Sotracib and EGFR antibodies for the treatment of cancers including KRAS G12C mutations

Abstract

This invention provides a method for treating cancers containing the KRAS G12C mutation in patients. [Solution] A method is provided comprising administering to a patient an effective amount of sotrasib and an anti-epidermal growth factor receptor (EGFR) antibody to treat cancer. A further method is provided comprising administering to a patient FOLFIRI (irinotecan, 5-FU and leucovorin).

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 241,601 filed on 8 September 2021, U.S. Provisional Patent Application No. 63 / 298,747 filed on 12 January 2022, and U.S. Provisional Patent Application No. 63 / 374,012 filed on 31 August 2022, which are each incorporated herein by reference in their entirety.

[0002] Integration by referencing electronically submitted documents The text file containing the sequence listing is named "55328P3_Seqlisting.XML", was created on August 23, 2022, and has a size of 13,982 bytes. The entire sequence listing is incorporated herein by reference. [Background technology]

[0003] The rat sarcoma (RAS) proto-oncogene has been identified as a carcinogenic 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 that express guanosine triphosphate (GTP)ases involved in regulating cell proliferation and survival. The RAS protein, Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus oncogene homolog (HRAS), and neuroblastoma RAS virus oncogene homolog (NRAS) can be mutant-activated at codons 12, 13, or 61 to cause human cancer. Different tumor types are associated with mutations in specific isoforms of RAS, with KRAS being the most frequently mutated isoform in most cancers. Although the role of KRAS mutations in human cancer has been known for decades, anticancer therapies that specifically target KRAS mutations had not been successfully developed until recently, as proteins were generally considered difficult to inhibit with small molecules. [Overview of the project] [Means for solving the problem]

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

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

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

[0007] [Figure 1]The mean plasma concentration-time profiles after once-daily oral administration of 180, 360, 720, or 960 mg of sotrasib on day 1 are shown, with N indicating the number of observations across all data points. [Figure 2] The mean plasma concentration-time profiles after once-daily oral administration of 180, 360, 720, or 960 mg of sotrasib on day 8 are shown, with N indicating the number of observations across all data points. [Modes for carrying out the invention]

[0008] This specification provides a method for treating cancer comprising the KRAS G12C mutation in a patient, comprising administering to the patient an effective amount of sotrasib and an anti-epidermal growth factor receptor (EGFR) antibody to treat the cancer. 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. In some embodiments, the method further comprises administering to the patient irinotecan and 5-FU.

[0009] The therapeutic methods disclosed herein with respect to the administration of two or more therapeutic agents to a patient (e.g., sotracib, EGFR antibody, irinotecan, 5-FU, leucovorin, etc.) include simultaneous administration of the therapeutic agents (e.g., within 1 hour, 45 minutes, 30 minutes, 15 minutes, or 10 minutes between each) and sequential administration (e.g., administration with intervals of at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 2 days, or at least 3 days). Unless otherwise stated herein, combination therapies of two or more therapeutic agents discussed herein include both combination and sequential administration.

[0010] Sotrasib Sotracib is KRAS G12CIt is a small molecule that irreversibly inhibits mutant proteins. Sotrasib is also known as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]-4-[(2S)-2-methyl-4-(propa-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidine-2(1H)-one, and has the following structure. [ka]

[0011] Sotrasib 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 and binds to the inactive guanosine diphosphate (GDP) in a three-dimensional structure that binds to KRAS. G12CIt contains a thiol-reactive moiety that locks KRAS. This blocks the interaction between KRAS and effectors such as rapidly progressive fibrosarcoma (RAF), thereby interfering with downstream signaling, including the phosphorylation of extracellular signal-regulated kinases (ERKs) (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 apoptosis cell proliferation and induction in tumor cell lines and xenografts with KRAS mutations (including KRAS G12C mutations) (Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016). Trials with sotracib confirmed these in vitro findings and similarly demonstrated inhibition and regression of growth in cells and tumors with the KRAS G12C mutation (Canon et al., 2019). See also LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revised 5 / 2021), which is incorporated herein by reference in its entirety.

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

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

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

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

[0016] The FOLFIRI regimen involves 180 mg / m² of irinotecan on day 1. 2 Racemic leucovorin 400 mg / m² on day 1. 2 , and 400 mg / m² of 5-fluorouracil on day 1. 2 IV bolus and 2400 mg / m² administered over 46-48 hours starting on day 1 of Q2W. 2It consists of IV continuous infusion (IVCI) (National Comprehensive Cancer Network (NCCN) Colon, Rectal, Anal Cancer Guidelines). Irinotecan in combination with 5-fluorouracil and leucovorin is approved by the FDA as a first-line treatment for patients with metastatic colorectal cancer (CAMPTOSAR® US Prescribing Information, Pharmacia and Upjohn Co., Division of Pfizer, Inc., NY, NY 10017 (Revision 1 / 2022), which is incorporated herein by reference in its entirety). In some embodiments, leucovorin in the FOLFIRI regimen is 200 mg / m² 2 It may be replaced with levoleucovorin.

[0017] Administration regimen In some embodiments, the method includes administering sotrasib in amounts ranging from 240 mg to 960 mg. In some embodiments, the method includes administering 960 mg of sotrasib to a patient once daily. In some embodiments, the method includes administering 720 mg of sotrasib to a patient once daily. In some embodiments, the method includes administering 480 mg to a patient once daily. In some embodiments, the method includes administering 240 mg to a patient once daily. In some embodiments, the method includes administering 480 mg to a patient twice daily. In some embodiments, the method includes administering 240 mg to a patient twice daily.

[0018] In some embodiments, the method involves administering panitumumab to the patient once every two weeks. In some embodiments, the method involves administering panitumumab at a dose of 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). The method includes administering the drug by IV once every two weeks in amounts ranging from g, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, or 6 mg / kg). In some embodiments, the method includes administering 6 mg / kg of panitumumab. In some embodiments, the method further includes administering 3 mg / kg of panitumumab.

[0019] In some embodiments, the method described herein includes administering to the patient (a) 960 mg of sotrasib daily; and (b) 6 mg / kg of panitumumab intravenously every two weeks. In some embodiments, the method described herein includes administering to the patient (a) 720 mg of sotrasib daily; and (b) 6 mg / kg of panitumumab intravenously every two weeks. In some embodiments, the method described herein includes administering to the patient (a) 480 mg of sotrasib daily; and (b) 6 mg / kg of panitumumab intravenously every two weeks. In some embodiments, the method described herein includes administering to the patient (a) 960 mg of sotrasib daily; and (b) 3 mg / kg of panitumumab intravenously every two weeks.

[0020] In some embodiments, the method further comprises administering irinotecan, 5-FU, and leucovorin to the patient. In some embodiments, the method involves administering 400 mg / m² by IV dose. 2administering leucovorin to a patient. In some embodiments, the method further comprises administering irinotecan, 5-FU, and leucovorin钙 to the patient. In some embodiments 2 the method further comprises administering 200 mg / m of leucovorin钙 to the patient by IV administration. In some embodiments, the method further comprises administering 180 mg / m 2 of irinotecan to the patient by IV administration. In some embodiments, the method further comprises administering 400 mg / m 2 of 5-FU to the patient.

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

[0022] In some embodiments, the method comprises administering, by IV administration, 180 mg / m 2 of irinotecan, 200 mg / m 2 of leucovorin钙, and 400 mg / m 2 of 5-FU by IV bolus and 2400 mg / m 2 of 5-FU by 46-48 hour IV continuous infusion to the patient every two weeks.

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

[0024] In various embodiments, patients require further treatment with antacids. Examples of antacids include, but are not limited to, proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and topical antacids. In some embodiments, patients require further treatment with PPIs or H2RAs. 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, patients requiring further antacid treatment are not administered proton pump inhibitors or H2 receptor antagonists in combination with sotrasib. In some embodiments, patients requiring further antacid treatment are not administered a proton pump inhibitor or H2 receptor antagonist in combination with sotrasib, but are administered a topical antacid in combination with sotrasib. In some embodiments, sotrasib is administered about 4 hours before or about 10 hours after the topical antacid.

[0025] In various embodiments, patients may require further treatment with CYP3A4 inducers. In some embodiments, patients may not be administered CYP3A4 inducers in combination with sotrasib. Exemplary CYP3A4 inducers include, but are not limited to, barbiturates, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, ellagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritabancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, terotristat, and troglitazone. For example, see Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), www.drug-interactions.medicine.iu.edu, accessed in May 2021. In some embodiments, patients are not administered potent CYP3A4 inducers in combination with sotrasib. Exemplary potent CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. For example, see www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed in May 2021.In one embodiment, potent CYP3A4 inhibitors include, but are not limited to, ombitasvir and paritaprevir and ritonavir and dasabuvir, indinavir and ritonavir, tipranavir and ritonavir, ritonavir, cobicistat, ketoconazole, troleandmycin, telaprevir, danoprevir and ritonavir, elvitegravir and ritonavir, saquinavir and ritonavir, lopinavir and ritonavir, itraconazole, indinavir, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, ronafarnib, posaconazole, telithromycin, grapefruit juice DS3, conivaptan, tucatinib, nefazodone, ceritinib, nelfinavir, saquinavir, ribociclib, idelalisib, and boceprevir.

[0026] In various embodiments, patients require treatment with a CYP3A4 substrate. In some embodiments, patients are not administered a CYP3A4 substrate in combination with sotrasib. 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, caliprazine, ceritinib, cerivastatin, chlorpheniramine, and siro Stazole, 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, erythro Mycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, imatinib, haloperidol, hydrocortisone, ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isabconazonium, ivabradine, ivacaftol, lansoprazole, lenvatinib, relcanidipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, midazolam, naldemedine, naloxegol, nate Glinide, 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,Examples of medications that can be used include, but are not limited to, rivaroxaban, roflumilast, lorapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus, sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus (FK506), tamoxifen, tasimerteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, bilazodone, vincristine, borapaxar, voriconazole, zaleplon, and ziprasidone. For example, see Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), https: / / drug-interactions.medicine.iu.edu, accessed in May 2021.

[0027] In various embodiments, patients require treatment with a P-glycoprotein (P-gp) substrate. In some embodiments, patients are not administered a P-gp substrate in combination with sotrasib. Exemplary P-gp substrates include, but are not limited to, dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine. See, for example, www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed May 2021. In some embodiments, patients are not administered a P-gp substrate in combination with sotrasib, and the P-gp substrate is a P-gp substrate with a narrow therapeutic range. Exemplary P-gp substrates with a narrow therapeutic range include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, and vincristine.

[0028] Patient characteristics In various embodiments, the patient undergoes KRAS before administration of sotrasib as disclosed herein. G12C The patient has cancer in which one or more cells expressing a mutant protein have been determined. KRAS G12C The determination of mutant proteins may be evaluated as described elsewhere in this disclosure.

[0029] In some embodiments, patients to whom sotrasib is administered in the manner described herein have been previously treated with a different anticancer therapy, e.g., at least one other systemic cancer therapy, such as 1, 2, or 3. In some embodiments, the patient has received sotrasib combination therapy as a second-line therapy, e.g., KRAS G12C The patient had previously been treated with one other systemic cancer therapy, so that it is a second-line therapy for treating metastatic colorectal cancer. In some embodiments, the patient had previously been treated with a third-line therapy, such as KRAS, sotrasib combination therapy provided herein. G12CThe patient had previously been treated with two other systemic cancer therapies, making sotracib combination therapy a third-line therapy for treating metastatic colorectal cancer. In some embodiments, the patient had previously been treated with sotracib combination therapy as a first-line therapy, e.g., KRAS. G12C The patient had not previously been treated with any other systemic cancer therapy, making it the first-line treatment for metastatic colorectal cancer.

[0030] In some embodiments, previous systemic cancer therapies are used in KRAS G12C This is a therapy using inhibitors. In a particular embodiment, the patient has KRAS G12C It shows reduced sensitivity to inhibitor therapy. In some embodiments, the patient has KRAS G12C It is resistant to inhibitor therapy. In some embodiments, KRAS G12C The inhibitors are sotrasib, adagrasib, GDC-6036, D-1553, JDQ443, LY3484356, BI1823911, JAB-21822, RMC-6291, or APG-1842. In certain embodiments, KRAS G12C The inhibitor is sotracib. In certain embodiments, KRAS G12C The inhibitor is adagracib. In some embodiments, the therapy is monotherapy. In some embodiments, the therapy is KRAS G12C Therapies that include the administration of inhibitors, for example, KRAS G12C This is a combination therapy involving the administration of an inhibitor and a MEK inhibitor or SHP2 inhibitor (e.g., sotrasib and trametenib, adaglasib and trametenib, sotrasib and RMC-4630, adaglasib and RMC-4630, sotrasib and TNO-155, and adaglasib and TNO-155). In one embodiment, KRAS G12C The inhibitor therapy is sotracib monotherapy. In another embodiment, KRAS G12C The inhibitor therapy is monotherapy with adagracib. In some embodiments, previous systemic cancer therapies are KRAS G12CThis is not an inhibitory therapy. RMC-4630 (CAS number 2172652-48-9, 6-(2-amino-3-chloropyridine-4-yl)sulfanyl-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-methylpyrazine-2-yl]methanol) is disclosed in International Publication No. 2021 / 142026, e.g., paragraph

[0005] . TNO-155 ((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine) is disclosed in International Publication No. 2021 / 224867, e.g., paragraph

[0014] .

[0031] As used herein, “sensitivity” refers to the mode in which cancer responds to a drug, for example, sotracib. In exemplary embodiments, “sensitivity” means “responsive to treatment,” and the concepts of “sensitivity” and “responsiveness” are positively related in that cancer or tumors that are responsive to drug treatment are said to be sensitive to that drug. In exemplary embodiments, “sensitivity” is defined, according to Pelikan, Edward, Glossary of Terms and Symbols used in Pharmacology (Pharmacology and Experimental Therapeutics Department Glossary at Boston University School of Medicine), as the ability of a population, individual or organization to respond qualitatively in the usual manner to a particular dose of a drug, compared to the ability of others. The lower the dose required to produce an effect, the more sensitive the response system is. “Sensitivity” may also be measured or described quantitatively based on the intersection of the dose-effect curve with the x-axis or a line parallel thereto; such a point corresponds to the 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 typical embodiments, "sensitivity" is the opposite of "resistance," and the concept of "resistance" is negatively related to "sensitivity." For example, a cancer resistant to drug treatment is either neither sensitive nor responsive to the drug, or initially sensitive to the drug but no longer sensitive once resistance is acquired; 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. Previous systemic cancer therapies of particular consideration include, but are not limited to, checkpoint inhibitor therapies (e.g., anti-PD1 therapy, anti-PDL-1 therapy), platinum-based chemotherapy, and anti-EGFR therapy. Some examples of anti-PD1 and anti-PDL-1 therapies include, but are not limited to, pembrolizumab, nivolumab, semiprimab, tisielizumab, tripalimab, aspartalizumab, dostallimab, retifanlimab, simtilimab, pidilizumab, atezolizumab, avelumab, durvalumab, and zelbarimab (AMG 404). Some examples of platinum-based chemotherapy include, but are not limited to, carboplatin, oxaliplatin, cisplatin, nedaplatin, satraplatin, lovaplatin, triplatin tetranitrate, picoplatin, ProLindac® (AP5346), and alloplatin. Some examples of anti-EGFR therapy include, but are not limited to, cetuximab and panitumumab.

[0033] In some embodiments, patients have previously received targeted systemic cancer therapy when their cancer is identified to have therapeutically applicable oncogenic driver mutations 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. In some cases, the patient has KRAS G12C Patients with mutated cancers, such as metastatic colorectal cancer and pancreatic cancer, have not received prior treatment. In such cases, sotracib therapy provided herein is the first-line treatment.

[0035] In some embodiments, the patient has previously received treatment with chemotherapy and anti-angiogenic agents. In some embodiments, the chemotherapy includes therapy with 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, patients exhibit an ECOG performance status of 0, 1, or 2 (see, for example, Zubrod et al., 1960). In some embodiments, patients exhibit an ECOG performance status of 0 or 1. Status 0 indicates fully active and able to continue all pre-disease activities without restriction. Status 1 indicates physically limited activity but able to walk and perform light or sedentary work. Status 2 indicates able to walk and perform all self-care but unable to work; awake and moving around for 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 completely immobile, unable to perform any self-care and spending all day in bed or chair. Status 5 indicates death.

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

[0038] In various cases, the patient has cancer that is MSI-H. In some cases, the MSI-H cancer is mCRC, and the patient has previously been treated with checkpoint inhibitors.

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

[0040] In various cases, patients have colorectal cancer, and the cancer does not contain the BRAF V600E mutation. Determination of the BRAF V600E mutation can be assessed from patient samples using approved mutation tests from numerous commercial sources.

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

[0042] The terms “adverse event” or “(AE)” as used herein mean any undesirable and unintended sign (including abnormal clinical laboratory findings), symptom, or disease that is temporally associated with the use of a medical treatment or procedure which may be considered related to a medical treatment or procedure.

[0043] In some embodiments, adverse events include hepatotoxicity (e.g., elevated liver enzymes), interstitial lung disease (ILD) / interstitial pneumonia, diarrhea, and / or nausea / vomiting.

[0044] hepatotoxicity In some embodiments, the adverse event is hepatotoxicity. The term “hepatotoxicity,” as used herein, refers to patients who have abnormal clinical laboratory levels 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 liver biomarkers that were not abnormal before administration of sotrasib or were lower than those measured after administration of sotrasib.

