycle. Imaging may also be performed more frequently if clinically indicated at the discretion of the managing physician. A confirmed radiographic response (complete response, PR) requires confirmation by a repeat scan at least 4 weeks after the initial documented response, but may be performed at a later time at the next scheduled scan. Radiographic and tumor assessments will be performed until the initiation of another anticancer treatment, withdrawal of consent, loss to follow-up, or death, whichever occurs first.

[0424] Scans will be submitted to the Center Diagnostic Imaging Core Laboratory for archival documentation, response assessment including RECIST 1.1, and / or exploratory analysis (e.g., volumetric and viable tumor measurements). BICR will continue to perform tumor assessments on acquired scans until initial BICR-assessed progression is achieved. Scans acquired after initial BICR-assessed progression will not be routinely evaluated by BICR.

[0425] Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Definition: Measurable lesions Measurable non-lymph node tumor lesions Non-lymph node lesions with well-defined borders that can be accurately measured in at least one dimension and a longest diameter of ≥10 mm on computed tomography (CT) / MRI scans with a slice thickness of 5 mm or less. When the slice thickness is greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness.

[0426] Lymph node involvement Lymph node involvement - Lymph nodes are considered measurable if they are ≥ 15 mm in the short axis when assessed by CT / MRI (recommended scan slice thickness of ≤ 5 mm). Only the short axis will be measured and tracked at baseline and follow-up.

[0427] Cystic lesions Cystic lesions thought to represent cystic metastases can be considered measurable lesions if they meet the definition of measurability described above for non-lymph node lesions.

[0428] Bone lesions with identifiable soft tissue components Bone lesions with a discernible soft tissue component that can be assessed by cross-sectional imaging techniques such as CT or MRI can be considered measurable lesions if the soft tissue component meets the definition of measurability described above for non-lymph node lesions.

[0429] Clinically measured lesions Visible or palpable lesions can be considered measurable if their longest diameter is 10 mm or greater for non-lymph nodes and their shortest diameter is 15 mm or greater for lymph nodes. Lesions should be measured radiologically if this is more accurate, otherwise they may be measured with a vernier caliper.

[0430] Irradiated lesions Tumor lesions located in previously irradiated areas or areas subjected to other locoregional therapy are not measurable unless measurable progression of the lesion has been documented prior to enrollment.

[0431] Nonmeasurable lesions All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with a short axis ≥10 mm to <15 mm and a CT scan slice thickness of 5 mm or less), are considered non-measurable. (When the slice thickness is greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness.)

[0432] Other examples of lesions that are usually considered non-measurable include: Previously Locally Treated Lesions: Tumor lesions located in areas previously irradiated or subjected to other locoregional therapy should not be considered measurable unless progression of the lesion has been documented. Classification-wise, clusters of small lesions, bone lesions without a soft tissue component, inflammatory breast disease, ascites, pleural / pericardial effusion, cutaneous lymphangitis / pneumonia, and leptomeningeal disease are not measurable.

[0433] Measurement method CT / MRI - Contrast-enhanced CT or MRI should be used to evaluate all lesions. Optimal visualization and measurement of metastases in solid tumors requires consistent IV contrast administration (dose and rate) and timing of scans. CT and MRI should be performed with contiguous slices ≤5 mm thick.

[0434] PET-CT - Currently, the low-dose or attenuation-corrected CT portion of a combined positron emission tomography (PET)-CT does not always have optimal diagnostic CT quality for use in RECIST measurements. However, if a facility can demonstrate that the CT performed as part of the PET-CT is of equivalent diagnostic quality to a diagnostic CT (with IV and oral contrast), the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT to accurately measure cancerous lesions over time.

[0435] Baseline documentation of "target" and "non-target" lesions Target Lesions - All measurable lesions, up to a maximum of two lesions per organ and five lesions total, representing all involved organs, should be identified, recorded, and measured as target lesions at baseline.

[0436] Target lesions should be selected based on their size (lesions with the longest diameter) and amenability to accurate repeated measurements.

[0437] Pathological lymph nodes (with a short axis of ≥15 mm) may be identified as target lesions. All other pathological lymph nodes (those ≥10 mm but with a short axis of <15 mm) should be considered non-target lesions.

[0438] Lymph nodes are considered an organ, and up to two measurable lymph nodes may be identified as target lesions.

[0439] For all target lesions, the sum of the diameters (longest diameter for non-lymph node lesions and short axis for lymph node lesions) will be calculated and reported as the baseline sum of the diameters. The baseline sum of the diameters will be used as the criterion for characterizing objective tumor response.

[0440] Non-target Lesions - All other lesions (or sites of disease), including diseased lymph nodes, should be identified as non-target lesions and should also be recorded at baseline. Measurement of these lesions is not required, and these lesions should be tracked throughout the study as "present," "absent," or "overt progression." In addition, multiple non-target lesions involving the same organ may be recorded as one item on the case report form (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases").

[0441] Response criteria Target Lesion Evaluation

[0442] [Table 34]

[0443] Evaluation of non-target lesions

[0444] [Table 35]

[0445] Best overall response assessment Assignment of a subject's best response depends on both target and non-target disease findings, taking into account the appearance of new lesions and confirmed responses. Best overall response (BOR) is the best response recorded based on all post-baseline disease assessments performed prior to disease progression and the initiation of subsequent anticancer treatment. To assign a best overall response of stable disease (SD), at least 7 weeks must elapse without radiological disease progression from the first dose of study drug tumor assessment to meet the minimum criterion for duration of SD. Generally, subjects who cannot be classified into a RECIST 1.1 response category due to insufficient data or early death are classified as not evaluable (NE) for BOR but are counted in the denominator of all response rate calculations.

[0446] [Table 36]

[0447] [Table 37]

[0448] Special notes for response evaluation "Too Small to Measure" Target Lesions - During the study, all lesions (lymph nodes and non-lymph nodes) recorded at baseline should have their measurements recorded at each subsequent assessment, even if they are very small (e.g., 2 mm). However, lesions or lymph nodes recorded as target lesions at baseline may be so faint on CT scans that the radiologist may be unsure about assigning an accurate measurement and report them as "too small to measure." If this occurs, it is important to record the value on the case report form. If the radiologist's opinion is that the non-lymph node lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is thought to be present and faintly visible but too small to measure, a default value of 5 mm should be assigned. (Note: This rule is unlikely to be used for lymph nodes because lymph nodes usually have a definable size and are often surrounded by fat, such as in the retroperitoneum; however, even in this situation, if a lymph node is thought to be present and faintly visible but too small to measure, a default value of 5 mm should be assigned.) This default value is derived from a 5 mm CT slice thickness (but should not be changed due to changes in CT slice thickness). Measurements of these lesions may not be reproducible, so providing this default value prevents erroneous responses or progression based on measurement error. However, again, if the radiologist can provide an accurate measurement, it should be recorded, even if it is less than 5 mm.

[0449] New Lesion - The term "new lesion" always refers to the presence of a new finding that is clearly a neoplasm. When a new lesion is identified by a modality other than CT or MRI, confirmation by CT or MRI is recommended unless the new lesion is considered to be clearly a neoplasm. New findings that are not definitively neoplastic but may be benign (e.g., infection, inflammation) will not be selected as new lesions until review confirms that they are neoplastic. -If a new lesion is uncertain, for example, due to small size, continued therapy and follow-up evaluation will clarify whether it actually represents new disease. If additional imaging confirms the definite presence of a new lesion, progression should be declared using the date of the initial scan. -Lesions identified on follow-up examination in an anatomical location not scanned at baseline will be considered new lesions and will represent disease progression, notwithstanding any response that may be observed in target or non-target lesions present from baseline.

[0450] Locoregional therapies not permitted by protocol: - Subjects who received non-protocol-permitted locoregional therapy during the study that directly affected one or more target lesions selected at baseline will be considered unevaluable for all disease assessments performed after the date of locoregional therapy, except for disease progression, except that if the pathology is benign and the lesion is completely resected, the subject will still be evaluable for a 0-dimensional response to be reported. -If locoregional therapy is administered to a non-target lesion, the lesion will always be assessed as present unless the pathology is benign.

[0451] Lesions that split or coalesce during treatment - When a non-lymph node lesion "fragments," the longest diameters of the fragmented portions should be added together to calculate the total target lesion and identified as a fragment of the original lesion. Similarly, when lesions coalesce, a plane between the lesions can be maintained, which can be useful for obtaining the maximum diameter measurement of the individual lesions. If the lesions truly coalesce and can no longer be separated, the longest diameter vector in this case should be the maximum longest diameter of the "combined lesion." - "Worsening of symptoms" alone does not qualify as objective progression. If objective progression has not been previously documented, every effort should be made to document it, even after treatment has ceased. -In some situations, it may be difficult to distinguish residual disease from scar or normal tissue. When assessment of CR depends on this determination, it is recommended that residual disease be further investigated by fine-needle aspiration / biopsy to confirm CR status. If a lesion disappears and then reappears at a later time point, measurements should continue. However, the patient's response at the time of the lesion's recurrence depends on the status of the patient's other lesions. For example, if a patient's tumor achieves CR status and the lesion recurs, the patient would be considered in PD at the time of recurrence. In contrast, if the tumor status is PR or SD and one lesion that disappeared reappears, its largest diameter should be added to the total of the remaining lesions to calculate response. In other words, the recurrence of a single lesion that apparently "disappeared" among many remaining lesions is not sufficient to qualify as PD. The sum of all lesions is required to meet the PD criteria.

[0452] Confirmatory measurement / duration of response Confirmation of CR and PR is required and must occur at least 4 weeks after the initial confirmation of CR or PR. If CR is pending confirmation and one or more subsequent NE and / or PR assessments designate the target lesion response as CR and the non-target lesion response as NE, CR may be subsequently confirmed if the target lesion response returns to CR. Similarly, if PR is pending confirmation and is designated at an assessment followed by one or more NE and / or SD assessments, PR may subsequently be confirmed. Subsequent target lesion responses following CR are limited to CR, PD, or NE; PD of the target lymph node is met only if the short-axis measurement of the lymph node target lesion reaches 15 mm or greater.

[0453] ECOG Performance and NYHA Classification

[0454] [Table 38]

[0455] New York Heart Association Functional Classification Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, or shortness of breath. Class II: Mild limitation of physical activity. Comfortable at rest, but ordinary physical activity causes fatigue, palpitations, or dyspnea. Class III: Significant limitation of physical activity. Comfortable at rest, but less than usual activity causes fatigue, palpitations, or dyspnea. Class IV: No physical activity can be performed without discomfort. Symptoms of heart failure may occur even at rest. Any physical activity increases discomfort.

[0456] Example 3 - Pharmacokinetic Analysis of Sotorasib at 960 mg, 360 mg, 180 mg, and 240 mg Preliminary pharmacokinetic (PK) data are available for patients with advanced solid tumors harboring a specific KRAS G12C mutation at doses ranging from 180 to 960 mg PO QD (Study 20170543; https: / / clinicaltrials.gov / ct2 / show / NCT03600883; CodeBreaK 100). A dose-related increase in exposure was observed from 180 to 960 mg PO QD on Day 1. The increase in exposure was less than the dose ratio on Day 1. There was no accumulation with multiple PO QD dosing over 8 days. The change in exposure from 180 to 960 mg PO QD was less than the dose ratio on Day 8. Rapid absorption was observed with tmax 1 to 2 hours after PO administration. Figure 1 shows the mean plasma concentration-time profiles following oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1. Figure 2 shows the concentrations after 8 days of once-daily dosing (day 8). The table below provides the pharmacokinetic parameters, AUC 0~24h is the area under the concentration-time curve from time zero to 24 hours after administration; C max is the maximum drug concentration during the dosing interval; t 1 / 2,z is the terminal elimination half-life; t max is C max Data are reported as median (range) and arithmetic mean (SD), respectively. max and t 1 / 2 Values ​​are reported to 0 and 2 significant figures, respectively, for CV% and t. max are reported to three significant figures, except for

[0457] [Table 39]

[0458] Example 4 - Contraindications for co-administration of antacids and sotorasib under fasting conditions This phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Subjects received 960 mg sotorasib on day 1, 40 mg omeprazole once daily on days 4–8, and 40 mg omeprazole on day 9 followed by 960 mg sotorasib. All doses were administered under fasting conditions. Blood samples for sotorasib PK were collected pre-dose and up to 48 hours after sotorasib administration. Plasma PK parameters of sotorasib were estimated using noncompartmental methods.

[0459] Coadministration of sotorasib and omeprazole increases the maximum plasma concentration (t max ) was delayed by 0.75 hours. 1 / 2 ) were similar after coadministration of sotorasib and omeprazole compared with administration of sotorasib alone. Geometric mean sotorasib AUC after coadministration of sotorasib and omeprazole inf (area under the curve from zero to infinity) and C max The maximum plasma concentrations (17,000 h*ng / mL and 3,100 ng / mL, respectively) were lower compared with sotorasib alone (29,300 h*ng / mL and 7,200 ng / mL, respectively). Sotorasib was safe and well tolerated when coadministered with 40 mg omeprazole or administered alone in healthy subjects.