[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, producing pyruvate and glutamate. When the liver is damaged, blood ALT levels may be elevated due to the leakage of ALT into the bloodstream from damaged or necrotic hepatocytes.

[0046] Aspartate transaminase (AST), also known as serum glutamate oxaloacetate transaminase (SGOT or GOT) or aspartate aminotransferase (ASAT), catalyzes the transfer of an amino group from aspartate to α-ketoglutarate, producing oxaloacetate and glutamate. AST levels can increase in response to liver injury. Elevated AST levels can also result from damage to other sources, including red blood cells, cardiac muscle, skeletal muscle, renal tissue, and brain tissue. The AST-to-ALT ratio can be used as a biomarker for 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 liver cells 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 the cells lining the bile ducts of the liver. Plasma ALP levels may 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 tract disease.

[0049] In some embodiments, the patient does not have a disorder that would result in elevated liver biomarkers. Disorders associated with elevated liver biomarkers (such as AST / ALT and / or TBL levels) include: hepatobiliary diseases; viral hepatitis (e.g., hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); any cause of hypoxia to the liver resulting in right heart failure, hypotension, or ischemia; and exposure to hepatotoxic drugs / medicines or hepatotoxins, including herbs and nutritional supplements, plants, and mushrooms. This includes, but is not limited to, genetic disorders that cause impaired glucuronidation (e.g., Gilbert's syndrome, Crigler-Nadjar 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).

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

[0051] Adverse event grades related to abnormal liver function are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 1. See also 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 events. “Abnormal” liver function, as used herein, refers to Grade 1 or higher adverse events.

[0054] Grade 1 liver dysfunction includes elevated ALT or AST levels greater than ULN and less than 3 times ULN, if baseline is normal; 1.5 to 3.0 × baseline, if baseline is abnormal. Grade 1 liver dysfunction also includes elevated bilirubin levels greater than ULN and less than 1.5 times ULN, if baseline is normal; >1.0 to 1.5 × baseline, if baseline is abnormal. Grade 1 liver dysfunction also includes elevated ALP levels greater than ULN and less than 2.5 times ULN, if baseline is normal; >2.0 to 2.5 × baseline, if baseline is abnormal.

[0055] Grade 2 liver dysfunction includes elevated ALT or AST levels greater than 3x but less than 5x the upper limit of normal (ULN) if baseline is normal; >3.0–5.0 × baseline if baseline is abnormal. Grade 2 liver dysfunction also includes elevated bilirubin levels greater than 1.5x the ULN but less than 3x the ULN if baseline is normal; >1.5–3.0 × baseline if baseline is abnormal. Grade 2 liver dysfunction also includes elevated ALP levels greater than 2.5x the ULN but less than 5x the ULN if baseline is normal; >2.5–5.0 × baseline if baseline is abnormal.

[0056] Grade 3 liver dysfunction includes elevated ALT, AST, or ALP levels greater than 5 times the ULN and less than 20 times the ULN if baseline was normal; if baseline was normal, >5.0 to 20.0 × baseline. Grade 3 liver dysfunction also includes elevated bilirubin levels greater than 3 times the ULN and less than 10 times the ULN if baseline was normal; if baseline was abnormal, >3.0 to 10 × baseline.

[0057] Grade 4 liver dysfunction includes elevated ALT, AST, or ALP levels greater than 20 times ULN if baseline is normal; >20 × baseline if baseline is abnormal. Grade 4 liver dysfunction also includes elevated bilirubin levels greater than 10 times ULN if baseline is normal; >10.0 × baseline if baseline is abnormal.

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

[0059] [Table 2]

[0060] In any of the methods described herein, the total daily dose of sotrasib was reduced when the patient's AST and / or ALT levels rose to, for example, grade 2 or grade 3 levels (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg), and the patient's baseline AST and / or ALT levels were below grade 2 or grade 3. In some embodiments, the total daily dose of sotrasib was reduced when the patient's AST and / or ALT levels rose to grade 1 levels (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg), and the patient's baseline AST and / or ALT levels were below grade 1.

[0061] Alternatively, in any of the methods disclosed herein, the total daily dose of sotrasib 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 increased to grade 1, grade 2, grade 3, or grade 4 levels, or (2) the patient's AST or ALP levels are increased, or (3) the patient's ALT and bilirubin levels are increased, or (4) the patient's ALT and ALP levels are increased, or (5) the patient's bilirubin and ALP levels are increased, and the patient's baseline AST, bilirubin, ALP, and / or ALT levels are 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, where 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 sotrasib is reduced when ALT and / or AST levels are greater than approximately 3 times the upper limit of normal range (ULN) (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg). In relevant embodiments, abnormal levels of ALT and / or AST are greater than an increase of approximately 3 to approximately 5 times the upper limit of normal range (ULN) (i.e., "grade 2 abnormality"). In some embodiments, if the patient has an abnormal baseline, grade 2 abnormality is an abnormal level of ALT and / or AST that is greater than an increase of approximately 3 to approximately 5 times the baseline. In some embodiments, abnormal levels of ALP are greater than an increase of approximately 2.5 to approximately 5 times the upper limit of normal range (ULN) (i.e., "grade 2 abnormality"). In some embodiments, if the patient has an abnormal baseline, grade 2 abnormality is an abnormal level of ALP that is greater than an increase of approximately 2.5 to approximately 5 times the baseline. In some embodiments, an abnormal bilirubin level is greater than approximately 1.5 to approximately 3 times the upper limit of the normal range (ULN) (i.e., "Grade 2 abnormality"). In some embodiments, if a patient has an abnormal baseline, a Grade 2 abnormality is an abnormal bilirubin level greater than approximately 1.5 to approximately 3 times the baseline.

[0063] In some embodiments, the total daily dose of sotrasib is reduced when ALT and / or AST levels are greater than approximately 5 times the upper limit of normal range (ULN) (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg). In some embodiments, the total daily dose is reduced when ALT, AST, or ALP levels are greater than approximately 5 to approximately 20 times the upper limit of normal range (ULN) (i.e., "grade 3 abnormality"). In some embodiments, if the patient has an abnormal baseline, grade 3 abnormality is an abnormal level of ALT and / or AST that is greater than approximately 5 to approximately 20 times the increase compared to baseline. In some embodiments, an abnormal level of ALP is greater than approximately 5 to approximately 20 times the increase compared to the upper limit of normal range (ULN) (i.e., "grade 3 abnormality"). In some embodiments, if the patient has an abnormal baseline, grade 3 abnormality is an abnormal level of ALP that is greater than approximately 5 to approximately 20 times the increase compared to baseline. In some embodiments, the total daily dose is reduced when the bilirubin level is greater than approximately 3 to 10 times the upper limit of the normal range (ULN) (i.e., “Grade 3 abnormality”). In some embodiments, if the patient has an abnormal baseline, Grade 3 abnormality is an abnormal level of bilirubin greater than approximately 3 to 10 times the baseline.

[0064] In some embodiments, the total daily dose of sotrasib is reduced when ALT and / or AST levels are greater than approximately 20 times the upper limit of the normal range (ULN) (i.e., “Grade 4 abnormality”) (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg). In some embodiments, if the patient has an abnormal baseline, Grade 4 abnormality is an abnormal level of ALT and / or AST that is greater than approximately 20 times the increase compared to baseline. In some embodiments, an abnormal level of ALP is greater than approximately 20 times the increase compared to the upper limit of the normal range (ULN) (i.e., “Grade 4 abnormality”). In some embodiments, if the patient has an abnormal baseline, Grade 4 abnormality is an abnormal level of ALP that is greater than approximately 20 times the increase compared to baseline. In some embodiments, the total daily dose is reduced when bilirubin levels are greater than approximately 10 times the increase compared to the upper limit of the normal range (ULN) (i.e., “Grade 4 abnormality”). In some embodiments, if a patient has an abnormal baseline, a Grade 4 abnormality is an abnormal level of bilirubin greater than approximately a 10-fold increase compared to baseline.

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

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

[0067] The adverse event grades for nausea and vomiting are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 3. See also 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 sotrasib administration in patients with ≥ Grade 3 nausea until the patient improves to ≤ Grade 1 or baseline. In some embodiments, once the patient has improved to ≤ Grade 1 or baseline, the method includes administering the patient a reduced total daily dose of sotrasib (e.g., 240 mg to 480 mg, or 480 mg to 960 mg).

[0070] In some embodiments, the methods described herein include withholding sotrasib administration in patients with ≥ Grade 3 vomiting until the vomiting improves to ≤ Grade 1 or baseline. In some embodiments, once the patient has improved to ≤ Grade 1 or baseline, the method includes administering the patient a reduced total daily dose of sotrasib (e.g., 240 mg to 480 mg, or 480 mg to 960 mg).

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

[0072] diarrhea In some embodiments, the adverse event is diarrhea. In some embodiments, diarrhea persists despite appropriate supportive care (e.g., antidiarrheal therapy).

[0073] The adverse event grades for diarrhea are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 4. See also 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 sotrasib administration in patients with ≥ Grade 3 diarrhea until the patient improves to ≤ Grade 1 or baseline. In some embodiments, once the patient has improved to ≤ Grade 1 or baseline, the method includes administering the patient a reduced total daily dose of sotrasib (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg).

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

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

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

[0079] Patients may respond to sotrasib 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 defined as stable disease, partial response (PR), or complete response (CR) (i.e., "at least SD" = SD + PR + CR, often referred to as disease control). In various embodiments, stable disease is neither sufficiently reduced to qualify as a partial response (PR) nor sufficiently expanded to qualify as progressive disease (PD). In various embodiments, patients may demonstrate at least a partial response (i.e., "at least PR" = PR + CR, often referred to as objective response).

[0080] Efficacy may be measured by one or more of the following: reduction in tumor size, suppression or reduction of tumor growth, reduction of target or tumor lesions, delay in progression-free survival, absence of new tumors or lesions, reduction in new tumor formation, increased survival or progression-free survival (PFS), and absence of metastasis. In various embodiments, disease progression in a patient may be assessed by evaluating the patient using computed tomography (CT) scans, positron emission tomography (PET) scans, magnetic resonance imaging (MRI) scans, X-rays, ultrasound, or a combination thereof, by measuring tumor size, tumor lesions, or the formation of new tumors or lesions.

[0081] Progression-free survival (PFS) may be assessed as described in the RECIST 1.1 protocol. In various embodiments, patients show a PFS of at least one month. In various embodiments, patients show a PFS of at least three months. In some embodiments, patients show a PFS of at least six months.

[0082] Additional means for evaluating efficacy are described in detail in the following examples and may be applied to methods generally disclosed herein.

[0083] KRAS G12C Cancer While I don't wish to be bound by any particular theory, the following is noteworthy: Sotrasib is KRAS G12C It is a small molecule that specifically and irreversibly inhibits (Hong et al., 2020). Hong et al. reported that "[p]Re-clinical studies have shown that [sotrasib] inhibits virtually all detectable phosphorylation of extracellular signal-regulated kinases (ERKs), which are important downstream effectors of KRAS, resulting in permanent and complete tumor regression in mice with KRAS p.G12C tumors" (see also Canon et al., 2019 and Lanman et al., 2020).

[0084] Sotrasib was evaluated in a phase 1 dose-escalation and expansion study in 129 patients with locally advanced or metastatic cancer containing histologically confirmed KRAS G12C mutations, identified by local molecular examination 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 that showed either stable disease (SD) or partial response (PR), as reported by Hong et al., were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary origin, ampulla cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma (Hong et al., 2020, pp. 1212 (Figure A), and appendix (pp. 59 (Figure S5) and pp. 63 (Figure S6)).

[0085] KRAS G12C mutations occur at the modification 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 cancer in which one or more cells express the KRAS G12C mutant protein. Therefore, KRAS G12C Sotracib, which binds specifically and irreversibly to [specific cancer], is useful in treating patients with cancers including, but not limited to, those listed in Table 5 below.

[0086] [Table 5]

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

[0088] Method 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. Determination of whether a tumor or cancer contains mutations can be performed, for example, by evaluating the nucleotide sequence encoding the protein, by evaluating the amino acid sequence of the protein, by evaluating the characteristics of a putative mutant protein, or by any other suitable method known in the art. Wild-type human KRAS (nucleotide sequence described in Genbank acceptance number BC010502; amino acid sequence described in Genbank acceptance 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 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-stranded DNA higher-order structure 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 thawing assays, and microarray analysis. In some embodiments, samples are evaluated for mutations such as the KRAS G12C mutation by real-time PCR. Real-time PCR uses fluorescent probes specific to particular mutations 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 methods of specific regions in the gene. This method 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 for detecting mutations include, but are not limited to, the use of mutant protein-specific binders (e.g., antibodies), protein electrophoresis and Western blotting, and direct peptide sequencing.

[0090] In some embodiments, multiplex PCR sequencing is used for mutation detection and may include several amplicons that provide improved sensitivity for detecting one or more genetic biomarkers. For example, multiplex PCR 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, multiplex PCR sequencing may include 61 amplicons. Amplicons generated using multiplex PCR sequencing range from approximately 15 bp to approximately 1000 bp (for example, approximately 25 bp to approximately 1000 bp, approximately 35 bp to approximately 1000 bp, approximately 50 bp to approximately 1000 bp, approximately 100 bp to approximately 1000 bp, approximately 250 bp to approximately 1000 bp, approximately 500 bp to approximately 1000 bp, approximately 750 bp to approximately 1000 bp, approximately 15 bp to approximately 750 bp, approximately 15 It may contain nucleic acids having lengths of approximately 500 bp, 15 bp to 300 bp, 15 bp to 200 bp, 15 bp to 100 bp, 15 bp to 80 bp, 15 bp to 75 bp, 15 bp to 50 bp, 15 bp to 40 bp, 15 bp to 30 bp, 15 bp to 20 bp, 20 bp to 100 bp, 25 bp to 50 bp, or 30 bp to 40 bp. For example, an amplicon produced using multiplex PCR sequencing may contain nucleic acids having a length of approximately 33 bp.

[0091] In some embodiments, the presence of one or more mutations in a sample obtained from a patient is detected using sequencing techniques (e.g., next-generation sequencing techniques). 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 in a sample obtained from a patient is detected using droplet digital PCR (ddPCR), a method known to be highly sensitive to mutation detection. In some embodiments, the presence of one or more mutations in a sample obtained from a patient is detected using other sequencing techniques, including, but not limited to, chain elongation termination techniques, shotgun techniques, synthetic sequencing methods, microfluidic techniques, 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 cell-free DNA samples).

[0093] In some embodiments, the presence of one or more mutations in a sample obtained from a patient is detected using an array-based method. For example, the step of detecting genetic modifications (e.g., one or more genetic modifications) 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 modifications. Non-limiting examples of array-based methods that may be used in any of the methods described herein include complementary DNA (cDNA) microarrays (see, e.g., Kumar et al. 2012; Laere et al. 2009; Mackay et al. 2003; Alizadeh et al. 1996), oligonucleotide microarrays (see, e.g., Kim et al. 2006; Lodes et al. 2009), bacterial artificial chromosome (BAC) clone chips (see, e.g., Chung et al. 2004; Thomas et al. 2005), single nucleotide polymorphism (SNP) microarrays (see, e.g., Mao et al. 2007; Jasmine et al. 2012), and microarray-based comparative genomic hybridization arrays (array-CGH) (see, e.g., Beers and Nederlof, 2006; Pinkel et al. 2005; Michels et al. Examples include 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] A variety of samples can be used to determine whether a tumor or cancer contains mutations. 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 treated with cell lysates. In some embodiments, the sample is treated with 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 the mutational status.

[0095] In various embodiments, tests approved by regulatory authorities such as the U.S. Food and Drug Administration (FDA) are used to determine whether a patient has a mutation, such as a KRASG12C mutation in cancer, or whether a tumor or tissue sample obtained from such a patient contains cells with the mutation. In some embodiments, the KRAS mutation test 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) of 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 excision, CNB, or FNA. Mutation testing for STK11, KEAP1, EGFR, ALK, and / or ROS1 can be performed using commercially available assays such as the Resolution Bioscience Resolution ctDx Lung® assay, which includes 24 genes (including those that can lead to treatment in NSCLC). Tissue samples can be tested using the Tempus xT 648 panel.

[0096] In some embodiments, cancer has been identified as having a KRAS G12C mutation. In some embodiments, cancer has been identified as having a mutation in STK11, for example, a loss-of-function mutation. In some embodiments, cancer has been identified as having a mutation in KEAP1, for example, a loss-of-function mutation. In some embodiments, cancer has been identified as having wild-type STK11. In some embodiments, cancer has been identified as having wild-type KEAP1.

[0097] In various embodiments, cancer has been identified as having loss-of-function mutations in STK11 and wild-type KEAP1. In some embodiments, cancer has been identified as having loss-of-function mutations in STK11 and loss-of-function mutations in KEAP1. In some embodiments, cancer has been identified as having wild-type STK11 and wild-type KEAP1. In some embodiments, cancer has been identified as having wild-type STK11 and loss-of-function mutations in KEAP1.