[0460] The results showed that coadministration of sotorasib and omeprazole in the fasted state significantly increased the AUC of sotorasib compared with administration of sotorasib alone. inf 42% and C max showed a 57% reduction in

[0461] Example 5 - Contraindications for co-administration of sotorasib with post-prandial antacids This was a phase 1, open-label, fixed-sequence, crossover, single-center study to explore mitigation strategies to limit the effect of antacids on sotorasib exposure. The study evaluated the PK of sotorasib administered alone and in combination with famotidine or omeprazole after meals in healthy men and women (14 subjects total). Subjects received a single dose of sotorasib on day 1, an evening dose of famotidine (10 hours before the sotorasib dose) on day 3, a single dose of sotorasib followed by a famotidine repeat dose 2 hours later on day 4, daily doses of omeprazole on days 6 through 10, and a single dose of both omeprazole and sotorasib on day 11. All sotorasib doses were administered after consumption of a standard-calorie, moderate-fat meal. Blood samples were collected at prespecified time points to characterize sotorasib plasma concentrations. Safety and tolerability monitoring was conducted throughout the study.

[0462] A total of 15 healthy subjects (1 female and 13 males) were enrolled in the study. Thirteen of the 14 subjects received all treatment and completed the study.

[0463] AUC of sotorasib inf and C max The geometric least squares mean ratios of AUC for sotorasib co-administered with famotidine after a meal compared with sotorasib alone were 0.622 and 0.654, respectively. inf and C max The geometric least squares mean ratios of 0.430 and 0.349 were compared for sotorasib coadministered with omeprazole and sotorasib alone, respectively. The 960 mg dose of sotorasib was safe and well tolerated when coadministered with a single 40 mg dose of famotidine after meals and after multiple daily doses of 40 mg omeprazole in healthy subjects.

[0464] In summary, coadministration of a single dose of famotidine (an H2 receptor antagonist) given 10 hours before and 2 hours after a single dose of sotorasib after a meal significantly reduced the C maxIn addition, coadministration of a single dose of sotorasib with multiple doses of omeprazole (a PPI) decreased the C value of sotorasib by 35% and the AUC by 38%. max reduced the α-amyloid β ...

[0465] Example 6 - Contraindications for coadministration of strong CYP34A4 inducers and sotorasib This phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 960 mg of sotorasib on days 1, 3, and 18 and 600 mg of rifampin on days 3 and 5-19. Blood samples for sotorasib PK were collected pre-dose and up to 48 hours after sotorasib administration. Plasma PK parameters of sotorasib were estimated using noncompartmental methods.

[0466] result Geometric Mean Sotorasib AUC Following Coadministration of Single Doses of Sotorasib and Rifampin inf (area under the curve from zero to infinity) and C max The maximum plasma concentrations (19600 h*ng / mL and 5340 ng / mL, respectively) were similar to those of sotorasib alone (25600 h*ng / mL and 6350 ng / mL, respectively). Geometric mean sotorasib AUC after multiple-dose coadministration of sotorasib and rifampin inf and C max (12400 h*ng / mL and 4110 ng / mL, respectively) were lower compared with sotorasib alone (25600 h*ng / mL and 6350 ng / mL, respectively).

[0467] Sotorasib was safe and well tolerated when coadministered with 600 mg of rifampin or administered alone to healthy subjects. Single doses of rifampin had no clinically meaningful effect on the PK of sotorasib, indicating that sotorasib is not a substrate of OATP1B1. Multiple doses of rifampin significantly increased the AUC of sotorasib. inf 51%, C maxby 35%, indicating that sotorasib is a CYP3A4 substrate, consistent with in vitro data.

[0468] Example 7 - Contraindications for co-administration of CYP34A substrates with sotorasib This phase 1, open-label, fixed-sequence study enrolled five subjects with previously untreated NSCLC and administered a single oral dose of 2 mg midazolam alone on day 1, 960 mg oral sotorasib on days 1 through 14, and a single oral dose of 2 mg midazolam at approximately the same time as the 960 mg oral sotorasib on day 15. Blood samples for sotorasib PK were collected pre-dose and up to 48 hours after sotorasib administration. Plasma PK parameters of sotorasib were estimated using noncompartmental methods.

[0469] Plasma PK data for single-dose midazolam were obtained after 14 days of multiple daily dosing with sotorasib from five subjects receiving midazolam alone and midazolam co-administered with sotorasib. Results showed that exposure to midazolam was reduced when co-administered with sotorasib after multiple daily dosing with sotorasib. Co-administration of midazolam (a sensitive CYP3A4 substrate) with sotorasib increased the C max reduced traffic by 48% and AUVs by 53%.

[0470] Example 8 - Contraindications with co-administration of sotorasib and P-gp substrates This phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 0.5 mg digoxin on day 1 and 960 mg sotorasib on day 7, followed by 0.5 mg digoxin. Blood samples for digoxin PK were collected pre-dose and up to 144 hours after digoxin administration. Samples were measured using a validated high-performance liquid chromatography-tandem mass spectrometry method. PK parameters were estimated using noncompartmental methods. Safety and tolerability were monitored throughout the study.

[0471] Time to maximum plasma concentration of digoxin (tmax ) and mean terminal half-life (t 1 / 2 ) were similar after coadministration of sotorasib and digoxin compared with digoxin alone. Geometric mean digoxin AUC after coadministration of sotorasib and digoxin inf The area under the curve from zero to infinity (40.3 h*ng / mL) was similar to that of digoxin alone (33.2 h*ng / mL). The geometric mean digoxin C after coadministration of sotorasib and digoxin max The maximum plasma concentration (3.64 ng / mL) was higher compared with digoxin alone (1.90 ng / mL). A single dose of 0.5 mg digoxin was safe and well tolerated when administered alone or coadministered with 960 mg sotorasib.

[0472] The results showed that coadministration of a single dose of sotorasib with digoxin significantly increased the AUC inf and C max were shown to increase the ATP levels by approximately 21% and 91%, respectively.

[0473] Example 9 - Sotorasib in combination with panitumumab and optionally FOLFIRI in treatment-naive patients with metastatic colorectal cancer compared with chemotherapy (FOLFOX or FOLFIRI) and optionally bevacizumab. The following example describes a phase 3, multicenter, randomized, open-label, active-controlled trial evaluating the efficacy and safety of sotorasib, panitumumab, and FOLFIRI versus FOLFOX or FOLFIRI with or without bevacizumab-awwb in treatment-naive metastatic colorectal cancer (mCRC) patients with KRAS G12C mutations.

[0474] The trial will consist of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Approximately 450 patients with treatment-naive mCRC harboring the KRAS G12C mutation will be enrolled and randomized 1:1 to receive either sotorasib, panitumumab, and FOLFIRI, or chemotherapy (FOLFOX or FOLFIRI) with or without bevacizumab-awwb.

[0475] Subjects will be stratified by region, number of organ sites of metastatic disease (1 vs. >1), and age (<70 vs. >70 years).

[0476] Day 1 of Cycle 1 is defined as the first day a subject receives study drug; tumor assessments are performed (by MRI and / or CT) at baseline and at 8-week + / - 1-week intervals until progression as assessed by BICR, initiation of another anti-cancer treatment, withdrawal of consent, loss to follow-up, or death, whichever occurs first. Tumor assessments and response are determined by BICR using RECIST 1.1. Subjects may discontinue treatment due to disease progression as assessed by BICR, intolerance to treatment leading to treatment discontinuation, initiation of another anti-cancer therapy, or withdrawal of consent.

[0477] For all subjects, information will be collected regarding the type and duration of subsequent therapy after disease progression, response to subsequent therapy, date of progression on subsequent therapy, and survival data. Subjects who discontinue treatment before RECIST 1.1 disease progression (e.g., due to unacceptable toxicity) will be followed radiographically until disease progression, withdrawal of consent, or initiation of another anticancer therapy, followed by further long-term follow-up via telephone or clinic visits to assess survival and document anticancer treatment. Subjects will be followed for 5 years from the last subject's randomization or until withdrawal of consent, loss to follow-up, or subject death, whichever occurs first. Assessments performed in this study are described below and will occur at the times specified in the Schedule of Assessments (SOA).

[0478] Disease progression will be assessed using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) as assessed by BICR.

[0479] Safety will be monitored by assessing serious and non-serious adverse events (AEs), clinical safety tests, and vital signs. The incidence, nature, and severity of all AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0).

[0480] Clinical safety tests will include hematology, blood chemistry, and urinalysis. Assessment of vital signs will include blood pressure and pulse rate; additional vital signs will be collected only if clinically warranted.

[0481] Samples will be collected for sotorasib PK analysis.

[0482] Patient-reported outcome (PRO) / quality of life (QOL) assessments will be assessed.

[0483] Samples for tumor markers are collected.

[0484] Additional plasma / blood / tissue biopsy samples will be collected as exploratory biomarkers for primary and secondary resistance mechanisms.

[0485] Inclusion Criteria: - Pathologically confirmed metastatic colorectal cancer -Center confirmation of KRAS p.G12C mutation Subjects must provide an archived tumor tissue sample (formalin-fixed, paraffin-embedded [FFPE] sample collected within 5 years) or undergo a pre-treatment tumor biopsy prior to enrollment - Measurable disease per RECIST 1.1 criteria. Previously irradiated lesions are not considered measurable unless they have progressed after radiation. -Age 18 or older Eastern Cooperative Oncology Group (ECOG) performance status of ≤1. ->6 month life expectancy If previously receiving adjuvant therapy for non-metastatic disease, adjuvant therapy must have been completed at least 6 months prior to identification of metastatic disease. Adequate hematologic and end-organ function within 10 days prior to randomization, as defined as: ANC ≥ 1500 cells / μL (without granulocyte colony-stimulating factor support within 2 weeks of the laboratory tests used to determine eligibility) Hemoglobin ≥ 9.0 g / dl (no transfusions within 2 weeks of the laboratory tests used to determine eligibility) Platelet count ≥ 100,000 / μl (no transfusion within 2 weeks of the laboratory tests used to determine eligibility) - Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels ≤ 2.5 times the upper limit of normal (ULN) Serum bilirubin ≤ 1.0 × ULN - International normalized ratio (INR) and activated partial thromboplastin time ≤ 1.5 x ULN Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 30 mL / min according to the Cockcroft-Gault formula or a 24-hour urine collection QTcF ≤ 470 msec for women and ≤ 450 msec for men - Ability to take oral medications and willingness to document daily adherence to investigational products