[0098] The term “loss-of-function mutation,” as used herein, refers to a mutation that results in the expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or absent wild-type biological or enzymatic activity), the expression of only a fragment of a protein that no longer exhibits wild-type activity, or a mutation that does not result in the expression of a wild-type protein (e.g., substitution, deletion, shortening, or frameshift mutation). For example, a loss-of-function mutation affecting the STK11 gene in a cell may result in decreased expression of the STK11 protein, expression of only a fragment of the STK11 protein, or expression of the STK11 protein that exhibits reduced or no enzymatic activity in cancer cells (e.g., no serine / threonine kinase enzyme activity). Similarly, a loss-of-function mutation affecting the KEAP1 gene in a cell may result in decreased expression of the KEAP1 protein, expression of only a fragment of the KEAP1 protein, or expression of the 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] Method 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 study to pembrolizumab treatment. This is a quantitative assay using monoclonal mouse anti-PD-L1, clone 22C3 PD-L1, and the EnVision FLEX visualization system on an automated staining device Lin 48 to detect PD-L1 in FFPE samples such as human non-small cell lung cancer tissue. Expression levels can be measured using a tumor ratio score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. Staining can indicate PD-L1 expression from 0% to 100%.

[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 study to nivolumab treatment. This quantitative assay uses monoclonal rabbit anti-PD-L1, clone 28-8, and the EnVision FLEX visualization system on an automated staining device Lin 48 to detect PD-L1 in formalin-fixed paraffin-embedded (FFPE) human cancer tissue.

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

[0102] In some embodiments, the PD-L1 TPS of cancer is determined as disclosed herein using tests approved by regulatory authorities such as the U.S. Food and Drug Administration (FDA). In various embodiments, the PD-L1 TPS is determined using immunohistochemistry (IHC) testing. In some embodiments, the IHC test is the PD-L1 IHC 22C3 pharmDx test. In various embodiments, the IHC test was performed using samples obtained, for example, by excision, CNB, or FNA.

[0103] In various embodiments, the patient has 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 less than 1%. In various embodiments, the patient has 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 less. 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 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 within a range limited by any of the values ​​cited in the embodiments described above. For example, the patient has a PD-L1 TPS score in the range of less than 50% and 1% or more, 50% or less and 1% or more, or less than 50% and 1%.

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

[0105] Embodiment 1. A method for treating cancer containing the KRAS G12C mutation in a patient, comprising administering to the patient an effective amount of sotrasib and an anti-epidermal growth factor receptor (EGFR) antibody for treating the cancer. 2. The method of Embodiment 1, comprising administering 960 mg of sotrasib to the patient daily. 3. The method of Embodiment 1, comprising administering 720 mg of sotrasib to the patient daily. 4. The method of Embodiment 1, comprising administering 480 mg of sotrasib to the patient daily. 5. The method of Embodiment 1, comprising administering 240 mg of sotrasib to the patient daily. 6. Any one of Embodiments 1 to 5, comprising administering sotrasib to the patient once daily. 7. Any one of Embodiments 1 to 5, comprising administering sotrasib to the patient twice daily. 8. Any one of Embodiments 1 to 5, comprising administering an anti-epidermal growth factor receptor (EGFR) antibody to a patient every two weeks. 9. The method of Embodiment 8, wherein the anti-EGFR antibody comprises the heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8. 10. The method of Embodiment 9, wherein the anti-EGFR antibody comprises the heavy chain variable region sequence of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 9. 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. A method according to any one of Embodiments 1 to 12, comprising administering 13.6 mg / kg of panitumumab to a patient. One of Embodiments 1 to 12, comprising administering 14.3 mg / kg of panitumumab to a patient. 15. (a) 960 mg of sotrasib daily; and (b) Panitumumab 6 mg / kg administered intravenously every two weeks. A method of any one of Embodiments 1 to 12, comprising administering to a patient. 16. (a) 720 mg of sotrasib daily; and (b) Panitumumab 6 mg / kg administered intravenously every two weeks. A method of any one of Embodiments 1 to 12, comprising administering to a patient. 17. (a) 480 mg of sotrasib daily; and (b) Panitumumab 6 mg / kg administered intravenously every two weeks. A method of any one of Embodiments 1 to 12, comprising administering to a patient. 18. (a) 960 mg of sotrasib daily; and (b) Panitumumab 3 mg / kg administered intravenously every two weeks. A method of any one of Embodiments 1 to 12, comprising administering to a patient. 19. Any one of Embodiments 1 to 18, further comprising administering irinotecan, 5-FU, and leucovorin to a patient. 20. 400 mg / m² administered via IV 2 The method of Embodiment 19, comprising administering leucovorin to the patient. 21. Any one of Embodiments 1 to 18, further comprising administering irinotecan, 5-FU, and levorucovorin to a patient. 22. 200 mg / m² administered via IV. 2 The method of Embodiment 21, comprising administering levoleucovorin to the patient. 23. 180 mg / m² administered via IV. 2 A method of any one of Embodiments 1 to 22, comprising administering irinotecan to a patient. 24. 400 mg / m² administered via IV 2 A method of any one of Embodiments 1 to 22, comprising administering 5-FU to a patient. 25. IV administration resulted in 180 mg / m² 2 Irinotecan, 400 mg / m² 2 Leucovorin, and 400 mg / m² 2 Administer 5-FU to the patient as an IV bolus every two weeks, and 2400 mg / m² 2 One of the methods of Embodiments 1-20 and 23-24, comprising administering 5-FU to the patient by continuous IV infusion over 46-48 hours. 26. IV administration resulted in 180 mg / m² 2 Irinotecan, 200 mg / m² 2 Levoleucovorin, and 400 mg / m² 2 IV bolus of 5-FU and 2400 mg / m² 2 One of the methods of Embodiments 1-18 and 21-24, comprising administering a continuous intravenous infusion of 5-FU over 46-48 hours to the patient every two weeks. 27. Any one of Embodiments 1 to 18, further comprising administering irinotecan and 5-FU to a patient. 28. 180 mg / m² administered via IV 2 The method of Embodiment 27, comprising administering irinotecan to a patient. 29. 150 mg / m² administered via IV. 2 The method of Embodiment 27, comprising administering irinotecan to a patient. 30. IV administration resulted in 180 mg / m² 2 Irinotecan, and 400 mg / m² 2 IV bolus of 5-FU and 2400 mg / m² 2 A method of any one of embodiments 1 to 18 and 28, comprising administering a continuous intravenous infusion of 5-FU over 46 to 48 hours to a patient every two weeks. 31. IV administration resulted in 150 mg / m² 2 Irinotecan, and 400 mg / m² 2 IV bolus of 5-FU and 2400 mg / m² 2 A method of any one of embodiments 1 to 18 and 27, comprising administering a continuous intravenous infusion of 5-FU over 46 to 48 hours to a patient every two weeks. 32. Any one of Embodiments 1 to 31, wherein the cancer is a solid tumor. 33. Any one of Embodiments 1 to 32, wherein the cancer is small intestine cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. 34. Any one of Embodiments 1 to 33, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer (CRC). 35. Any one of Embodiments 1 to 33, wherein the cancer is non-small cell lung cancer (NSCLC). 36. Any one of Embodiments 1 to 33, wherein the cancer is metastatic pancreatic cancer. 37. Any one of Embodiments 1 to 36, wherein the patient has previously received at least one other systemic cancer therapy. 38. At least one systemic cancer therapy is KRAS G12C The method of Embodiment 37, selected from inhibitor therapy, anti-PD-1 therapy, anti-PD-L1 therapy, and platinum-based chemotherapy. 39. At least one systemic cancer therapy is KRAS G12C The method of Embodiment 37, which is not a therapy using an inhibitor. 40. Any one of Embodiments 1 to 39, wherein the cancer is colorectal cancer (CRC). 41. Any one of embodiments 1 to 34 and 39, wherein the patient has previously received therapy with 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 had KRASG12C A method from any one of embodiments 1-34 and 40-42 that is resistant to inhibitor therapy. 44. 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. Any one of Embodiments 1-34, 36, and 40-43, wherein the patient has previously received one other therapy for metastatic disease. 46. ​​Any one of embodiments 1-34 and 40, wherein the patient has not received prior therapy for metastatic disease. 47. Any one of Embodiments 1 to 46, wherein the patient does not have active brain metastases from a non-brain tumor or leptomeningeal disease. 48. Any one of Embodiments 1 to 47, wherein the patient did not have a myocardial infarction six months prior to the start of treatment. 49. Any one of Embodiments 1 to 48, wherein the patient exhibits at least stable disease (SD) 1, 3, or 6 months after sotracib and panitumumab therapy, as measured by the RECIST 1.1 protocol. 50. Any one of Embodiments 1 to 49, wherein the patient exhibits at least a partial response (PR) 1, 3, or 6 months after sotrasib and panitumumab therapy, as measured by the RECIST 1.1 protocol. 51. Any one of Embodiments 1 to 50, wherein the patient exhibits progression-free survival (PFS) of at least 3 months. 52. Any one of Embodiments 1 to 51, wherein the patient is not infected with hepatitis A, hepatitis B, or hepatitis C. 53. Any one of Embodiments 1 to 52, wherein the patient does not have interstitial pneumonia or pulmonary fibrosis. 54. Any one of Embodiments 1 to 53, wherein the patient requires further treatment with antacids. 55. The method of Embodiment 54, wherein the antacid is a proton pump inhibitor (PPI), an H2 receptor antagonist (H2RA), or a topical antacid. 56. The method of Embodiment 54 or Embodiment 55, wherein the antacid is a topical antacid, and sotrasib is administered about 4 hours before or about 10 hours after the topical antacid. 57. The method of Embodiment 55 or Embodiment 56, wherein the topical antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide. 58. Any one of Embodiments 1 to 57, wherein the patient requires further 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 sotracib. 60. A method according to any one of Embodiments 55, 58, or 59, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. 61. A method according to any one of Embodiments 55, 58, or 59, wherein H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine. 62. Any one of embodiments 1 to 61, wherein the patient requires further treatment with a CYP3A4 inducer. 63. The method of Embodiment 62, wherein the patient is not administered a CYP3A4 inducer in combination with sotracib. 64. The method of Embodiment 62 or 63, wherein the CYP3A4 inducer is barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, ellagolix, enzalutamide, eslicarbazepine, glucocorticoid, letermovir, lorlatinib, modafinil, nevirapine, oritabancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, terotristat, and troglitazone. 65. The method of Embodiment 62 or Embodiment 63, wherein the patient is not administered a potent CYP3A4 inducer in combination with sotracib. 66. The method of Embodiment 65, wherein the potent CYP3A4 inducer is phenytoin or rifampin. 67. Any one of embodiments 1 to 66, wherein the patient requires further treatment with a CYP3A4 substrate. 68. The method of Embodiment 67, wherein the patient is not administered a CYP3A4 substrate in combination with sotrasib. 69. 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, caliprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, and clarithromycin. Icin, 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, F Inasteride, flibanserin, imatinib, haloperidol, hydrocortisone, ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isabconazonium, ivabradine, ivacaftol, lansoprazole, lenvatinib, relcanidipine, 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, lorapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus,The method of Embodiment 67 or 68, wherein the drug is sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus (FK506), tamoxifen, tasimerteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, virazodone, vincristine, borapaxar, voriconazole, zarepron, or ziprasidone. 70. Any one of embodiments 1 to 69, wherein the patient requires further 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 sotrasib. 72. The method of Embodiment 70 or Embodiment 71, wherein the P-gp substrate is etexilate, digoxin, or fexofenadine. 73. Any one of Embodiments 1 to 72, wherein cancer exhibits a PD-L1 tumor ratio score (TPS) of 1-49%. 74. Any one of Embodiments 1 to 73, wherein cancer exhibits a PD-L1 tumor ratio score (TPS) of less than 1%. 75. Any one of Embodiments 1 to 74, wherein cancer exhibits a PD-L1 tumor ratio score (TPS) of 50-100%. 76. A method of cancer further comprising an STK11 mutation, according to any one of Embodiments 1 to 75. 77. A method of cancer further comprising a KEAP1 mutation, any one of embodiments 1 to 76. 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 for treating cancer containing the KRAS G12C mutation in a patient, comprising administering to the patient an effective amount of sotrasib and an anti-epidermal growth factor receptor (EGFR) antibody for treating the cancer. 2. The method of Embodiment 1, comprising administering 960 mg of sotrasib to the patient daily. 3. The method of Embodiment 1, comprising administering 240 mg of sotrasib to the patient daily. 4. Any one of Embodiments 1 to 3, comprising administering sotrasib to the patient once daily. 5. Any one of Embodiments 1 to 3, comprising administering sotrasib to the patient twice daily. 6. Any one of Embodiments 1 to 5, comprising administering an anti-epidermal growth factor receptor (EGFR) antibody to a patient every two weeks. 7. The method of Embodiment 6, wherein the anti-EGFR antibody comprises the heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8. 8. The method of Embodiment 7, wherein the anti-EGFR antibody comprises the heavy chain variable region sequence of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 9. 9. The method of Embodiment 7, 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. 10. The method of Embodiment 7, wherein the anti-EGFR antibody is panitumumab. One of the methods of Embodiments 1 to 10, comprising administering 11.6 mg / kg of panitumumab to a patient. 12. (a) 960 mg of sotrasib daily; and (b) Panitumumab 6 mg / kg administered intravenously every two weeks. A method of any one of Embodiments 1 to 10, comprising administering to a patient. 13. (a) 240 mg of sotrasib daily; and (b) Panitumumab 6 mg / kg administered intravenously every two weeks. A method of any one of Embodiments 1 to 10, comprising administering to a patient. 14. Any one of Embodiments 1 to 13, further comprising administering irinotecan, 5-FU, and leucovorin to a patient. 15. 400 mg / m² administered via IV 2The method of Embodiment 14, comprising administering leucovorin to the patient. 16. Any one of Embodiments 1 to 13, further comprising administering irinotecan, 5-FU, and levorucovorin to a patient. 17. 200 mg / m² administered via IV. 2 The method of Embodiment 16, comprising administering levoleucovorin to a patient. 18. 180 mg / m² administered via IV 2 A method of any one of Embodiments 1 to 17, comprising administering irinotecan to a patient. 19. 400 mg / m² administered via IV 2 A method of any one of Embodiments 1 to 18, comprising administering 5-FU to a patient. 20. IV administration resulted in 180 mg / m² 2 Irinotecan, 400 mg / m² 2 Leucovorin, and 400 mg / m² 2 Administer 5-FU to the patient as an IV bolus every two weeks, and 2400 mg / m² 2 One of the methods of Embodiments 1 to 15 and 18 to 19, comprising administering 5-FU to the patient by continuous IV infusion over 46 to 48 hours. 21. IV administration resulted in 180 mg / m² 2 Irinotecan, 200 mg / m² 2 Levoleucovorin, and 400 mg / m² 2 IV bolus of 5-FU and 2400 mg / m² 2 One of embodiments 1-13, 16, and 17, comprising administering a continuous intravenous infusion of 5-FU over 46-48 hours to a patient every two weeks. 22. Any one of Embodiments 1 to 13, further comprising administering irinotecan and 5-FU to a patient. 23. 180 mg / m² administered via IV. 2 The method of Embodiment 22, comprising administering irinotecan to a patient. 24. 150 mg / m² administered via IV. 2 The method of Embodiment 22, comprising administering irinotecan to a patient. 25. IV administration resulted in 180 mg / m² 2 Irinotecan, and 400 mg / m² 2 IV bolus of 5-FU and 2400 mg / m² 2 A method of any one of embodiments 1 to 13 and 23, comprising administering a continuous intravenous infusion of 5-FU over 46 to 48 hours to a patient every two weeks. 26. IV administration resulted in 150 mg / m² 2 Irinotecan, and 400 mg / m² 2 IV bolus of 5-FU and 2400 mg / m² 2 A method of any one of embodiments 1 to 13 and 24, comprising administering a continuous intravenous infusion of 5-FU over 46 to 48 hours to a patient every two weeks. 27. Any one of Embodiments 1 to 26, wherein the cancer is a solid tumor. 28. Any one of Embodiments 1 to 27, wherein the cancer is small intestine cancer, appendiceal cancer, endometrial cancer, hepatobiliary tract cancer, small cell lung cancer, cervical cancer, pancreatic cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. 29. Any one of Embodiments 1 to 28, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer (CRC). 30. Any one of Embodiments 1 to 29, wherein the cancer is non-small cell lung cancer (NSCLC). 31. Any one of Embodiments 1 to 28, wherein the cancer is metastatic pancreatic cancer. 32. Any one of Embodiments 1 to 28, wherein the cancer is colorectal cancer. 33. Any one of Embodiments 1 to 32, wherein the patient has previously received at least one other systemic cancer therapy. 34. At least one systemic cancer therapy is KRAS G12C The method of Embodiment 33, selected from inhibitor therapy, anti-PD-1 therapy, anti-PD-L1 therapy, and platinum-based chemotherapy. 35. At least one systemic cancer therapy is KRAS G12C The method of Embodiment 33, which is not a therapy using an inhibitor. 36. Any one of Embodiments 1 to 28, wherein the cancer is metastatic colorectal cancer (mCRC). 37. Any one of Embodiments 1 to 36, wherein the patient has previously received at least one other systemic cancer therapy. 38. Any one of Embodiments 1 to 36, wherein the patient has previously received at least two other systemic cancer therapies. 39. The method of Embodiments 37 and 38, wherein the systemic cancer therapy comprises administering fluoropyrimidine, irinotecan, and oxaliplatin to the patient. 40. The mCRC is determined to be MSI-H, and the systemic cancer therapy is a therapy comprising administering a checkpoint inhibitor to the patient, one of the embodiments 36 to 39. 41. Any one of Embodiments 36 to 40, wherein the mCRC contains the BRAF V600E mutation, and the systemic cancer therapy comprises administering encorafenib and cetuximab to the patient. 42. Any one of embodiments 36 to 41, wherein the systemic cancer therapy is adjuvant therapy, and the cancer has progressed within 6 months after completion of adjuvant therapy. 43. Any one of embodiments 36 to 42, wherein systemic cancer therapy is adjuvant therapy after resection of mCRC. 44. Any one of embodiments 36 to 43, wherein the patient exhibits an ECOG performance status of 2 or less. 45. Any one of embodiments 36 to 44, wherein the patient does not have active brain metastases. 46. ​​Any one of embodiments 36 to 45, wherein the patient does not have a leptomeningeal disease. 47. Any one of embodiments 36 to 46, wherein the patient does not have human immunodeficiency virus (HIV) infection. 48. Any one of embodiments 36 to 47, wherein the patient does not have hepatitis B or hepatitis C infection. 49. Any one of Embodiments 37 to 48, wherein the systemic cancer therapy comprises administering (i) trifluridine and tipiracil, and (ii) regorafenib to the patient. 50. Systemic therapy is KRAS G12C Any one of embodiments 37 to 49, which is not a therapy involving the administration of an inhibitor to a patient. 51. KRAS G12C The method of Embodiment 50, wherein the inhibitor is sotrab. 52. KRAS G12C The method of Embodiment 50, wherein the inhibitor is adagrab. 53. Any one of Embodiments 37 to 52, wherein the systemic therapy does not involve administering trifluridine and tipiracil to the patient. 54. Any one of Embodiments 37 to 53, wherein the systemic therapy does not involve administering regorafenib to the patient. 55. Any one of Embodiments 1 to 36, wherein the patient has not previously received any other systemic cancer therapy. 56. The method of Embodiment 55, wherein the patient does not have active brain metastases. 57. The methods of embodiments 55 and 56, wherein the patient does not have a leptomeningeal disease. 58. Any one of embodiments 55 to 57, wherein the mCRC does not contain the BRAF V600E mutation. 59. Any one of embodiments 55 to 58, wherein mCRC is determined not to be MSI-H. 60. Systemic therapy is KRAS G12C A method of any one of embodiments 55 to 59, which is a therapy comprising administering an inhibitor to a patient. 61. KRAS G12C The method of Embodiment 60, wherein the inhibitor is sotrab. 62. KRAS G12C The method of Embodiment 60, wherein the inhibitor is adagrab. 63. Any one of embodiments 55 to 62, wherein the patient does not have dihydropyrimidine dehydrogenase deficiency. 64. Any one of embodiments 55 to 63, wherein the patient does not have UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease. 65. Any one of embodiments 55 to 64, wherein the patient does not have hepatitis B or hepatitis C infection. 66. A method according to any one of embodiments 55 - 64, wherein the patient does not have heart disease of New York Heart Association class II or higher, myocardial infarction within less than 6 months before treatment, unstable arrhythmia, or unstable angina. 67. A method according to any one of embodiments 55 - 64, wherein the patient has an ECOG performance status of 1 or less. 68. A method according to 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. A method according to embodiment 68 or 69, wherein the patient has received one other systemic cancer therapy and progression occurred during or after said therapy. 71. A method according to any one of embodiments 68 - 70, wherein one other systemic cancer therapy is adjuvant therapy and mCRC has progressed within 6 months after completion of adjuvant therapy. 72. A method according to any one of embodiments 68 - 70, wherein mCRC is determined to be MSI - H and one other systemic cancer therapy is a therapy comprising administering a checkpoint inhibitor. 73. A method according to any one of embodiments 68 - 70, wherein one other systemic therapy does not comprise administering a KRAS G12C inhibitor to the patient. 74. The method of embodiment 73, wherein the KRAS G12C inhibitor is sotorasib. 75. The method of embodiment 73, wherein the KRAS G12C inhibitor is adagrasib. 76. A method according to any one of embodiments 68 - 70, wherein one other systemic therapy does not comprise a therapy comprising administering irinotecan. 77. A method according to any one of embodiments 68 - 76, wherein the patient has an ECOG performance status of 1 or less. 78. A method according to any one of embodiments 68 - 77, wherein the patient does not have active brain metastases. 79. Any one of embodiments 68 to 78, wherein the patient does not have a leptomeningeal disease. 80. A method according to any one of embodiments 68 to 79, wherein the mCRC does not contain the BRAF V600E mutation. 81. Any one of embodiments 68 to 80, wherein the patient does not have dihydropyrimidine dehydrogenase deficiency. 82. Any one of embodiments 68 to 81, wherein the patient does not have UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease. 83. Any one of embodiments 68 to 82, wherein the patient does not have hepatitis B or hepatitis C infection. 84. Any one of embodiments 68 to 83, wherein the patient does not have New York Heart Association class II or higher heart disease, myocardial infarction less than 6 months prior to treatment, unstable arrhythmia, or unstable angina. 85. Any one of Embodiments 1 to 84, wherein the patient exhibits at least stable disease (SD) 1, 3, or 6 months after sotrasib and panitumumab therapy, as measured by the RECIST 1.1 protocol. 86. Any one of Embodiments 1 to 85, wherein the patient exhibits at least a partial response (PR) 1, 3, or 6 months after sotracib and panitumumab therapy, as measured by the RECIST 1.1 protocol. 87. Any one of Embodiments 1 to 86, wherein the patient exhibits progression-free survival (PFS) of at least 3 months. 88. Any one of Embodiments 1 to 87, wherein the patient requires further treatment with antacids. 89. The method of Embodiment 88, wherein the antacid is a proton pump inhibitor (PPI), an H2 receptor antagonist (H2RA), or a topical antacid. 90. The method of Embodiment 88 or Embodiment 89, wherein the antacid is a topical antacid, and sotrasib is administered about 4 hours before or about 10 hours after the topical antacid. 91. The method of Embodiment 89 or Embodiment 90, wherein the topical antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide. 92. Any one of embodiments 1 to 91, wherein the patient requires further 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 sotracib. 94. A method according to any one of Embodiments 89, 92, or 93, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. 95. A method according to any one of Embodiments 89, 92, or 93, wherein H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine. 96. Any one of Embodiments 1 to 95, wherein the patient requires further treatment with a CYP3A4 inducer. 97. The method of Embodiment 96, wherein the patient is not administered a CYP3A4 inducer in combination with sotrasib. 98. The method of Embodiment 96 or 97, wherein the CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolyx, enzalutamide, eslicarbazepine, glucocorticoid, letermovir, lorlatinib, modafinil, nevirapine, oritabancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, terotristat, or troglitazone. 99. The method of Embodiment 96 or Embodiment 97, wherein the patient is not administered a potent CYP3A4 inducer in combination with sotrasib. 100. The method of Embodiment 99, wherein the potent CYP3A4 inducer is phenytoin or rifampin. 101. Any one of Embodiments 1 to 100, wherein the patient requires further treatment with a CYP3A4 substrate. 102. The method of Embodiment 101, wherein the patient is not administered a CYP3A4 substrate in combination with sotracib. 103. 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, caliprazine, 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, isabconazonium, ivabradine, ivacaftol, lansoprazole, lenvatinib, relcanidipine, 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, lorapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus,The method of Embodiment 101 or 102, wherein the drug is sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus (FK506), tamoxifen, tasimerteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, bilazodone, vincristine, borapaxar, voriconazole, zarepron, or ziprasidone. 104. Any one of Embodiments 1 to 103, wherein the patient requires further 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 sotracib. 106. The method of Embodiment 104 or Embodiment 105, wherein the P-gp substrate is etexilate, digoxin, or fexofenadine. 107. Any one of Embodiments 1 to 106, wherein cancer exhibits a PD-L1 tumor ratio score (TPS) of 1-49%. 108. Any one of Embodiments 1 to 107, wherein cancer exhibits a PD-L1 tumor ratio score (TPS) of less than 1%. 109. Any one of Embodiments 1 to 108, wherein cancer exhibits a PD-L1 tumor ratio score (TPS) of 50–100%. 110. A method by which cancer further includes an STK11 mutation, any one of Embodiments 1 to 109. 111. A method of cancer further comprising a KEAP1 mutation, any one of Embodiments 1 to 110. 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 cancer containing a KRAS G12C mutation in a patient, comprising administering to the patient an effective amount of (a) sotrasib and (b) an anti-epidermal growth factor receptor (EGFR) antibody for treating the cancer. 2. The method of embodiment 1, comprising administering 960 mg of sotrasib to a patient daily. 3. The method of embodiment 1, comprising administering 240 mg of sotrasib to a patient daily. 4. The method of any one of embodiments 1 to 3, comprising administering sotrasib to a patient once a day. 5. The method of any one of embodiments 1 to 3, comprising administering sotrasib to a patient twice a day. 6. The method of any one of embodiments 1 to 5, wherein the anti-EGFR antibody is panitumumab. 7. The method of embodiment 6, comprising administering 6 mg / kg of panitumumab to a patient. 8. (a) 960 mg of sotrasib daily; and (b) 6 mg / kg of panitumumab by IV administration every two weeks The method of embodiment 6 or embodiment 7, comprising administering to a patient. 9. (a) 240 mg of sotrasib daily; and (b) 6 mg / kg of panitumumab by IV administration every two weeks The method of embodiment 6 or embodiment 7, comprising administering to a patient. 10. The method of any one of embodiments 1 to 13, further comprising administering to a patient (c) irinotecan, (d) 5-FU, and (e) leucovorin or levoleucovorin. 11. The method of embodiment 10, comprising administering 400 mg / m 2 of leucovorin to a patient by IV administration. 12. The method of embodiment 10, comprising administering 200 mg / m 2 of levoleucovorin to a patient by IV administration. 13. The method of any one of embodiments 10 to 12, comprising administering 180 mg / m 2 of irinotecan to a patient by IV administration. 14. The method of any one of embodiments 10 to 13, comprising administering 400 mg / m 2 of 5-FU to a patient by IV administration. 15. By IV administration, 180 mg / m 2Irinotecan, 400 mg / m² 2 Leucovorin, and 400 mg / m² 2 Administer 5-FU to the patient as an IV bolus every two weeks, and 2400 mg / m² 2 The method of Embodiment 10, comprising administering 5-FU to the patient by continuous intravenous infusion over 46 to 48 hours. 16. IV administration resulted in 180 mg / m² 2 Irinotecan, 200 mg / m² 2 Levoleucovorin, and 400 mg / m² 2 IV bolus of 5-FU and 2400 mg / m² 2 The method of Embodiment 10, comprising administering a continuous intravenous infusion of 5-FU over 46-48 hours to the patient every two weeks. 17. Any one of Embodiments 1 to 16, wherein the cancer is a solid tumor. 18. Any one of Embodiments 1 to 17, wherein the cancer is non-small cell lung cancer (NSCLC). 19. Any one of Embodiments 1 to 17, wherein the cancer is metastatic pancreatic cancer. 20. Any one of Embodiments 1 to 17, wherein the cancer is colorectal cancer. 21. Any one of Embodiments 1 to 17, wherein the cancer is metastatic colorectal cancer (mCRC). 22. Any one of Embodiments 1 to 36, wherein the patient has received at least one prior systemic cancer therapy. 23. Any one of Embodiments 1 to 36, wherein the patient has received at least two prior systemic cancer therapies. 24. The method of Embodiments 22 and 23, wherein the systemic cancer therapy comprises administering fluoropyrimidine, irinotecan, and oxaliplatin to the patient. 25. 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 a checkpoint inhibitor to the patient. 26. Any one of Embodiments 21 to 25, wherein the mCRC contains the BRAF V600E mutation, and the systemic cancer therapy comprises administering encorafenib and cetuximab to the patient. 27. Any one of embodiments 21 to 26, wherein the patient exhibits an ECOG performance status of 2 or less. 28. Any one of embodiments 21 to 27, wherein the patient does not have active brain metastases. 29. Systemic therapy is KRAS G12C Any one of embodiments 22 to 28, which is not a therapy involving the administration of an inhibitor to a patient. 30. Any one of Embodiments 1 to 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. A method according to either Embodiment 30 or Embodiment 31, wherein the mCRC does not contain the BRAF V600E mutation. 33. Any one of embodiments 30 to 32, wherein mCRC is determined not to be MSI-H. 34. Systemic therapy is KRAS G12C A method of any one of embodiments 30 to 33, which is a therapy comprising administering an inhibitor to a patient. 35. Any one of embodiments 30 to 34, wherein a patient exhibits an ECOG performance status of 1 or less. 36. One of Embodiments 1 to 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 is undergoing systemic cancer therapy and the disease progresses during or after such therapy. 39. Systemic therapy is KRAS G12C Any one of embodiments 36 to 38, which is not a therapy involving the administration of an inhibitor to a patient. 40. Any one of embodiments 36 to 38, wherein the systemic therapy does not involve the administration of irinotecan. 41. Any one of embodiments 36 to 40, wherein a patient exhibits an ECOG performance status of 1 or less. 42. Any one of embodiments 36 to 41, wherein the patient does not have active brain metastases. 43. Any one of embodiments 36 to 42, wherein the mCRC does not contain the BRAF V600E mutation. 44. Any one of Embodiments 1 to 43, wherein the patient exhibits at least stable disease (SD) 1, 3, or 6 months after sotracib and panitumumab therapy, as measured by the RECIST 1.1 protocol. 45. Any one of Embodiments 1 to 43, wherein the patient exhibits at least a partial response (PR) 1, 3, or 6 months after sotrasib and panitumumab therapy, as measured by the RECIST 1.1 protocol. 46. ​​Any one of Embodiments 1 to 45, wherein the patient requires further treatment with antacids. 47. The method of Embodiment 46, wherein the antacid is a proton pump inhibitor (PPI), an H2 receptor antagonist (H2RA), or a topical antacid. 48. The method of Embodiment 46 or Embodiment 47, wherein the antacid is a topical antacid, and sotrasib is administered about 4 hours before or about 10 hours after the topical antacid. 49. Any one of Embodiments 1 to 48, wherein the patient requires further 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 sotracib. [Examples]