[0486] Exclusion criteria: - Previous systemic therapy for metastatic disease - Active brain metastases. The phrase "active brain metastases," as used herein, refers to cancer that has spread to the brain from the original (primary, non-brain) tumor. Active brain metastases can be assessed by the presence of intracranial lesions. Although "metastases" is plural, it should be understood that a patient who exhibits only one intracranial lesion under the criteria set forth below is a patient with "active brain metastases." In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 5 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 5 mm but less than 10 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 10 mm. If a patient has undergone resection of brain metastases or completed radiation therapy at least 4 weeks prior to Study Day 1, they are not considered to have active brain metastases and are eligible if they meet all of the following criteria: a) residual neurological symptoms of grade ≦2; b) if applicable, receiving a stable dose of dexamethasone or equivalent for at least 2 weeks; and c) a follow-up MRI performed within 28 days of Day 1 shows no progression or appearance of new lesions. For determination of the grade of any neurological symptoms attributable to intracranial disease, please refer to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE), published by the National Cancer Institute on November 27, 2017, which is incorporated herein by reference in its entirety. -Leptomeningeal disease. - Tumor is known to harbor a BRAF V600E mutation. - The tumor is known to be MSI-H. - Unresolved toxicity attributable to prior antineoplastic therapy defined as CTCAE version 5.0 Grade 0 or 1 or not resolved to the level indicated in the eligibility criteria, excluding alopecia (any grade is acceptable), neuropathy (up to Grade 2 is acceptable), or toxicity from prior antineoplastic therapy that is deemed irreversible (defined as present for >6 months and stable), or endocrine AE that has been maintained stable with appropriate replacement therapy. For determination of the grade of any neurological symptoms attributable to intracranial lesions, see the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE), published November 27, 2017 by the National Cancer Institute, which is incorporated herein by reference in its entirety. - Anti-tumor therapy (chemotherapy, antibody therapy, molecularly targeted therapy, retinoid therapy, hormone therapy [excluding subjects receiving long-term adjuvant endocrine therapy, and subjects with a history of complete resection of breast cancer without active disease for >5 years], or investigational drug) within 4 weeks of Study Day 1; note that bisphosphonate or anti-RANKL antibody therapy is allowed if needed for management of hypercalcemia or prevention of skeletal-related events. - Curative or palliative radiation therapy within 2 weeks of Study Day 1. Subjects must have recovered from radiation therapy-related toxicity of CTCAE version 5.0 Grade 1 or less, excluding alopecia (alopecia of any grade is acceptable). - Currently receiving treatment from another investigational device or investigational drug study or less than 4 weeks since completing another investigational device or investigational drug study. - Other investigational treatments are excluded -KRAS G12C Previous treatment with inhibitors. - Received cumulative radiation to more than 25% of the bone marrow - Known dihydropyrimidine dehydrogenase deficiency -Known UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease - Known sensitivity to any of the products or ingredients to be administered during administration. - Subject has, to the investigator's knowledge, required a dose reduction or delay of either 5-fluorouracil or irinotecan due to toxicity in a previous chemotherapy regimen. - Use of known cytochrome P450 (CYP) 3A4 sensitive substrates and P-gp substrates (with narrow therapeutic window) within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that have not been reviewed and approved by the investigator and medical monitor. Use of strong inducers of CYP3A4 (including herbal dietary supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 without review and approval by the investigator and medical monitor. Use of a known CYP3A4 or UGT1A1 inhibitor at least 1 week prior to initiating irinotecan therapy, unless reviewed and approved by the investigator and medical monitor. Use of antiretroviral or viral medications that have the potential to interact with the study drug unless reviewed and approved by the principal investigator and medical monitor. - Female subjects of childbearing potential who are unwilling to use protocol-specified contraceptive methods during treatment and for the following additional periods: 7 days after the last dose of sotorasib - 2 months after the last dose of panitumumab - 6 months after last dose of FOLFIRI - 9 months after last dose of FOLFOX - 6 months after last dose of bevacizumab - Women who are currently breastfeeding or plan to breastfeed during the study until: 7 days after the last dose of sotorasib - 2 months after the last dose of panitumumab - 6 months after last dose of FOLFIRI - 3 months after last dose of FOLFOX - 6 months after last dose of bevacizumab -Women who plan to become pregnant during the study between: 7 days after the last dose of sotorasib - 2 months after the last dose of panitumumab - 6 months after last dose of FOLFIRI - 9 months after last dose of FOLFOX - 6 months after last dose of bevacizumab - Female subjects of childbearing potential with a positive pregnancy test as assessed by a high-sensitivity urine or serum pregnancy test at screening or Day 1. - Male subjects with a female partner of childbearing potential who are willing to practice sexual abstinence (abstain from heterosexual intercourse) or not use contraception during treatment and for the following additional periods: 7 days after the last dose of sotorasib - 6 months after last dose of FOLFIRI - 6 months after last dose of FOLFOX - 6 months after last dose of bevacizumab - Male subjects with a pregnant partner who are unwilling to abstain or use condoms during treatment and for the following additional periods: 7 days after the last dose of sotorasib - 6 months after last dose of FOLFIRI - 6 months after last dose of FOLFOX - 6 months after last dose of bevacizumab - Men who are willing to abstain from sperm donation during the study and for the following additional periods: 7 days after the last dose of sotorasib - 6 months after last dose of FOLFIRI - 6 months after last dose of FOLFOX - 6 months after last dose of bevacizumab - Use of warfarin. Other anticoagulants may be permitted with approval of the medical monitor. Known HIV with CD4+ T-cell count <350 cells / μl - History of an opportunistic infection defining acquired immunodeficiency syndrome within the past 12 months - Known hepatitis B with detectable viral load or hepatitis C with detectable viral load - Malignancies other than CRC within 5 years prior to randomization, except those treated with a negligible risk of metastasis or death and with the expectation of a curative outcome (e.g., adequately treated cervical carcinoma in situ, basal cell carcinoma, squamous cell carcinoma of the skin, localized prostate cancer treated with curative intent, or ductal carcinoma in situ of the breast treated surgically with curative intent). Major surgery within 28 days of study day 1 - Any uncontrolled serious complication that, in the opinion of the investigator, could affect adherence to protocol procedures or interpretation of results or pose a risk to the subject's safety -Severe gastrointestinal disorders resulting in severe malabsorption, the need for intravenous nutritional support, or the inability to tolerate oral medications - History of interstitial pneumonia or pulmonary fibrosis, or evidence of interstitial pneumonia or pulmonary fibrosis on baseline CT scan - History of evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection unless agreed with the medical monitor and meets the following criteria: - Negative SARS-CoV-2 test according to local standard of care within 72 hours of first dose of sotorasib - No acute symptoms of coronavirus disease 2019 (COVID19) illness within 10 days prior to the first dose of sotorasib - Significant cardiovascular disease, such as New York Heart Association (Class II or higher), myocardial infarction, unstable arrhythmia, or unstable angina within 6 months prior to randomization Uncontrolled hypertension (SBP>140 or DB>90) in subjects in whom the investigator plans to use bevacizumab if the subject is randomized to the arm of the investigator's choice - Peripheral neuropathy ≥ grade 2 in subjects with investigator's choice of FOLFOX or FOLFOX and bevacizumab. - Oral or intravenous therapeutic antibiotics within 2 weeks prior to randomization. Prophylactic antibiotic use is permitted.

[0487] Test products: Sotorasib 960 mg or 240 mg orally once daily Panitumumab 6mg / kg IV once every 2 weeks Bevacizumab-awwb 5mg / kg IV once every 2 weeks

[0488] FOLFIRI: Irinotecan 180 mg / m every 2 weeks 2 IV Leucovorin 400mg / m once every 2 weeks 2 IV -5-fluorouracil 400 mg / m 2 IV bolus once every 2 weeks -5-fluorouracil 2400 mg / m 2 IVCI: Administered over 46-48 hours once every two weeks

[0489] FOLFOX: -oxaliplatin 85mg / m 2 IV once every two weeks Leucovorin 400mg / m once every 2 weeks 2 IV -5-fluorouracil 400 mg / m 2 IV bolus once every 2 weeks -5-fluorouracil 2400 mg / m 2 IVCI: Administered over 46-48 hours once every two weeks

[0490] Objectives / Evaluation Items:

[0491] [Table 40]

[0492] Example 10 - Sotorasib in combination with panitumumab and optionally FOLFIRI in patients with metastatic colorectal cancer compared to treatment with FOLFIRI and optionally bevacizumab. The following example describes a phase 3, multicenter, randomized, open-label, active-controlled study evaluating the efficacy and safety of sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb in patients with previously treated metastatic colorectal cancer (mCRC) harboring a KRAS G12C mutation.

[0493] The study will consist of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Approximately 350 patients with previously treated mCRC harboring the KRAS G12C mutation will be enrolled and randomized 1:1 to receive either sotorasib, panitumumab, and FOLFIRI, or FOLFIRI with or without bevacizumab-awwb.

[0494] Subjects will be stratified by region, number of organ sites of metastatic disease (1 vs. >1), and age (<70 vs. >70 years).

[0495] Day 1 of Cycle 1 is defined as the first day a subject receives study drug; tumor assessments are performed (by MRI and / or CT) at baseline and at 8-week + / - 1-week intervals until progression as assessed by BICR, initiation of another anti-cancer treatment, withdrawal of consent, loss to follow-up, or death, whichever occurs first. Tumor assessments and response are determined by BICR using RECIST 1.1. Subjects may discontinue treatment due to disease progression as assessed by BICR, intolerance to treatment leading to treatment discontinuation, initiation of another anti-cancer therapy, or withdrawal of consent.

[0496] For all subjects, information will be collected regarding the type and duration of subsequent therapy after disease progression, response to subsequent therapy, date of progression on subsequent therapy, and survival data. Subjects who discontinue treatment before RECIST 1.1 disease progression (e.g., due to unacceptable toxicity) will be followed radiographically until disease progression, withdrawal of consent, or initiation of another anticancer therapy, followed by further long-term follow-up via telephone or clinic visits to assess survival and document anticancer treatment. Subjects will be followed for 5 years from the last subject's randomization or until withdrawal of consent, loss to follow-up, or death of the subject, whichever occurs first.

[0497] The evaluations performed in this study are described below and will occur at the times specified in the Schedule of Evaluations (SOA). Disease progression will be assessed using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) as assessed by BICR. Safety will be monitored by assessing serious and non-serious adverse events (AEs), clinical safety tests, and vital signs. The incidence, nature, and severity of all AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0). - Clinical safety testing will include hematology, blood chemistry, and urinalysis. Vital sign assessment will include blood pressure and pulse rate; additional vital signs will be collected only if clinically warranted. -Samples will be collected for sotorasib PK analysis. - Patient-reported outcomes (PROs) / quality of life (QOL) assessments will be assessed. -Samples will be collected for sotorasib PK analysis. -Samples for tumor markers are collected. -Additional plasma / blood / tissue biopsy samples will be collected as exploratory biomarkers for primary and secondary resistance mechanisms.

[0498] Inclusion Criteria: - Pathologically confirmed metastatic colorectal cancer Center confirmation of KRAS G12C mutation previously identified by local testing Subjects must provide an archived tumor tissue sample (formalin-fixed, paraffin-embedded [FFPE] sample collected within 5 years) or undergo a pre-treatment tumor biopsy prior to enrollment - Measurable disease per RECIST 1.1 criteria. Previously irradiated lesions are not considered measurable unless they have progressed after radiation. -Age 18 or older Eastern Cooperative Oncology Group (ECOG) performance status of ≤1. ->6 month life expectancy -Subjects must have received and progressed on or after one prior line of systemic therapy for metastatic disease. If prior adjuvant therapy was administered for non-metastatic disease, metastatic disease identified within 6 months of the end of adjuvant therapy will count as a line of therapy for metastatic disease. If the tumor is MSI-H, subjects must have received a checkpoint inhibitor for metastatic disease, if available in their region or country, and the subject has no medical contraindications to that therapy. Adequate hematologic and end-organ function within 10 days prior to randomization, as defined as: ANC ≥ 1500 cells / μL (without granulocyte colony-stimulating factor support within 2 weeks of the laboratory tests used to determine eligibility) Hemoglobin ≥ 9.0 g / dl (no transfusions within 2 weeks of the laboratory tests used to determine eligibility) Platelet count ≥ 100,000 / μl (no transfusion within 2 weeks of the laboratory tests used to determine eligibility) - Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels ≤ 2.5 times the upper limit of normal (ULN) Serum bilirubin ≤ 1.0 × ULN - International normalized ratio (INR) and activated partial thromboplastin time ≤ 1.5 x ULN Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 30 mL / min according to the Cockcroft-Gault formula or a 24-hour urine collection QTcF ≤ 470 msec for women and ≤ 450 msec for men - Ability to take oral medications and willingness to document daily adherence to investigational products