[0108] The term “subject” is used interchangeably with “patient” throughout the examples, for treatment by one or more of the methods described herein.

[0109] Example 1 - Sotracib in combination with panitumumab and, optionally, FOLFIRI. While we do not wish to be bound by any particular theory, the following points are noteworthy: Sotrasib 960 mg QD was shown to be safe and effective under trial conditions in trial 20170543 (https: / / clinicaltrials.gov / ct2 / show / NCT03600883;CodeBreaK100). Since resistance to sotrasib may be mediated by upregulation of signaling via the epidermal growth factor receptor (EGFR) pathway, adding an EGFR inhibitor to sotrasib therapy may block bypass activation of mitogen-activated kinase (MAPK) signaling, leading to improved antitumor activity. FOLFIRI has been successfully used in combination with panitumumab in a phase 3 trial for metastatic colorectal cancer and is therefore a choice as a chemotherapy backbone (Peeters et al, 2010). Therefore, in this study, trial 20190135 (https: / / clinicaltrials.gov / ct2 / show / NCT04185883;CodeBreaK 101), subprotocol H will investigate sotracib in combination with panitumumab (EGFR-targeted monoclonal antibody) and, optionally, folfiri.

[0110] Overall design: A multicenter, open-label trial will be established to evaluate the safety, tolerability, pharmacokinetics (PK), disease progression (PD), and efficacy of sotrasib in combination with panitumumab (or panitumumab + folfiri) in patients with KRAS G12C mutation-associated chronic renal cell carcinoma (CRC), non-steroidal cell carcinoma (NSCLC), and advanced solid tumors.

[0111] On the day the PK sample is collected in Cycle 1, and after dose retention of sotrasib, treatment is administered in the following order: sotrasib, panitumumab, and FOLFIRI, if applicable. Sotrasib is administered orally once daily (QD). Alternatively, twice-daily administration may be used, but the total daily dose will be the same. Panitumumab 6 mg / kg is administered every two weeks (Q2W) as an intravenous (IV) infusion over 60 minutes (≤1000 mg) or 90 minutes (>1000 mg). FOLFIRI is administered 180 mg / m² by IV infusion on day 1. 2Irinotecan and 400 mg / m² 2 Racemic leucovorin, and 400 mg / m² of 5-fluorouracil (5-FU) on day 1. 2 An IV bolus, followed by 2400 mg / m² over 46-48 hours starting on day 1 of Q2W. 2 It consists of a continuous infusion of 200 mg / m² instead of racemic leucovorin. 2 Levoleucovorin may be used.

[0112] The first dose of panitumumab is administered 2 hours after sotrasib administration. Subsequent doses of panitumumab may be administered immediately after sotrasib administration. In Part 1 Cohort B, FOLFIRI is administered after panitumumab.

[0113] This trial 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 sotrasib with panitumumab. The dose of sotrasib will begin with a total daily dose of 960 mg. If necessary, two dose levels lower for sotrasib and one dose level lower for panitumumab may be considered. Part 1 Cohort B will consist of dose-finding for sotrasib, panitumumab, and FOLFIRI, and will begin when the recommended phase 2 doses (RP2D) for sotrasib and panitumumab are defined in Part 1 Cohort A. Part 2, consisting of eight distinct cohorts, begins when the dose of sotracib and panitumumab combination is defined in Part 1 Cohort A, except for certain cohorts, which begin when the dose of sotracib combined with panitumumab + FOLFIRI is defined in Part 1 Cohort B. The eight cohorts of Part 2 (i.e., Cohorts A-H) are as follows:

[0114] Sotrasib + Panitumumab dose expansion cohort Cohort A: Fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenic agent, and in the case of high-frequency microsatellite instability (MSI-H), checkpoint inhibitor (CPI) if approved in that region, previously treated, KRAS G12C Inhibitor-naive KRAS G12C mutant metastatic colorectal cancer (n = up to 40).

[0115] Cohort B: Any KRAS G12C Inhibitor-resistant KRAS G12C mutant solid tumors (n = up to 20).

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

[0117] Cohort D: Previously treated with one prior line of therapy for metastatic disease, KRAS G12C Inhibitor-naive KRAS G12C mutant metastatic colorectal cancer (n = up to 20). The initiation of this cohort is dependent on the activity of this combination in other cohorts of this trial and the combination data of new sotorasib.

[0118] Cohort E: (Twice-daily [BID] cohort): Fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenic agent, and in the case of MSI-H, CPI if approved in that region, previously treated, KRAS G12C Inhibitor-naive KRAS G12C mutant metastatic colorectal cancer (n = up to 40). The initiation of this cohort is dependent on the activity of sotorasib and panitumumab in other cohorts of this trial and the monotherapy and combination data of new sotorasib.

[0119] Cohort H: Having received at least one previous therapy for metastatic disease or refusing or ineligible for standard chemotherapy, KRAS G12C Inhibitor-naive KRAS G12C mutant pancreatic cancer (n = up to 40).

[0120] Sotrasib + Panitumumab + FOLFIRI dose expansion cohort Cohort F: Patients with metastatic disease who have not received prior therapy, KRAS G12C Inhibitor-naive patients with KRAS G12C mutations in metastatic colorectal cancer (n=up to 40).

[0121] Cohort G: KRAS patients who have received at least one prior therapy for metastatic disease. G12C Inhibitor-naive KRAS G12C mutation metastatic colorectal cancer.

[0122] To continue enrollment in each cohort, at least two responses must be observed in the first 20 subjects of cohorts A, C, E, F, G, or H in Part 2. Part 2 will confirm the safety of sotrasib in combination with panitumumab, and sotrasib in combination with panitumumab and FOLFIRI, and evaluate their preliminary antitumor activity.

[0123] Overall, approximately 310 participants will be enrolled in the exam for both Part 1 and Part 2.

[0124] Part 1: Dosage Discovery The primary objective of Part 1 is to evaluate the safety and tolerability of sotrasib in combination with panitumumab, and sotrasib in combination with panitumumab plus folfiri. Therefore, the primary endpoints include the evaluation of dose-limiting toxicity, adverse events occurring during treatment, and treatment-related adverse events.

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

[0126] Part 1, Cohort B Dose Level 1: On day 1 of Q2W, the total daily oral dose of sotrasib identified from Part 1 Cohort A + 6 mg / kg of panitumumab IV (or 3 mg / kg if it is the dose identified from Part 1 Cohort A) ± 180 mg / m² of irinotecan on day 1. 2 Leucovorin 400 mg / m² on day 1 2 , and 5-FU 400 mg / m² on day 1 2 IV bolus and 2400 mg / m² administered over 46-48 hours starting on day 1 of Q2W. 2 Continuous intravenous infusion (IVCI). In clinical trial sites using levoleucovorin instead of racemic leucovorin, the dose of levoleucovorin is 200 mg / m². 2 It will become.

[0127] Dose Level -1: On day 1 of Q2W, the total daily oral dose of sotrasib identified from Part 1 Cohort A + 6 mg / kg of panitumumab IV (or 3 mg / kg if it is the dose identified from Part 1 Cohort A) ± 180 mg / m² of irinotecan on day 1. 2 , and 5FU 2400 mg / m² administered from day 1 of Q2W for 46-48 hours. 2 Continuous intravenous infusion (IVCI).

[0128] Dose Level -2: On day 1 of Q2W, the total daily oral dose of sotrasib identified from Part 1 Cohort A + 6 mg / kg of panitumumab IV (or 3 mg / kg if it is the dose identified from Part 1 Cohort A) ± 150 mg / m² of irinotecan on day 1. 2 , and 5-fluorouracil 2400 mg / m² administered from day 1 of Q2W for 46-48 hours. 2 Continuous intravenous infusion (IVCI).

[0129] Part 2 - Dose expansion of sotrasib + panitumumab (and + FOLFIRI, cohorts F and G only) The main objective of Part 2 is to provide information to those who have previously received chemotherapy and anti-angiogenic therapy, and in the case of MSI-H, have received CPI if approved in their region, and are KRAS G12C Inhibitor-naive KRAS G12C-mutated metastatic CRC (Cohorts A and E); previously exposed to KRAS G12C inhibitors and with advanced KRAS G12C-mutated progressive solid tumors (Cohort B); KRAS-mutated patients who have received at least one systemic therapy. G12C KRAS G12C mutation NSCLC (Cohort C) naive to inhibitors; and metastatic disease receiving one or fewer prior line therapies, KRAS G12C KRAS G12C mutation metastatic CRC (Cohort D) that is naive to inhibitors; and KRAS that has received at least one prior treatment for progressive disease, or has refused or is ineligible for standard chemotherapy. G12C The objective is to evaluate the safety and preliminary antitumor activity of sotrasib in combination with panitumumab in inhibitor-naive KRAS G12C-mutated metastatic pancreatic cancer (Cohort H). Sotrasib in combination with panitumumab and folfiri will be evaluated in KRAS patients who have not received prior therapy for metastatic disease (Cohort F) and those who have received at least one prior therapy for metastatic disease (Cohort G). G12C It is also evaluated in KRAS G12C mutation-associated transmissible carcinomas (CRCs) that are naive to inhibitors.

[0130] Objective response rate (ORR), as measured by RECIST 1.1, provides primary evidence of antitumor activity and is included as a secondary endpoint for this portion of the trial. Other relevant efficacy measures, including progression-free survival (PFS), duration of response, disease control rate, and time to response, provide additional supporting evidence of antitumor activity and are included as secondary endpoints.

[0131] Cohort A: Fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenic agent, and in the case of MSI-H, if approved in that region, by CPI, previously treated, KRAS G12C Inhibitor-naive KRAS G12C mutant metastatic colorectal cancer: On day 1 Q2W, oral total daily dose of sotorasib specified from Part 1 Cohort A of this trial + 6 mg / kg (or 3 mg / kg if the dose specified in Part 1 Cohort A) of panitumumab IV.

[0132] Cohort B: Any KRAS G12C Inhibitor-resistant KRAS G12C mutant solid tumors: On day 1 Q2W, oral total daily dose of sotorasib specified from Part 1 Cohort A of this trial + 6 mg / kg (or 3 mg / kg if the dose specified in Part 1 Cohort A) of panitumumab IV.

[0133] Cohort C: Previously treated with at least one prior line of systemic therapy, KRAS G12C Inhibitor-naive KRAS G12C mutant NSCLC: On day 1 Q2W, oral total daily dose of sotorasib specified from Part 1 Cohort A of this trial + 6 mg / kg (or 3 mg / kg if the dose specified in Part 1 Cohort A) of panitumumab IV.

[0134] Cohort D: Receiving one or fewer prior lines of therapy for metastatic disease, KRAS G12C Inhibitor-naive KRAS G12C mutant metastatic CRC: On day 1 Q2W, oral total daily dose of sotorasib specified from Part 1 Cohort A of this trial + 6 mg / kg (or 3 mg / kg if the dose specified in Part 1 Cohort A) of panitumumab IV. The start of this cohort is subject to the activity of this combination in other cohorts of this trial and the combination data of new sotorasib.

[0135] Cohort E (BID Cohort): In subjects receiving sotracib on the BID dosing schedule, previously treated KRAS with fluoropyrimidines, oxaliplatin, irinotecan, and anti-angiogenic agents, and in the case of MSI-H, with CPI if approved in the region. G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer: On day 1 at Q2W, a total daily oral dose of sotrasib 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) of panitumumab IV. Initiation of this cohort depends on the activity of sotrasib and panitumumab in other cohorts of this study, as well as new sotrasib monotherapy and combination data.

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

[0137] Cohort F: Patients with metastatic disease who have not received prior therapy, KRAS G12C Inhibitor-naive KRAS G12C-mutated metastatic colorectal cancer: On day 1 of Q2W, panitumumab IV plus the FOLFIRI dose identified in Part 1 Cohort B, total daily oral dose of sotrasib identified in Part 1 Cohort B of this study, plus 6 mg / kg (or 3 mg / kg if the dose identified in Part 1 Cohort B).

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

[0139] The duration of this study for the subjects is approximately 3 years. The screening period is a maximum of 28 days. The planned treatment period for subjects is until disease progression or the occurrence of unacceptable toxicity. The treatment period for individual subjects is expected to be approximately 8 months, thereafter, a safety follow-up (SFU) visit will be conducted 30(+3) days after the last dose of the investigational product or therapies mandated by the protocol. Subjects will be followed up until analysis of progression-free survival (PFS) or 3 years after the enrollment of the last subject, whichever is later.

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

[0141] Part 1 Cohort A: - Metastatic colorectal cancer with a KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. In the United States, this testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) accredited laboratory. - Previously KRAS G12C If you have previously received treatment with an inhibitor, the target group is KRAS. G12CInhibitor dose reduction may be necessary, or KRAS G12C Patients must not be intolerant to the inhibitor. At least two subjects per dose level must have KRAS G12C It must be naive about inhibitors. - The subject must have previously received at least one treatment for a progressive disease.

[0142] Part 1 Cohort B: - Metastatic colorectal cancer with a KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. In the United States, this testing must be performed at a CLIA-accredited laboratory. - Previously KRAS G12C If you have previously received treatment with an inhibitor, the target group is KRAS. G12C Inhibitor dose reduction may be necessary, or KRAS G12C Patients must not be intolerant to the inhibitor. At least two subjects per dose level must have KRAS G12C It must be naive about inhibitors. - If the subject has previously received treatment with FOLFIRI, the subject should not require dose reduction of any component of the FOLFIRI regimen due to toxicity. - Participants must have previously received at least one treatment for a progressive disease.

[0143] Part 2 Cohort A: - Metastatic colorectal cancer with a KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. In the United States, this testing must be performed at a CLIA-accredited laboratory. - The target is KRAS G12C They may not be receiving treatment with inhibitors. - The subjects must have progressed after receiving fluoropyrimidines, oxaliplatin, irinotecan, and anti-angiogenic drugs. For patients with tumors known to be MSI-H, clinical CPI treatment is required if any of these drugs are approved for that indication in their region or country.

[0144] Part 2 Cohort B: - Metastatic, progressive solid tumors with the KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. In the United States, this testing must be performed at a CLIA-accredited laboratory. - The target is KRAS G12C Intolerance to the inhibitor is unacceptable. - If a subject has previously required dose reduction of sotrasib, and the principal investigator assesses that treatment may be beneficial and that the previous dose reduction was due to toxicity that, in the principal investigator's opinion, may not have been caused by sotrasib, the subject may be eligible with the approval of the medical monitor. - The target is KRAS G12C The disease must have progressed at the time of the last dose of the inhibitor or within two months thereafter. - The patient must have previously received at least one treatment for a progressive disease, and at least one of those previous treatments must have included KRAS. G12C It must contain an inhibitor.

[0145] Part 2 Cohort C: - Metastatic NSCLC with a KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. In the United States, this testing must be performed at a CLIA-accredited laboratory. - The target is KRAS G12C They may not be receiving treatment with inhibitors. - Participants must have previously received at least one treatment for a progressive disease.

[0146] Part 2 Cohort D: - Metastatic CRC with KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. In the United States, this testing must be performed at a CLIA-accredited laboratory. - The target is KRAS G12C They may not be receiving treatment with inhibitors. - Patients must have received only one previous treatment regimen for metastatic disease.

[0147] Part 2 Cohort E (BID administration): - Metastatic colorectal cancer with a KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. - The target is KRAS G12C They may not be receiving treatment with inhibitors. The subjects must have progressed after receiving fluoropyrimidines, oxaliplatin, irinotecan, and anti-angiogenic drugs. For patients with tumors known to be MSI-H, prior anti-PD1 therapy is required if they are clinically eligible for anti-PD1 therapy and any of these drugs are approved for that indication in their region or country.

[0148] Part 2 Cohort H: - Metastatic pancreatic cancer with a KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. In the United States, this testing must be performed at a CLIA-accredited laboratory. - The target is KRAS G12C They may not be receiving treatment with inhibitors. - Patients must have previously received at least one treatment for metastatic disease, or must have refused standard chemotherapy, or standard chemotherapy is contraindicated. - If the patient's condition progresses within six months of completing neoadjuvant or adjuvant therapy, neoadjuvant or adjuvant therapy is counted as a line of treatment for metastatic disease.

[0149] Part 2 Cohort F: - Metastatic CRC with KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. - The target is KRAS G12C They may not be receiving treatment with inhibitors. - The subjects may not have previously received systemic therapy for metastatic disease.

[0150] Part 2 Cohort G: - Metastatic CRC with KRAS G12C mutation, identified by pathologically confirmed molecular testing performed in accordance with national requirements. - The target is KRAS G12C They may not be receiving treatment with inhibitors. - Patients must have previously received at least one systemic therapy for metastatic disease.

[0151] Participants must be willing to undergo pre-treatment and intra-treatment tumor biopsies, if clinically feasible. If a pre-treatment tumor biopsy is not medically feasible, or if the sample does not contain sufficient tissue for examination, participants must be willing to provide a stored tumor tissue sample (formalin-fixed paraffin-embedded [FFPE] sample) recovered within the past five years, if available. Participants with a previously molecularly confirmed KRAS G12C mutation who do not have available stored tissue may be admitted without undergoing a tumor biopsy, based on informed consent from the principal investigator and medical monitor, if a tumor biopsy is not clinically feasible.

[0152] Diseases measurable according to the criteria of the Solid Tumor Efficacy Assessment Criteria Version 1.1 (RECIST v1.1).

[0153] An East Coast Cancer Clinical Trials Group (ECOG) performance status of ≤2.

[0154] The principal investigator's opinion is that the patient has a life expectancy of >3 months.

[0155] You are able to take oral medication and are willing to record your daily adherence to the investigational product.

[0156] A corrected QT interval (QTc) of 470 milliseconds or less for women and 450 milliseconds or less for men (based on the average of three electrocardiogram screenings).

[0157] The subject has sufficient blood, kidney, and liver function and coagulation. Appropriate hematological clinical laboratory evaluations are as follows: - Absolute Neutrophil Count (ANC) ≥ 1.5 × 10 9 / L - Platelet count ≥ 100 × 10 9 / L -Hemoglobin ≥ 9 × g / dL

[0158] Appropriate renal clinical laboratory assessments should include measured creatinine clearance or estimated glomerular filtration rate (FIV) based on dietary modification disease (MDRD) calculations ≥ 60 mL / min / 1.73 m². 2 It includes.

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

[0160] Appropriate clinical coagulation test evaluations are as follows: - Prothrombin time (PT) or activated partial thromboplastin time (PTT) or activated PTT < 1.5 × ULN, or international normalized ratio (INR) < 1.5 × ULN, or within the target range if receiving prophylactic anticoagulation therapy.

[0161] Exclusion criteria: Disease-related Primary brain tumor. Carcinomatous meningitis from active brain metastases and / or non-brain tumors. The term “active brain metastases,” as used herein, refers to cancer that has spread from the original (primary, non-brain) tumor to the brain. Active brain metastases can be assessed by the presence of intracranial lesions. While “metastases” is plural, it should be understood that a patient exhibiting only one intracranial lesion under the following criteria is considered to have “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 brain metastases or has completed radiotherapy at least four weeks prior to day 1 of the trial, the patient is not considered to have active brain metastases and is eligible if all of the following criteria are met: a) residual neurological symptoms of grade ≤ 2; b) administration of a stable dose of dexamethasone, if applicable; and c) no new lesions appearing on follow-up MRI performed within 30 days. For the determination of the grade of any neurological symptoms resulting from 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 whole.

[0162] Other medical conditions Unless there is no evidence of disease for more than two years and the patient has been cured by treatment, the patient has a history of or is currently suffering from a hematological malignancy.

[0163] History of other malignancies within the past two years, with the following exceptions: - Malignant tumors treated with the aim of cure, with no active disease observed for more than two years prior to registration, and considered by the attending physician to have a low risk of recurrence; - Well-treated non-melanoma skin cancer or malignant lentigo without evidence of disease; - Well-treated in vitro cervical cancer with no evidence of disease; - Well-treated in vivo ductal carcinoma with no evidence of disease; - Intraepithelial neoplasia of the prostate without evidence of prostate cancer; - Well-treated urothelial papillary non-invasive carcinoma or in-vivo carcinoma.

[0164] On day 1 of the trial, the following conditions must be met: myocardial infarction within the past six months, symptomatic congestive heart failure (New York Heart Association Class II), unstable angina, or cardiac arrhythmias requiring medication.

[0165] Gastrointestinal (GI) tract disorders that make oral medication impossible, malabsorption syndromes, the need for IV nutritional support, and uncontrolled inflammatory GI diseases (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); - Positive for hepatitis B core antibodies; negative for HepBsAg; - Positive for hepatitis C virus antibody: Hepatitis C virus RNA detection by polymerase chain reaction (PCR) is required. The detection of hepatitis C virus RNA suggests chronic hepatitis C.

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

[0168] A history of interstitial pneumonia or pulmonary fibrosis, or evidence of interstitial pneumonia or pulmonary fibrosis.

[0169] Aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) cannot be interrupted for any period other than 5 days (8 days for long-acting drugs such as piroxicam) with an aspirin dose of 1.3 g or less per day.

[0170] The patient has an active infection requiring systemic therapy.