[0499] Exclusion criteria: - Active brain metastases. The phrase "active brain metastases," as used herein, refers to cancer that has spread to the brain from the original (primary, non-brain) tumor. Active brain metastases can be assessed by the presence of intracranial lesions. Although "metastases" is plural, it should be understood that a patient who exhibits only one intracranial lesion under the criteria set forth below is a patient with "active brain metastases." In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 5 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 5 mm but less than 10 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion greater than 10 mm. If a patient has undergone resection of brain metastases or completed radiation therapy at least 4 weeks prior to Study Day 1, they are not considered to have active brain metastases and are eligible if they meet all of the following criteria: a) residual neurological symptoms of grade ≦2; b) if applicable, receiving a stable dose of dexamethasone or equivalent for at least 2 weeks; and c) a follow-up MRI performed within 28 days of Day 1 shows no progression or appearance of new lesions. For determination of the grade of any neurological symptoms attributable to intracranial disease, please refer to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE), published by the National Cancer Institute on November 27, 2017, which is incorporated herein by reference in its entirety. -Leptomeningeal disease. - Tumor is known to harbor a BRAF V600E mutation. - Unresolved toxicity attributable to prior antineoplastic therapy defined as CTCAE Version 5.0 Grade 0 or 1 or not resolved to the level indicated in the eligibility criteria except for alopecia (any grade is acceptable), neuropathy (up to Grade 2 is acceptable), or toxicity from prior antineoplastic therapy that is deemed irreversible (defined as present and stable for >6 months), or endocrine AEs that are maintained stable with appropriate replacement therapy. - Anti-tumor therapy (chemotherapy, antibody therapy, molecularly targeted therapy, retinoid therapy, hormone therapy [excluding subjects receiving long-term adjuvant endocrine therapy, and subjects with a history of complete resection of breast cancer without active disease for >5 years], or investigational drug) within 4 weeks of Study Day 1; note that bisphosphonate or anti-RANKL antibody therapy is allowed if needed for management of hypercalcemia or prevention of skeletal-related events. - Curative or palliative radiation therapy within 2 weeks of Study Day 1. Subjects must have recovered from radiation therapy-related toxicity of CTCAE version 5.0 Grade 1 or less, excluding alopecia (alopecia of any grade is acceptable). - Currently receiving treatment from another investigational device or investigational drug study or less than 4 weeks since completing another investigational device or investigational drug study. - Other investigational treatments are excluded -KRAS G12C Previous treatment with inhibitors. - Received cumulative radiation to more than 25% of the bone marrow - Known dihydropyrimidine dehydrogenase deficiency -Known UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease - Known sensitivity to any of the products or ingredients to be administered during administration. - Subject has, to the investigator's knowledge, required a dose reduction or delay of either 5-fluorouracil or irinotecan due to toxicity in a previous chemotherapy regimen. - Has received prior treatment with irinotecan for metastatic disease. - Use of known cytochrome P450 (CYP) 3A4 sensitive substrates and P-gp substrates (with narrow therapeutic window) within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that have not been reviewed and approved by the investigator and medical monitor. Use of strong inducers of CYP3A4 (including herbal dietary supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 without review and approval by the investigator and medical monitor. Use of a known CYP3A4 or UGT1A1 inhibitor at least 1 week prior to initiating irinotecan therapy, unless reviewed and approved by the principal investigator and medical monitor. Use of antiretroviral or viral medications that have the potential to interact with the study drug unless reviewed and approved by the principal investigator and medical monitor. - Female subjects of childbearing potential who are unwilling to use protocol-specified contraceptive methods during treatment and for the following additional periods: 7 days after the last dose of sotorasib - 2 months after the last dose of panitumumab - 6 months after last dose of FOLFIRI - 6 months after last dose of bevacizumab - Women who are currently breastfeeding or plan to breastfeed during the study until: 7 days after the last dose of sotorasib - 2 months after the last dose of panitumumab 7 days after the last dose of FOLFIRI - 6 months after last dose of bevacizumab -Women who plan to become pregnant during the study between: 7 days after the last dose of sotorasib - 2 months after the last dose of panitumumab - 6 months after last dose of FOLFIRI - 6 months after last dose of bevacizumab - Female subjects of childbearing potential with a positive pregnancy test as assessed by a high-sensitivity urine or serum pregnancy test at screening or Day 1. - Male subjects with a female partner of childbearing potential who are willing to practice sexual abstinence (abstain from heterosexual intercourse) or not use contraception during treatment and for the following additional periods: 7 days after the last dose of sotorasib - 6 months after last dose of FOLFIRI - 6 months after last dose of bevacizumab - Male subjects with a pregnant partner who are unwilling to abstain or use condoms during treatment and for the following additional periods: 7 days after the last dose of sotorasib - 6 months after last dose of FOLFIRI - 6 months after last dose of bevacizumab - Men who are willing to abstain from sperm donation during the study and for the following additional periods: 7 days after the last dose of sotorasib - 6 months after last dose of FOLFIRI - 6 months after last dose of bevacizumab - Use of warfarin. Other anticoagulants may be permitted with approval of the medical monitor. Known HIV with CD4+ T-cell count <350 cells / μl - History of an opportunistic infection defining acquired immunodeficiency syndrome within the past 12 months - Known hepatitis B with detectable viral load or hepatitis C with detectable viral load - Malignancies other than CRC within 5 years prior to randomization, except those treated with a negligible risk of metastasis or death and with the expectation of a curative outcome (e.g., adequately treated cervical carcinoma in situ, basal cell carcinoma, squamous cell carcinoma of the skin, localized prostate cancer treated with curative intent, or ductal carcinoma in situ of the breast treated surgically with curative intent). Major surgery within 28 days of study day 1 - Any uncontrolled serious complication that, in the opinion of the investigator, could affect adherence to protocol procedures or interpretation of results or pose a risk to the subject's safety -Severe gastrointestinal disorders resulting in severe malabsorption, the need for intravenous nutritional support, or the inability to tolerate oral medications - History of interstitial pneumonia or pulmonary fibrosis, or evidence of interstitial pneumonia or pulmonary fibrosis on baseline CT scan - History of evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection unless agreed with the medical monitor and meets the following criteria: - Negative SARS-CoV-2 test according to local standard of care within 72 hours of first dose of sotorasib - No acute symptoms of coronavirus disease 2019 (COVID19) illness within 10 days prior to the first dose of sotorasib - Significant cardiovascular disease, such as New York Heart Association (Class II or higher), myocardial infarction, unstable arrhythmia, or unstable angina within 6 months prior to randomization Uncontrolled hypertension (SBP>140 or DB>90) in subjects in whom the investigator plans to use bevacizumab if the subject is randomized to the arm of the investigator's choice - Oral or intravenous therapeutic antibiotics within 2 weeks prior to randomization. Prophylactic antibiotic use is permitted.

[0500] Test products: Sotorasib 960 mg or 240 mg orally daily Panitumumab 6mg / kg IV once every 2 weeks Bevacizumab-awwb 5mg / kg IV once every 2 weeks

[0501] FOLFIRI: Irinotecan 180 mg / m every 2 weeks 2 IV Leucovorin 400mg / m once every 2 weeks 2 IV -5-fluorouracil 400 mg / m 2 IV bolus once every 2 weeks -5-fluorouracil 2400 mg / m 2 IVCI: Administered over 46-48 hours once every two weeks

[0502] Objectives / Evaluation Items:

[0503] [Table 41]

[0504] All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0505] 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 apparent that certain changes and modifications may be practiced within the scope of the appended claims.

[0506] References: Albert et al.,2007,Nat.Methods,4:903-905. Alizadeh et al., 1996, Nat. Genet., 14:457-460. Beers and Nederlof,2006,Breast Cancer Res.,8(3):210. Bertone et al.,2006,Genome Res.16(2):271-281. Canon et al.,2019,Nature 575(7781),217. Cecil Textbook of Medicine,pp.2317-2341,WBSaunders & Co.(1985) Cerami et al.2012, Cancer Discov.,2(5),401. Chung et al.,2004,Genome Res.,14(1):188-196. CAMPTOSAR (Registered Trademark) US Prescribing Information, Pharmacia and Upjohn Co., Division of Pfizer, Inc., NY, NY 10017 (revision 1 / 2022) Cully M, Downward J., 2008, Cell, 133:1292. Dalma-Weiszhausz et al. 2006 Methods Enzymol., 410:3-28. Eisenhauer et al., 2009, Eur.J.Cancer, 45:228-247. Fakih et al., 2021, Abstract #3245: European Society for Medical Oncology (ESMO), September 16-21, 2021. Fakih et al., 2021, ePoster #3245: European Society for Medical Oncology (ESMO), September 16-21, 2021. Forshew et al., 2012, Sci Transl Med., 4:136ra68. Gao et al., 2013, Science Signaling, 6(269), pl1. Haber and Velculescu, 2014, Cancer Discov., 4:650-61. Hong et al., 2020, N.Engl.J.Med., 383, 1207. Hughes et al., 2001, Nat.Biotechnol., 19(4):342-347. Irizarry, 2003, Nucleic Acids Res., 31:e15. Janes et al., 2018, Cell., 172(3):578-589. Jasmine et al., 2012, PLoS One, 7(2):e31968. Kim et al., 2006, Carcinogenesis, 27(3): 392 - 404. Kinde et al., 2011, Proc Natl Acad Sci USA; 108: 9530 - 5. Kuboki et al., 2022, European Society for Medical Oncology (ESMO), September 9 - 13, 2022. Kumar et al., 2012, J. Pharm. Bioallied Sci., 4(1): 21 - 26. Laere et al., 2009, Methods Mol. Biol., 512: 71 - 98. Lanman et al., 2020, J. Med. Chem., 63, 52. Lin et al., 2010, BMC Genomics, 11: 712. Liu et al., 2017, Biosens Bioelectron, 92: 596 - 601. Lodes et al., 2009, PLoS One, 4(7): e6229. LUMAKRAS (registered trademark) US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 5 / 2021) Mackay et al., 2003, Oncogene, 22: 2680 - 2688. Mao et al., 2007, Curr. Genomics 8(4): 219 - 228. McDonald et al., 2017, Cell, 170(3): 577 - 592. Michels et al., 2007, Genet. Med., 9: 574 - 584. Mockler and Ecker, 2005, Genomics, 85(1): 1 - 15. National Cancer Institute Common Terminology Criteria for Adverse Events v5.0(NCI CTCAE)published Nov.27,2017 by the National Cancer Institute 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 Discov.,15(11):771-785. Patricelli et al.,2016,Cancer Discovery,6:316-329. Peeters et al.,2010,J Clin Oncol.,28:4706-13 Pinkel et al., 2005, Nat. Genetics, 37: S11-S17. Simanshu et al.,2017,Cell,170:17-33. Thomas et al., 2005, Genome Res., 15(12):1831-1837. Thompson et al.,2012,PLoS ONE,7:e31597. VECTIBIX® US Prescribing Information. Amgen Inc., Thousand Oaks, California, 91320, revision 8 / 2021 Wang et al.,2012,Cancer Genet.,205(7-8):341-55. Wei et al., 2008, Nucleic Acids Res., 36(9):2926-2938. International Publication No. 2021 / 142026 Brochure International Publication No. 2021 / 224867 Brochure Xie et al.,2017,Front Pharmacol.,8:823. Zubrod et al.,1960,J Chronic Disease,11:7-33.