[0171] Pre-treatment / Combination 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 drugs other than sotrasib within 28 days of day 1 of the study; targeted small molecule inhibitors within 14 days of day 1 of the study, unless at least five half-lives have elapsed. In Part 2 Cohort B, there is no minimum time requirement since the last sotrasib administration, as long as all sotrasib-related toxicities have recovered to grade 1 or lower.

[0172] Therapeutic or symptomatic radiotherapy within two weeks of day 1 of the trial. Participants must have recovered from all radiotherapy-related toxicity of Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1 or lower.

[0173] Radiotherapy to the lungs exceeding 30 Gy within 6 months of the first dose of the clinical trial treatment.

[0174] Cumulative radiation received by more than 25% of the bone marrow in Part 1 Cohort B, Part 2 Cohort F, and Cohort G.

[0175] Known dihydropyrimidine dehydrogenase deficiencies in Part 1 Cohort B, Part 2 Cohort F, and Cohort G

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

[0177] Use of a known cytochrome P450 (CYP)3A4-sensitive substrate and P-gp substrate (e.g., with a narrow therapeutic range) within 14 days prior to the initiation of therapy, or within 5 half-lives of a CYP3A4 or P-glycoprotein (P-gp) substrate or its major active metabolite, whichever is longer. CYP3A4 sensitive substrates include abemaciclib, buspirone, isabconazole, ridafololimus, ABT-384, caplavillin, itacitinib, saquinavir, acalabrutinib, casopitant, ivabradine, sildenafil, alfentanil, cobimetinib, ibaftol, simeprevir, arisporivir, conivaptan, L-771, 688, simvastatin, almorexant, danoprevir, levometadil (LAAM), sirolimus, alpha-dihydroergocriptine, dalifenacin, lomitapide, tacrolimus, aplaviloc, darunavir, lopinavir, terfenadine, aprepitant, dasatinib, lovastatin, ticagrelor, asunaprevir, doronedarone, lumefantrine. This includes tyridine, atazanavir, ebastine, lurasidone, tipranavir, atorvastatin, eletriptan, maraviroc, tolvaptan, avanafil, eliglustat (in patients with CYP2D6 dysmetabolism (PM)), midazolam, triazolam, AZD1305, elvitegravir, midostaurin, ulipristal, BIRL355, entrectinib, naloxegol, vardenafil, blonanserin, eplerenone, neratinib, venetoclax, bosutinib, everolimus, nisoldipine, bicriviroc, blekanavir, felodipine, paritaprevir, viraprisan, brotizolam, ibrutinib, perospirone, voclosporine, budesonide, indinavir, and quetiapine. P-gp substrates with a narrow therapeutic range include digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, and vincristine. P450 (CYP)3A4-sensitive substrates with a narrow therapeutic range include alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanil, pimozide, quinidine, tacrolimus, and sirolimus.

[0178] Use of potent CYP3A4 inducers (including herbal nutritional supplements such as St. John's wort) within 14 days prior to the start of therapy or within 5 half-lives (whichever is longer). Potent inducers of CYP3A4 include ombitasvir and paritaprevir and ritonavir and dasabuvir, indinavir and ritonavir, tipranavir and ritonavir, ritonavir, cobicistat, ketoconazole, troleandmycin, telaprevir, danoprevir and ritonavir, elvitegravir and ritonavir, saquinavir and ritonavir, lopinavir and ritonavir, itraconazole, indinavir, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, ronafarnib, posaconazole, telithromycin, grapefruit juice DS3, conivaptan, tucatinib, nefazodone, ceritinib, nelfinavir, saquinavir, ribociclib, idelalisib, and boceprevir.

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

[0180] Unrecovered toxicity resulting from previous antitumor therapy, defined as Grade 0 or 1 of the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, or not having recovered to the level indicated in the eligibility criteria other than alopecia (or any grade is acceptable). Grade 2 or 3 toxicity resulting from previous antitumor therapy that is considered irreversible [defined as having been present for more than 6 months and being stable], such as oxaliplatin-induced neuropathy, may be acceptable if they are not listed in the exclusion criteria and consent has been obtained from both the principal investigator and the sponsor.

[0181] Those affected cannot undergo either iodine contrast agent for CT scans or gadolinium contrast agent for MRI scans.

[0182] Experience in pre- / combination clinical trials Currently, if you are receiving treatment in another investigational device or drug trial, or if it has been less than 28 days since your last intervention in another investigational device or drug trial, except in the sotrasib trial, there is no minimum time requirement since your last sotrasib dose, as long as all sotrasib-related toxicity has recovered to grade 1 or lower. Other trial procedures during participation in this trial are excluded.

[0183] Other exclusions The subject had a known susceptibility to any of the products or components that would be administered during the treatment.

[0184] The subjects had previously required dose reduction or dose postponement of panitumumab due to toxicity.

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

[0186] The subject may be unable to complete all trial visits or procedures required in the clinical trial protocol, and / or may be unable to follow all necessary trial procedures (e.g., clinical outcome evaluation) to the best of the subject's and the principal investigator's knowledge.

[0187] A history or evidence of any other clinically significant impairment, condition, or disease (other than those outlined above) that would raise a risk to the safety of the subject or would interfere with the evaluation, procedure, or completion of the study.

[0188] This program is for women who may be pregnant and whose pregnancy test is positive, as assessed by screening using serum and / or urine pregnancy tests.

[0189] Female subjects who are pregnant or breastfeeding, or planning to become pregnant or breastfeed, during treatment and for 7 days after the last dose of sotrasib.

[0190] The study includes women who are pregnant, lactating, or planning to become pregnant or lactate during treatment and for two months after the last dose of panitumumab.

[0191] Female subjects who are pregnant, lactating, or planning to become pregnant or lactate during treatment and for six months after the last dose of FOLFIRI.

[0192] This medication is intended for women of potential pregnancy who do not wish to use one highly effective method of contraception during treatment and for 7 days after the last dose of sotrasib.

[0193] This is for women of potential pregnancy who do not wish to use one highly effective method of contraception during treatment and for two months after the last dose of panitumumab.

[0194] This medication is intended for women of potential pregnancy who do not wish to use one highly effective method of contraception during treatment and for six months after the last dose of FOLFIRI.

[0195] This treatment is for men who practice sexual abstinence (refraining from heterosexual intercourse) during treatment and for 7 days after the last dose of sotrasib, or who have a female partner who does not wish to use contraception and may become pregnant.

[0196] This treatment is for men with a pregnant partner who do not wish to abstain from sex or use condoms during treatment and for 7 days after the last dose of sotrasib.

[0197] This study is for men who do not wish to refrain from sperm donation during the trial and for 7 days after the last dose of sotrasib.

[0198] This treatment is for men who practice sexual abstinence (refraining from heterosexual intercourse) during treatment and for six months after the last dose of FOLFIRI, or who have a female partner who does not wish to use contraception and may become pregnant.

[0199] This applies to men who are undergoing treatment and, for six months after the last dose of FOLFIRI, have a pregnant partner or a partner who does not wish to abstain from sex or use condoms.

[0200] This study is for men who do not wish to refrain from sperm donation during the trial and for six months after their last dose of FOLFIRI.

[0201] Objectives and evaluation items

[0202] [Table 6]

[0203] FOLFIRI regimen premedication and supportive medications Prior to FOLFIRI administration, all patients should be given an antiemetic (e.g., oral or IV dexamethasone, 5-hydroxyiptamine 3[5-HT3] receptor antagonist). Antiemetic administration should be started at least 30 minutes before irinotecan administration on the day of treatment. Alternative and additional antiemetics may be used at the discretion of the principal investigator or in accordance with standard site or local practice, where clinically necessary. Prophylactic or therapeutic IV or subcutaneous atropine for cholinergic symptoms may be used at the discretion of the principal investigator or in accordance with standard site or local practice.

[0204] Growth factor support may be used at the discretion of the principal investigator or in accordance with standard site or local practice.

[0205] Medications for managing diarrhea should be used at the discretion of the principal investigator or in accordance with standard facility or local practice.

[0206] Treatments, medical devices, and / or procedures excluded during the trial period Antitumor therapies such as chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, or hormone therapy (excluding those with breast cancer receiving adjuvant therapy).

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

[0208] Unless otherwise approved by the principal investigator and medical monitor, known CYP3A4 and / or P-gp-sensitive substrates with a narrow therapeutic range.

[0209] Unless approved by the Principal Investigator and Medical Monitor, CYP3A4 and / or UGT1A1 inhibitors (Part 1 Cohort B, Part 2 Cohort F, and Cohort G only) are not permitted. - Other investigational drugs Other anti-EGFR targeting drugs besides panitumumab.

[0210] If a participant requires palliative radiotherapy or surgery for pain management during the study period, administration of all investigational drugs should be withheld. The participant may be permitted to resume administration of the investigational drug after consultation with the principal investigator and medical monitor.

[0211] Dose-limiting toxicity: The dose-limiting toxicity (DLT) frame (i.e., DLT evaluable period) is the first 28 days of sotrasib and panitumumab treatment (start of cycle 1, day 1). AE grading is performed based on the guidelines provided in CTCAE version 5.0. A subject is DLT evaluable if they complete the above DLT frame and receive 80% or more of the planned dose of sotrasib and panitumumab within the first 28 days, or if they experience a DLT at any point during the DLT frame. A DLT is defined as an adverse event occurring during the first treatment cycle, attributed to sotrasib and / or panitumumab, and meeting the following criteria.

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

[0213] If a subject experiences a DLT during the DLT evaluation period, the study treatment for that subject should be discontinued. However, if the principal investigator believes the subject is receiving a clinical benefit from the therapy, the therapy may be restarted, with consideration to dose reduction.

[0214] Guidelines for adjusting sotrasib dose for hematological and non-hematological toxicity

[0215] [Table 7]

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

[0217] The following table provides dose reduction levels for sotrasib for toxicity management in individual subjects.

[0218] [Table 8]

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

[0220] [Table 9]

[0221] Hepatotoxic reactions: Patients with abnormal liver clinical 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 completely discontinuing sotrasib.

[0222] The following discontinuation and / or suspension rules apply to subjects for whom another cause has been identified for the changes in liver biomarkers (TBL, INR, and transaminase). Other important causes of elevated AST / ALT and / or TBL levels include, but are not limited to, hepatobiliary diseases; viral hepatitis (e.g., hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); causes of hypoxia to the liver resulting in right heart failure, hypotension, or ischemia; exposure to hepatotoxic drugs / medicines or hepatotoxins, including herbs and nutritional supplements, plants, and mushrooms; genetic disorders that cause impaired glucuronidation (e.g., Gilbert's syndrome, Crigler-Nadjar 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 impaired liver tests (ALT, AST, ALP) and / or elevated TBL is found and / or if the abnormal clinical laboratory values ​​return to normal or baseline, reloading may be considered.

[0224] [Table 10]

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

[0226] [Table 11]

[0227] The following table provides exemplary guidelines for adjusting the dose of panitumumab due to skin toxicity.

[0228] [Table 12]

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

[0230] Because sunlight can worsen any skin reactions that may occur, it is recommended that patients wear sunscreen and hats and limit their exposure to sunlight while receiving panitumumab. Aggressive skin treatment, including skin moisturizers, sunscreen (SPF > 15 UVA and UVB), and topical steroid creams (1% hydrocortisone or less), may help manage skin toxicity. Patients may be advised to apply moisturizers 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 of 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 area, and / or oral antibiotics prescribed by a physician.

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

[0232] For toxicity other than skin or lung toxicity, if there is grade 3 or 4 panitumumab-related toxicity, the use of panitumumab should be withheld, with the following exceptions: - Panitumumab is reserved only for symptomatic grade 3 or 4 hypomagnesemia and / or hypocalcemia that persists despite aggressive magnesium and / or calcium supplementation. - Panitumumab is reserved only for grade 3 or 4 nausea, diarrhea, or vomiting that persists despite maximum supportive care.

[0233] In cases of toxicity other than cutaneous toxicity: If panitumumab is withheld, administration may be resumed when the adverse event improves to grade 1 or less, or when the adverse event returns to baseline.

[0234] Injection reaction: Infusion reactions may manifest as fever, chills, difficulty breathing, bronchospasm, hypotension, or anaphylaxis.

[0235] In patients experiencing a mild or moderate (grade 1 or 2) infusion reaction, the infusion rate should be reduced by 50% during the infusion period.

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

[0237] Dose reduction of FOLFIRI

[0238] [Table 13]

[0239] The doses of irinotecan, 5-fluorouracil, and leucovorin are calculated based on height and weight on day 1 of cycle 1 and should be recalculated using the current weight at each dose. If it is facility policy, the FOLFIRI dose does not need to be recalculated if the subject's weight change is less than 10%. The reason for any change in FOLFIRI dose is recorded in each subject's CRF.

[0240] FOLFIRI Dosage Adjustment Guidelines

[0241] [Table 14]

[0242] [Table 15]

[0243] Radiological imaging evaluation The severity of the disease is assessed by contrast-enhanced MRI / CT according to RECIST v1.1. The lowest possible dose should be used to reduce radiation exposure to the patient.

[0244] Screening scans must be performed within 28 days prior to enrollment and will be used as baseline scans. Imaging performed as part of standard treatment within the screening frame for scans may be used as baseline scans, provided they meet the screening scan requirements. All subsequent scans should be performed using the same contrast agent, preferably on the same scanner, and in the same manner as the screening scans. Radiologic evaluations must include chest CT, contrast-enhanced abdominal and pelvic CT or MRI, and evaluation of all other known sites of the disease, as detailed in the institutional imaging manual.

[0245] The same imaging modality, MRI field intensity, and IV and oral contrast agents used during 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 should be used in accordance with National Health Institute guidelines, or, where more stringent, local standards.

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

[0247] All NSCLC patients, patients with a history of brain metastases, and patients with signs and symptoms suggestive of brain metastases must have undergone a brain MRI performed within 28 days prior to the first dose of sotrasib. Thereafter, brain scans may be performed at any time as deemed necessary by the attending physician. All brain scans in the protocol must be MRI unless MRI is contraindicated, followed by contrast-enhanced CT, which is acceptable.

[0248] Radiographic evaluations at the end of the trial or during the end-of-treatment (EOT) visit should only be performed for patients whose treatment is discontinued for reasons other than disease progression, in accordance with the RECIST v1.1 guidelines.

[0249] The determination of disease response for clinical management of the target population is assessed at the clinical site in accordance with RECIST v1.1. Scans may be submitted to the center's core radiology laboratory for archiving and (if necessary) independent response assessment using RECIST v1.1 criteria. Exploratory radiological analyses are performed at the center and may include tumor volume measurement, viability measurement, tissue necrosis rate, and lesion histological analysis (radiomics).

[0250] Criteria for evaluating the effectiveness of solid tumor treatment, version 1.1 (RECIST 1.1) definition Measurable lesions Measurable tumor lesions are non-lymph node lesions with clearly defined boundaries that can be accurately measured in at least one dimension, and with a maximum diameter of ≥10 mm on 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.

[0251] Lymph node lesions – Lymph nodes are considered pathologically enlarged and measurable, and when evaluated by CT / MRI (scan slice thickness of 5 mm or less is recommended), they must be ≥15 mm in the short axis. At baseline and follow-up, only the short axis is measured and tracked. Node size is usually reported as two-dimensional in the axial plane. Of these measurements, the smaller one is the short axis (perpendicular to the long axis).

[0252] Radiation-treated lesions—tumor lesions located in areas previously irradiated or treated with other local therapies—are unmeasurable unless progression of the lesion has been demonstrated prior to registration.

[0253] Unmeasurable 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 unmeasurable and are characterized as non-target lesions.

[0254] Other examples of unmeasurable lesions include lesions with previous local treatment: tumor lesions located in areas previously irradiated or subjected to other local therapies should not be considered measurable unless progression of the lesion has been demonstrated; biopsied lesions; and, for classification purposes, clusters of small lesions, bone lesions, inflammatory breast disease, and leptomeningeal disease are untargetable.

[0255] Measurement method Lesion Measurement - The longest diameter of the selected lesion should be measured in the plane (axial plane) from which the image was acquired. All measurements should be taken and recorded in metric units. All baseline evaluations should be performed as close to the start of treatment as possible, and no later than four weeks before day 1 of the trial.

[0256] Evaluation Methods - The same evaluation methods and techniques should be used to characterize each identified and reported lesion throughout the clinical trial.

[0257] All lesions should be evaluated using CT / MRI-contrast-enhanced CT or MRI. Optimal visualization and measurement of metastases in solid tumors require consistent administration (dosage and rate) of IV contrast agent and timing of scans. CT and MRI should be performed on adjacent slices ≤5 mm thick.

[0258] Baseline evaluation of "targeted" and "non-targeted" lesions Target lesions—all measurable lesions, up to two per organ and a total of up to five lesions, representing all involved organs, should be identified, recorded, and measured as target lesions at baseline. -Target lesions should be selected based on their size (the lesion with the longest diameter) and their suitability for accurate repeated measurements. -Pathological lymph nodes (with a short axis of ≥15 mm) can be identified as target lesions. All other pathological lymph nodes (≥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, short axis for lymph node lesions) is calculated and reported as the baseline sum of diameters. The baseline sum of diameters is used as a criterion to characterize objective tumor response.

[0259] Non-target lesions—all other lesions (or sites of disease), including pathological lymph nodes, should be identified as non-target lesions and recorded at baseline. Measurement of these lesions is not required, and they should be tracked as “present,” “absent,” or “obvious progression” throughout the study. In addition, multiple non-target lesions involving the same organ can be recorded as a single item on the case report form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).

[0260] Criteria for determining effectiveness

[0261] [Table 16]

[0262] [Table 17]

[0263] Overall effectiveness evaluation The best overall response is the best response recorded from the start of the investigational treatment to the end of treatment or disease progression / relapse (the smallest measurement recorded since the start of treatment is taken as the criterion for PD).

[0264] Generally, the allocation of the best-efficacy target depends on findings in both the target and non-target diseases, and also takes into account the emergence of new lesions.

[0265] [Table 18]

[0266] [Table 19]

[0267] [Table 20]

[0268] Special notes regarding efficacy 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 during the examination. To qualify for CR, each lymph node must reach a short-axis of <10 mm, rather than complete disappearance. The short-axis measurement of the lymph node target lesion is added together with the longest diameter measurement of the target lesion to create the total diameter of the target lesion for a specific evaluation (time point).

[0269] Target lesions that are "too small to measure" - During the test, all lesions (lymph nodes and non-lymph nodes) recorded at baseline should have their measurements recorded at their respective subsequent evaluations. If the lesion is smaller than 5 mm, the accuracy of the measurement decreases. Therefore, lesions smaller than 5 mm are considered "too small to measure" and are not measured. By this designation, they are assigned to the default measurement of 5 mm. Unless the lesion has completely disappeared and "0" can be recorded for the measurement, lesion measurements smaller than 5 mm do not need to be recorded.

[0270] Novel Lesions - The term "novel lesion" always refers to the presence of a new finding that is clearly a tumor. Novel findings that could be tumorous but also be benign (such as infection or inflammation) are not selected as novel lesions until they are confirmed to be tumorous through review. For example, if a new lesion is uncertain due to its small size, continued therapy and follow-up evaluation will clarify whether it actually becomes a new disease. If repeated scans confirm the clear presence of a new lesion, the progression should be reported using the date of the initial scan. - Lesions identified in follow-up studies at anatomical locations not scanned at baseline are considered novel lesions and will indicate disease progression, regardless of any response observed in target or non-target lesions that were present from baseline.

[0271] At that point, any patient who has an overall deterioration in health that necessitates discontinuation of treatment without objective evidence of disease progression should be classified as having “worsening symptoms.” Even after discontinuation of treatment, every effort should be made to document objective progression through additional imaging assessments.

[0272] Under certain circumstances, it may be difficult to distinguish residual disease from scar or normal tissue. When the assessment of complete response (CR) depends on this decision, it is recommended to further investigate the residual lesion by fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET / computed tomography (PET / CT), or, if appropriate, by fine-needle aspiration / biopsy, to confirm the CR status.

[0273] Confirmation measurement / response period Confirmation of response - In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is necessary to ensure that the identified response is not the result of measurement error.

[0274] Overall response duration - Overall response duration is measured from the time the criteria for CR / PR were first met (first recorded) to the first day of objectively recorded relapse or progressive disease or death, whichever comes first.

[0275] The duration of stable disease (SD) is measured from the start of treatment until the criteria for disease progression are met, and is taken as the baseline of the lowest recorded measurement since the start of treatment or death, whichever comes first.

[0276] ECOG Performance and NYHA Classification

[0277] [Table 21]

[0278] Functional classification of the New York Heart Association Class I: No restrictions on physical activity. Normal physical activity does not cause excessive fatigue, palpitations, or shortness of breath. Class II: Mild limitation of physical activity. Comfortable at rest, but fatigue, palpitations, or shortness of breath occur with normal physical activity. Class III: Significant limitation of physical activity. While comfortable at rest, fatigue, palpitations, or shortness of breath occur with less activity than usual. Class IV: No physical activity can be performed without discomfort. Symptoms of heart failure may appear even at rest. Discomfort increases with any physical activity.

[0279] Preliminary results (data cut on April 23, 2021): Eight patients (five females, three males, median age: 60.5 years [range: 31–79 years]) were enrolled in dose exploration with sotrasib 960 mg QD and panitumumab 6 mg / kg IV Q2W. The median number of lines of therapy for metastatic disease was 3.5 (range: 1–10); five patients had previously received sotrasib treatment. The median duration of treatment (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 associated with sotrasib or panitumumab were reported in four and eight patients, respectively. No grade 4 or fatal TRAEs occurred. Two patients had panitumumab TRAEs that triggered a panitumumab dose change (one: acneiform dermatitis, one: dry skin, rash, hypokalemia, hypomagnesemia), and one patient had a sotrasib TRAE that triggered a sotrasib dose change (diarrhea). One patient showed a partial response, five had stable disease (SD), one had progressive disease (PD), and one had clinical PD but was not evaluated. Of the patients previously treated with sotrasib, four had a reduction in the total size of target lesions; four had SD, and one with PD developed new lesions despite a reduction in the size of target lesions. Sotrasib exposure was similar to that observed in monotherapy trials.

[0280] The results showed that the combination of sotrasib (960 mg QD) and panitumumab (6 mg / kg IV Q2W) was safe and well-tolerated, and demonstrated promising efficacy in severely prior-treatment patients with KRAS G12C mutations and CRC. Adverse events were consistent with known adverse events of sotrasib and panitumumab. See also Fakih et al., 2021 (Abstract #3245).

[0281] Additional preliminary results (data cut on August 6, 2021): Thirty-one patients (21 women, 10 men, median age 58 years, range 31–79 years) were enrolled in dose exploration with sotrasib 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 sotrasib therapy. The median duration of treatment at the 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%) (14 patients (45.2%) were related to sotrasib, and 23 patients (74.2%) were related to panitumumab). 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), and the panitumumab dose was changed; one patient experienced grade 3 acneiform dermatitis and myalgia (panitumumab-related), and the panitumumab dose was changed only for the acneiform dermatitis; one patient experienced grade 3 diarrhea (sotrasib-related), and the sotrasib dose was changed; and one patient experienced grade 3 cellulitis, peripheral edema, and acneiform dermatitis (panitumumab-related), but there was no change in the dose of either sotrasib or panitumumab. Of the TRAEs that resulted in dose changes, three patients (9.7%) presented with TRAEs (diarrhea, fatigue, and hypokalemia), leading to a change in the sotrasib dose; and two patients (6.5%) presented with TRAEs (acne-like dermatitis and dry skin / rash / hypokalemia / hypomasemia), resulting in a change in the panitumumab dose. Sotrasib in combination with panitumumab was well-tolerated and did not cause fatal TRAEs.

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

[0283] [Table 22]

[0284] Overall, 27% of patients (7 out of 26) achieved a response (including unconfirmed responses awaiting confirmation), and 81% of patients (21 out of 26) achieved disease control. In Part 1 Cohort A, 5 out of 8 patients undergoing dose exploration had previously received KRAS. G12C Despite receiving inhibitor therapy, the majority of patients (75%, 6 out of 8 patients) still experienced a reduction in target lesion size (-14.5% to -100.0%). G12C The majority of patients (80%, 4 out of 5 patients) exposed to the inhibitor showed the best response to stable disease. KRAS G12C Of the five patients receiving inhibitor therapy, four showed a reduction in target lesion size of 14.5% to 30.3%. One patient (KRAS) G12C Inhibitor-naive patients achieved a partial response (PR) within two months of treatment and were continuing treatment at the data cutoff point. A 100% reduction in target lesion size was observed in respondents in this cohort.

[0285] In Part 2, Cohort A (n=18), overall, 83% of patients were continuing treatment, and at 6 months, two patients were still receiving treatment. A reduction in target lesion size (-2.4% to -61.8%) was observed in the majority of the chemotherapy-resistant metastatic colorectal cancer (mCRC) population treated with dose escalation (83%, 15 out of 18 patients) (Part 2, Cohort A, n=18). This reduction is expected to persist. Mean progression-free survival cannot yet be determined.

[0286] Sotrasib exposure in patients treated with both sotrasib and panitumumab was similar to that of patients treated with sotrasib alone (in the CodeBreaK 100 trial NCT03600883). Day 1: In combination therapy, max (Time) 1.0, 1.9 in monotherapy; In combination therapy, C max (μg / mL) 8.01, 9.71 in monotherapy; In combination therapy, AUC 0-24h (Time * μg / mL) 77.2, 103 in monotherapy Day 8: In combination therapy, max (Time) 1.0, 2.0 in monotherapy; In combination therapy, C max (μg / mL) 7.50, 6.50 in monotherapy; In combination therapy, AUC 0-24h (Time * μg / mL) 51.7, 50.3 in monotherapy

[0287] In summary, the results showed that the combination of sotrasib (960 mg QD) and panitumumab (6 mg / kg IV Q2W) was safe and tolerable, and demonstrated promising efficacy in chemotherapy-resistant patients with KRAS G12C mutations in chronic renal cell carcinoma (CRC). Adverse events were consistent with known adverse events of sotrasib and panitumumab. The response rates for the sotrasib-panitumumab combination were 15.4% confirmed ORR and 26.9% ORR (including unconfirmed responses awaiting confirmation). These ORRs were numerically higher than those of sotrasib monotherapy in KRAS G12C mutations (7.1% ORR) (Hong et al., 2020). Sotrasib exposure was similar to that observed in monotherapy trials. Sotrasib in combination with panitumumab has been associated with early signals of promising efficacy in patients with KRAS.G12C mutations in 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 dose exploration with sotrasib 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 data cut on August 6, 2021, reported above. The median number of therapy lines for metastatic disease was 2; 7 patients (18%) had previously received regorafenib therapy, and 7 patients (18%) had previously received trifluridine / tipiracil therapy. (One patient received both regorafenib as third-line therapy and trifluridine / tipiracil as fourth-line therapy).

[0289] Safety and tolerability Treatment-related adverse events (TRAEs) of any grade were reported in 37 patients (93%) (26 patients (65%) were associated with sotrasib, and 37 patients (93%) were associated with 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, progression of malignant neoplasm, pulmonary embolism, acneiform dermatitis, and pruritus (n=1 patient each, 3%). Of the TRAEs that resulted in dose changes, six patients (15%) presented with TRAEs (pruritus, rash, anemia, diarrhea, hypokalemia), leading to a change in the sotrasib dose; and ten patients (25%) presented with TRAEs (acne-like dermatitis, rash, dry skin, conjunctivitis, diarrhea, hypomagnesemia, paronychia, pruritus, pustular rash, blurred vision), leading to a change in the panitumumab dose. Sotrasib in combination with panitumumab was well-tolerated and did not result in fatal or grade 4 TRAEs. None of the medications needed to be discontinued.

[0290] Pharmacokinetics Sotrasib exposure in patients treated with both sotrasib and panitumumab (n=35) was similar to that in patients treated with sotrasib alone (n=32) (CodeBreaK 100 trial NCT03600883). t max (h), Median (range): 1.0 (1.0-6.0) for combination therapy, 2.0 (0.3-6.0) for monotherapy. C max (μg / mL), mean (CV%): 9.64 (55%) for combination therapy, 7.50 (98%) for monotherapy. AUC 0-24h (Time * μg / mL), mean (CV%): 65.8 (56%) for combination therapy, 65.3 (82%) for monotherapy. The value is t max Except for AUC and CV%, the results are reported with 3 significant figures, represented as 2 significant figures and the nearest integer, respectively. 0-24h , area under the concentration-time curve from 0 to 24 hours after administration; Cmax, highest observed drug concentration; t max , C max Time to reach a certain point; CV, coefficient of variation.

[0291] Effectiveness:

[0292] [Table 23]

[0293] In patients with chemotherapy-resistant mCRC, the confirmed objective response rate (ORR) with sotrasib plus panitumumab was 30%, and the disease control rate (DCR) was 93%. ORR subgroup analysis based on primary tumor location was performed (left vs. right). No significant differences in response based on tumor location were observed (left (n=27, 30% ORR); right (n=13; 31% ORR)).

[0294] A reduction in RECIST target lesions was observed in 88% of patients. The median (range) duration of treatment was 5.9 (0.5, 11.3) months, and 25% of patients were still receiving treatment at the data cutoff. The median response time was 4.4 months (range, 2.8–7.4 months).

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

[0296] [Table 24]

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

[0298] [Table 25]

[0299] In summary, the results indicate that the combination of sotrasib (960 mg QD) and panitumumab (6 mg / kg IV Q2W) is safe and tolerable, and shows promising efficacy in chemotherapy-resistant patients with KRAS G12C mutation-induced chronic renal cell carcinoma (CRC). Adverse events were consistent with known adverse events of sotrasib and panitumumab. The confirmed 30% ORR was three times higher than previously reported for sotrasib monotherapy in KRAS G12C-mutated CRC (7.1% ORR) (Hong et al., 2020), and the DCR was 93%. No significant differences were observed based on tumor location. Sotrasib exposure was similar to that observed in monotherapy trials. The median PFS of 5.7 months is clinically significant and longer than that reported for sotrasib 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 regarding the triple combination therapy (sotrasib, panitumumab, and FOLFIRI) (data cutoff: June 9, 2022): As previously mentioned, trial 20190135 is a sotrasib protocol that examines sotrasib in combination with other anticancer therapies. Subprotocol H of this protocol examines combinations of sotrasib and panitumumab, and sotrasib, panitumumab, and folfiri. Part 1 cohort B of subprotocol H is a dose-finding cohort for the combination of sotrasib, panitumumab, and folfiri. A snapshot of the data was taken on June 9, 2022. In this cohort, six subjects were enrolled in dose level 1 (sotrasib 960 mg orally daily, panitumumab 6 mg / kg intravenously every two weeks, and folfiri chemotherapy every two weeks), and no dose-limiting toxicity (DLT) was identified during the 28-day DLT evaluation period. These six subjects had previously received a median of three lines of chemotherapy (ranging from 1 to 5), five had previously received irinotecan chemotherapy, and all six had previously received fluoropyrimidine chemotherapy. The objective response rate was 50% (3 out of 6 subjects showed partial response), and the disease control rate was 100% (subjects with complete response, partial response, or stable disease as best response). Although the sample size was small, an objective response rate of 50% in a heavily pre-treated population with a median of three lines of therapy previously is very promising and favorable compared to the 10% response rate observed with sotrasib monotherapy in the CRC cohort of trial 20170543 Phase 2 and the 30% response rate observed with the sotrasib and panitumumab combination in trial 20190135 Subprotocol H Part 2 Cohort A. Dose level 1 has been declared the recommended dose for Phase 2, and enrollment in the expanded Part 2 cohort is underway, with enrollment taking place for Part 2 Cohort F (treatment-naive patients with metastatic colorectal cancer with KRAS G12C mutations) and Part 2 Cohort G (previously treated patients with metastatic colorectal cancer with KRAS G12C mutations).

[0301] Example 2 - Panitumumab vs. sotrasib in combination with trifluridine and tipiracil or regorafenib This is a Phase 3, multicenter, randomized, open-label, active-controlled trial evaluating the efficacy and safety of two different doses of sotrasib and panitumumab versus (1) trifluridine and tipiracil or (2) regorafenib in previously treated metastatic clinical research cells (CRCs) with KRAS G12C mutations. The trial will be conducted at approximately 100 sites. The trial will consist of a screening period, a treatment period, safety follow-up periods, and a long-term follow-up period. Approximately 153 previously treated metastatic CRCs with KRAS G12C mutations will be enrolled and randomized in a 1:1:1 ratio to receive either sotrasib 240 mg QD and panitumumab, sotrasib 960 mg QD and panitumumab, or investigator's choice ((1) trifluridine and tipiracil, or (2) regorafenib). Investigator's choice must be declared prior to randomization. This clinical trial is currently enrolling participants (Trial 20190172, https: / / clinicaltrials.gov / ct2 / show / NCT05198934;CodeBreaK 300).

[0302] Participants are stratified by previous anti-angiogenic therapy (Y vs. N), time from initial diagnosis of metastatic disease to randomization (18 months or more, less than 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 the study drug; tumor assessment is performed (by MRI and / or CT) at 8-week (±7-day) intervals until baseline, progression as assessed by a blinded independent central review (BICR), initiation of another chemotherapy treatment, withdrawal of consent, failure to follow, or death, whichever comes first. Safety follow-up CT / MRI should only be performed for subjects who discontinue treatment for reasons other than disease progression in accordance with RECIST 1.1 and who have not received radiographic imaging within 8 weeks (±7 days of visit). For subjects without progression as assessed by BICR, radiographic imaging should be continued at LTFU every 8 weeks (±7-days) until progression as assessed by BICR, initiation of another chemotherapy treatment, withdrawal of consent, failure to follow, or death, whichever comes first. Tumor assessment and response are determined by BICR using RECIST 1.1. For subjects selected by the investigator, crossover to sotracib and panitumumab is permitted after the primary analysis of PFS only if PFS shows a clinically and statistically significant improvement in the PFS of the sotracib and panitumumab arms compared to the investigator's choice arm, and if safety and efficacy data strongly support the sotracib and panitumumab arms. For subjects who previously discontinued investigator selection due to progressive disease as determined by BICR, crossover to sotracib or panitumumab may be proposed after the primary analysis if it is determined to be appropriate. Subjects who discontinued treatment before progressive disease as determined by BICR are not permitted to crossover unless they subsequently develop progressive disease as determined by BICR before initiating another systemic therapy. Subjects who withdraw their consent are not permitted to crossover. Subjects may discontinue treatment due to disease progression, treatment intolerance leading to treatment discontinuation, initiation of another anticancer therapy, or withdrawal of consent. Continuation of the study treatment after radiological progression may be permitted in the opinion of the principal investigator if the subject is clinically beneficial, clinically stable, has no unacceptable toxicity from the study drug, consents to biopsy, and has received approval from the medical monitor. For subjects who continue treatment after progression, tumor evaluation will continue according to schedule until the subject discontinues all study drugs.