Claims

1. 1. A pharmaceutical composition for use in a method for treating colorectal cancer comprising a KRAS G12C mutation in a patient, said pharmaceutical composition comprising sotorasib, said method comprising administering to said patient (a) the pharmaceutical composition and (b) panitumumab in amounts effective to treat said cancer, wherein said amounts effective to treat said cancer are 960 mg of sotorasib once daily and 6 mg / kg of panitumumab administered IV every two weeks.

2. The pharmaceutical composition of claim 1 , wherein the colorectal cancer is metastatic colorectal cancer (mCRC).

3. The pharmaceutical composition of claim 2 , wherein the patient has undergone at least one prior systemic cancer therapy.

4. The pharmaceutical composition of claim 2 , wherein the patient has received at least two prior systemic cancer therapies.

5. 4. The pharmaceutical composition of claim 3, wherein the systemic cancer therapy is a therapy comprising administering to the patient a fluoropyrimidine, irinotecan, and oxaliplatin.

6. 4. The pharmaceutical composition of claim 3, wherein the mCRC is determined to be MSI-H and the systemic cancer therapy comprises administering to the patient a checkpoint inhibitor.

7. 4. The pharmaceutical composition of claim 3, wherein the mCRC comprises a BRAF V600E mutation and the systemic cancer therapy comprises administering encorafenib and cetuximab to the patient.

8. 3. The pharmaceutical composition of claim 2, wherein the patient exhibits an ECOG performance status of 0, 1, or 2.

9. The pharmaceutical composition of claim 2, wherein the patient does not have active brain metastases.

10. The systemic therapy is Ｇ１２Ｃ The pharmaceutical composition of claim 3, which is not a therapy comprising administering an inhibitor to the patient.

11. 3. The pharmaceutical composition of claim 2, wherein the method comprises administering to the patient (c) irinotecan, (d) 5-FU, and (e) leucovorin or levoleucovorin.

12. The method comprises administering 400 mg / m ２ 12. The pharmaceutical composition of claim 11, comprising administering to said patient:

13. The method comprises administering 200 mg / m ２ 12. The pharmaceutical composition of claim 11, comprising administering to the patient:

14. The method comprises administering 180 mg / m ２ 12. The pharmaceutical composition of claim 11, comprising administering to said patient:

15. The method comprises administering 400 mg / m ２ 12. The pharmaceutical composition of claim 11, comprising administering to said patient 5-FU of

16. The method comprises administering 180 mg / m ２ of irinotecan administered IV once every 2 weeks at 400 mg / m ２ of leucovorin administered IV once every 2 weeks at 400 mg / m ２ of 5-FU administered as an IV bolus once every 2 weeks, and 2400 mg / m ２ 3. The pharmaceutical composition of claim 2, comprising administering 5-FU of 5-FU of 5-FU per 46-48 hours by IV continuous infusion once every two weeks.

17. The method comprises administering 180 mg / m ２ of irinotecan administered IV once every 2 weeks at 200 mg / m ２ of leucovorin administered IV once every 2 weeks at 400 mg / m ２ of 5-FU administered as an IV bolus once every 2 weeks, and 2400 mg / m ２ 3. The pharmaceutical composition of claim 2, comprising administering 5-FU of 5-FU of 5-FU per 46-48 hours by IV continuous infusion once every two weeks.

18. The pharmaceutical composition of claim 11 , wherein the patient has not received prior systemic cancer therapy.

19. 19. The pharmaceutical composition of claim 18, wherein the patient does not have active brain metastases.

20. 19. The pharmaceutical composition of claim 18, wherein the mCRC does not contain a BRAF V600E mutation.

21. 19. The pharmaceutical composition of claim 18, wherein the mCRC is determined to not be MSI-H.

22. The systemic therapy is Ｇ１２Ｃ The pharmaceutical composition of claim 3, which is a therapy comprising administering the inhibitor to the patient.

23. 19. The pharmaceutical composition of claim 18, wherein the patient exhibits an ECOG performance status of 0 or 1.

24. The pharmaceutical composition of claim 11 , wherein the patient has received one prior systemic cancer therapy.

25. 25. The pharmaceutical composition of claim 24, wherein if the cancer is determined to be MSI-H, the systemic cancer therapy uses a checkpoint inhibitor.

26. 25. The pharmaceutical composition of claim 24, wherein the patient is undergoing systemic cancer therapy and is experiencing disease progression during or after said therapy.

27. The systemic therapy is Ｇ１２Ｃ 25. The pharmaceutical composition of claim 24, which is not a therapy comprising administering an inhibitor to the patient.

28. 25. The pharmaceutical composition of claim 24, wherein the systemic therapy is not a therapy comprising administering irinotecan.

29. 25. The pharmaceutical composition of claim 24, wherein the patient exhibits an ECOG performance status of 0 or 1.

30. 25. The pharmaceutical composition of claim 24, wherein the patient does not have active brain metastases.

31. 25. The pharmaceutical composition of claim 24, wherein the mCRC does not contain a BRAF V600E mutation.

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