[0304] For patients who continue treatment after disease progression or crossover, the date of progression assessed in the initial BICR is used for the primary PFS analysis, and tumor assessments after the initial progression are not used for the primary analysis to evaluate objective response metrics.

[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 during subsequent therapy, and survival data. Subjects who discontinued treatment before disease progression according to RECIST 1.1 (e.g., due to unacceptable toxicity) will be followed by radiography until disease progression, withdrawal of consent, or initiation of another anticancer therapy. Thereafter, subjects who have not withdrawn consent will undergo further long-term follow-up by telephone or clinic visit for survival assessment and recording of anticancer treatment. Subjects will be followed for one year from the enrollment of the last subject, or until withdrawal of consent, loss of follow-up, or death of the subject, whichever comes first.

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

[0307] The assessments performed in this test are described below and will be conducted at the times specified in the Assessment Schedule (SOA).

[0308] Disease progression is assessed using the BICR-based criteria for evaluating the response to solid tumors, version 1.1 (RECIST v1.1).

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

[0310] Clinical safety tests include hematology, blood chemistry, urinalysis, thyroid function, cholesterol, and triglycerides. Vital signs are assessed by blood pressure and pulse rate; additional vital signs are collected only when clinically appropriate.

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

[0312] The samples are collected for sotracib 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 patients with lesions that are likely to be biopsied (core needle or fine-needle aspiration (FNA)) at an advanced stage are encouraged to undergo a biopsy at that stage. - All patients treated with sotrasib and panitumumab, who have biopsyable lesions and wish to continue treatment beyond the progression stage, should undergo a biopsy at the progression stage, if medically feasible, before continuing treatment beyond the progression stage.

[0315] In this trial, an independent Data Monitoring Committee (DMC) is planned to review safety data in accordance with the DMC Charter. Interim safety analyses will be conducted by the DMC approximately every six months after approximately 75 subjects have been enrolled and given the opportunity to complete at least eight weeks of the trial treatment, and thereafter approximately annually until the end of the trial.

[0316] A primary PFS analysis is planned to compare the PFS advantage between the sotrasib and panitumumab arm and the investigator's choice arm. A PFS PA will occur when approximately 60 PFS events are observed in the sotrasib 960 mg and panitumumab arm, as well as the investigator's choice arm.

[0317] Test product Daily oral sotrasib 240 mg or 960 mg.

[0318] Panitumumab 6 mg / kg IV Q2W Trifluridine and tipiracil 35 mg / m² 2 Administer a maximum of 80 mg (based on the trifluridine component) orally twice daily, within one hour after the end of breakfast and dinner, on days 1-5 and 8-12 of each 28-day cycle. Round the dose to the nearest 5 mg increment.

[0319] Take 160 mg of oral regorafenib daily for 21 days, in 28-day cycles. Take after a low-fat meal.

[0320] Inclusion criteria: Must be 18 years of age or older.

[0321] Pathologically confirmed metastatic colorectal cancer.

[0322] The KRAS G12C mutation has been confirmed by center testing.

[0323] Subjects must have previously received at least one line of therapy for metastatic disease. Subjects must have experienced disease progression or recurrence during or after administration of fluoropyrimidine, irinotecan, and oxaliplatin administered for metastatic disease, unless, in the opinion of the investigator, the subject is not a candidate for fluoropyrimidine, irinotecan, or oxaliplatin, in which case the subject may be eligible after consultation between the investigator and 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 checkpoint inhibitor therapy available in their region, unless there are medical contraindications, in which case the subject may be eligible after consultation between the investigator and the medical monitor.

[0324] Patients with tumors known to carry the BRAF V600E mutation must have previously received treatment with encorafenib and cetuximab, if available in their country or region for this indication. - If the patient's disease progresses within six months of completing adjuvant therapy, adjuvant therapy is counted as a line of treatment for metastatic disease. Maintenance therapy is not considered a separate regimen of treatment. - Adjuvant therapy performed after surgical resection of metastatic disease is considered a line of treatment for metastatic disease. - In metastatic disease, perioperative chemotherapy with or without chemoradiotherapy is counted as one line of therapy for metastatic disease if it is part of a multidisciplinary surgical treatment plan.

[0325] Participants must either be willing to provide stored tumor tissue samples (formalin-fixed paraffin-embedded [FFPE] samples recovered within the last five years) or agree to undergo a pre-treatment tumor biopsy (excision or core biopsy) before registration.

[0326] Diseases measurable according to the RECIST 1.1 criteria. Lesions previously treated with radiation are not considered measurable unless they have progressed since radiation exposure.

[0327] An East Coast Cancer Clinical Trials Group (ECOG) performance status of ≤2.

[0328] The principal investigator's opinion is that the patient has a life expectancy of >3 months.

[0329] Within the two weeks prior to day 1 of cycle 1, adequate blood and peripheral organ function as defined below: -ANC≧1.5×10 9 Cells / L (without granulocyte colony-stimulating factor support within 2 weeks of the clinical test used to determine eligibility). - Hemoglobin ≥ 9.0 g / dL (no blood transfusions within 2 weeks of the clinical test used to determine eligibility). - Platelet count ≥ 100 × 10 9 Cells / L (no blood transfusions within 2 weeks of the clinical test used to determine eligibility). - Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels ≤ 2.5 times the upper limit of the normal range. -Serum bilirubin ≤ 1.0 × ULN. In subjects with Gilbert's disease, direct bilirubin ≤ 1.0 × ULN. - International normalized ratio (INR) and activated partial thromboplastin time (or partial thromboplastin time) ≤ 1.5 × ULN. In facilities where the laboratory does not report INR, prothrombin time (PT) ≤ 1.5 × ULN may be used instead of INR. Estimated glomerular filtration rate based on dietary modification disease (MDRD) calculations in renal disease ≥ 30 ml / min / 1.73 m³ 2 . -Fridericia's correction formula (QTcF) ≤ 470 milliseconds.

[0330] You are able to take oral medication and are willing to record your daily adherence to the investigational product.

[0331] Exclusion criteria: Disease-related: Active brain metastases. As used herein, the term “active brain metastases” refers to cancer that has spread from the original (primary, non-brain) tumor to the brain. Active brain metastases can be assessed by the presence of intracranial lesions. While “metastases” is plural, it should be understood that a patient exhibiting only one intracranial lesion under the following criteria is considered to have “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 has completed radiotherapy at least four weeks prior to day 1 of the study, the patient is not considered to have active brain metastases and is eligible if all of the following criteria are met: a) residual neurological symptoms of grade ≤ 2; b) administration of a stable dose or equivalent of dexamethasone, where applicable, for at least two weeks; and c) follow-up MRI performed within 28 days of day 1 shows no progression or appearance of new lesions. For the determination of the grade of any neurological symptoms resulting from 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 whole.

[0332] Other medical conditions: Unless there is no evidence of disease for more than two years and the patient has been cured by treatment, the patient has a history of or is currently suffering from a hematological malignancy.

[0333] History of other malignancies within the past three years, with the following exceptions: • Malignant tumors treated with the aim of cure, no active disease observed for more than three years prior to registration, and considered by the attending physician to have a low risk of recurrence. • Well-treated non-melanoma skin cancer or malignant lentigo with no evidence of disease. • Well-treated, in-vivo cervical cancer with no evidence of disease. • Well-treated in vivo ductal carcinoma with no evidence of disease. • Prostatic intraepithelial neoplasia without evidence of prostate cancer. • Well-treated urothelial papillary non-invasive carcinoma or in-vivo carcinoma.

[0334] Leptomeningeal disease.

[0335] Severe GI disorder resulting from severe malabsorption, need for IV nutritional support, or inability to take oral medications.

[0336] A history of interstitial pneumonia or pulmonary fibrosis, or evidence of interstitial pneumonia or pulmonary fibrosis.

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

[0338] In the opinion of the principal investigator or medical monitor, any uncontrolled serious complications that could affect adherence to protocol procedures or interpretation of results, or that could pose a risk to the safety of the subject.

[0339] Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures more than monthly. Patients with a PleurX catheter or intraperitoneal drainage catheter may be included in the study with the approval of the medical monitor.

[0340] A 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). - Positive for hepatitis B core antibodies, but negative for HepBsAg (a hepatitis B core antibody test is not required for screening, but if it is performed and positive, a hepatitis B surface antibody [anti-HBs] test is required). In this situation, the undetectable presence of anti-HBs suggests an unclear possible infection and should be ruled out). - Positive for hepatitis C virus antibody: Hepatitis C virus RNA detected by polymerase chain reaction is required. If hepatitis C virus RNA is detectable, the subject is ineligible.

[0342] If the above antibody / antigen test results are not obtained, the hepatitis B or C virus load is positive.

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

[0344] Unresolved toxicity (any grade is acceptable), neuropathy (up to grade 2 is acceptable), or toxicity from previous antitumor therapy that is considered irreversible [defined as present for more than 6 months and stable], as defined in CTCAE version 5.0, grade 0 or 1, or eligibility criteria other than alopecia, resulting from previous antitumor therapy, or endocrine AEs that are stably maintained with appropriate replacement therapy.

[0345] KRAS G12C Previous treatment with inhibitors.

[0346] Prior treatment with trifluridine and tipiracil in subjects where the choice of trifluridine and tipiracil would be made by the principal investigator.

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

[0348] Therapeutic or symptomatic radiotherapy within two weeks of day 1 of the study. Participants must have recovered from all radiotherapy-related toxicity of CTCAE version 5.0 grade 1 or lower, except for alopecia (alopecia of any grade is acceptable).

[0349] Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormone therapy [excluding subjects receiving long-term adjuvant endocrine therapy or those with a history of complete mastectomy for breast cancer without active disease for more than 3 years] or investigational drug) within 4 weeks of day 1 of the trial is also excluded. Note that bisphosphonate or anti-RANKL antibody therapy is permitted if necessary for the management of hypercalcemia or the prevention of bone-related events. Checkpoint inhibitor therapy within 6 weeks from day 1 of the trial is also excluded.

[0350] Dose reduction of panitumumab previously 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 range) within 14 days prior to day 1 of the trial, or within 5 half-lives of the drug or its major active metabolite, whichever is longer, without review and approval by the principal investigator and medical monitor.

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

[0354] If the investigator's choice is regorafenib: Use of potent CYP3A4 inhibitors (including herbal nutritional supplements such as goldenseal) within 14 days prior to day 1 of the trial or within 5 half-lives (whichever is longer) that have not been reviewed and approved by the investigator and medical monitor, or use of grapefruit juice or grapefruit-containing products within 7 days prior to day 1 of the trial.

[0355] Oral or intravenous administration of therapeutic antibiotics within two weeks prior to randomization. Prophylactic use of antibiotics is permitted.

[0356] Experience in pre- / combination clinical trials: Currently, you are receiving treatment as part of another investigational medical device or drug trial, or it has been less than four weeks since the completion of another investigational medical device or drug trial, or, if a checkpoint inhibitor is involved, it has been less than six weeks since you received another investigational drug in the trial.

[0357] Diagnostic evaluation: If the investigator chooses regorafenib, the patient must have uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg).

[0358] Other exclusions: This applies to women of potential pregnancy who do not wish to use the contraceptive methods specified in the protocol during treatment and / or for the following periods: - 7 days after the last dose of sotrasib. - Two months after the last dose of panitumumab. - Six months after the last dose of trifluridine and tipiracil. - Two months after the last dose of regorafenib.

[0359] This program is for women who are currently breastfeeding or who plan to breastfeed during the trial period or within the following timeframe: - 7 days after the last dose of sotrasib. - Two months after the last dose of panitumumab. - Six months after the last dose of trifluridine and tipiracil. - Two months after the last dose of regorafenib.

[0360] This applies to women who are planning to become pregnant during the following period, from the time of the exam: - 7 days after the last dose of sotrasib. - Two months after the last dose of panitumumab. - Six months after the last dose of trifluridine and tipiracil. - Two months after the last dose of regorafenib.

[0361] This program is for women who may be pregnant and who have a positive pregnancy test result using a highly sensitive urine or serum pregnancy test at the time of screening or on day 1.

[0362] For men who practice sexual abstinence (refraining from heterosexual intercourse) during treatment and for the following periods, or who have a female partner who does not wish to use contraception or who may become pregnant: - 7 days after the last dose of sotrasib. - Six months after the last dose of trifluridine and tipiracil. - Two months after the last dose of regorafenib.

[0363] This applies to men with a pregnant partner who are undergoing treatment and, for the following periods as well, do not wish to abstain from sex or use condoms: - 7 days after the last dose of sotrasib. - Six months after the last dose of trifluridine and tipiracil. - Two months after the last dose of regorafenib.

[0364] For men who do not wish to refrain from sperm donation during the trial and / or the following periods: - 7 days after the last dose of sotrasib. - Six months after the last dose of trifluridine and tipiracil. - Two months after the last dose of regorafenib.

[0365] Major surgery within 28 days of the first day of the exam.

[0366] The subject had a known susceptibility to any of the products or components that would be administered during the treatment.

[0367] The subject may be unable to complete all trial visits or procedures required in the clinical trial protocol, and / or may be unable to follow all necessary trial procedures to the best of the subject's and the principal investigator's knowledge.

[0368] A history or evidence of any other clinically significant impairment, condition, or disease (other than those outlined above) that, in consultation with the principal investigator or physician, would raise a risk to the safety of the subject or would likely interfere with the evaluation, procedure, or completion of the study.

[0369] Treatments, medical devices, and / or procedures excluded during the trial period: (1) Chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, or hormone therapy (excluding patients with breast cancer receiving adjuvant therapy); (2) Antitumor therapies such as therapeutic or symptomatic radiotherapy for non-targeted lesions may be permitted for symptom control if discussed and agreed upon between the principal investigator and the medical monitor prior to radiotherapy. The study drug must be withheld during radiotherapy.

[0370] For those taking sotrasib or regorafenib: Avoid potent CYP3A4 inducers (including herbal nutritional supplements such as St. John's wort) unless approved by medical monitor.

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

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

[0373] Other investigational drugs Other anti-EGFR targeted drugs besides panitumumab Objectives / Evaluation Items:

[0374] [Table 26]

[0375] [Table 27]

[0376] Rules for dose adjustment, delay, suspension, or resumption of sotrasib, and permanent discontinuation. The starting dose of sotrasib used in the study is 960 or 240 mg / day. Sotrasib is administered orally in a 28-day treatment cycle, with or without food. Patients should take their sotrasib dose (all tablets taken simultaneously) with or without food each day at approximately the same time. The sotrasib dose should not be taken more than 2 hours earlier than the target time based on the previous day's dose. If 6 hours have passed since the scheduled time of administration, the dose for that day should be skipped. Take the next dose as prescribed the following day. Do not take two doses at the same time to make up for a missed dose. If vomiting occurs after taking sotrasib, do not take an additional dose. Take the next dose as prescribed the following day.

[0377] Administration to subjects with difficulty swallowing solids: Do not crush the tablet. Disperse it in 120 mL (4 ounces) of room temperature non-carbonated water. Do not use any other liquids. Stir until the tablet is dispersed into small pieces (the tablet will not dissolve completely), and take 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 on any tablet fragments. Rinse the container with another 120 mL (4 ounces) of water and take. If the mixture is not consumed immediately, stir the mixture again to ensure the tablet is properly dispersed.

[0378] Dose-modified sotrasib for toxicity management of individual subjects is provided in the table below.

[0379] [Table 28]

[0380] Patients receiving 240 mg of sotrasib may have up to two dose-free periods, but sotrasib will not be reduced upon resumption if it is deemed medically safe and appropriate at the discretion of the principal investigator. Patients in the 960 mg sotrasib treatment arm who require three or more dose reductions due to sotrasib-related toxicity management, and patients in the 240 mg sotrasib treatment arm who require three or more dose-free periods due to sotrasib-related toxicity management, should have sotrasib treatment permanently discontinued.

[0381] [Table 29]

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

[0383] The following discontinuation and / or suspension rules apply to subjects for whom another cause has been identified for the changes in liver biomarkers (TBL, INR, and transaminase). Other important causes of elevated AST / ALT and / or TBL levels include, but are not limited to, hepatobiliary diseases; viral hepatitis (e.g., hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); causes of hypoxia to the liver resulting in right heart failure, hypotension, or ischemia; exposure to hepatotoxic drugs / medicines or hepatotoxins, including herbs and nutritional supplements, plants, and mushrooms; genetic disorders that cause impaired glucuronidation (e.g., Gilbert's syndrome, Crigler-Nadjar 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 impaired liver tests (ALT, AST, ALP) and / or elevated TBL is found and / or if the abnormal clinical laboratory values ​​return to normal or baseline, reloading may be considered.

[0385] [Table 30]

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

[0387] [Table 31]

[0388] Hepatotoxic reactions: Patients with abnormal liver clinical 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 completely discontinuing sotrasib.

[0389] Rules for dose adjustment, delay, suspension, or resumption of panitumumab, and permanent discontinuation. The starting dose of panitumumab used in this study is 6 mg / kg Q2W. Panitumumab is administered as an IV infusion over 60 minutes (≤1000 mg) or 90 minutes (>1000 mg) at Q2W. If the initial infusion is tolerated, subsequent infusions should be administered 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 sotrasib on day 1 of cycle 1. There is no need to wait 2 hours for subsequent panitumumab administrations. Panitumumab can be administered immediately after the start of sotrasib C1D15. After cycle 1, sotrasib does not need to be administered before panitumumab, as long as it is within acceptable limits on that day. The panitumumab dose is calculated based on the patient's 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 patient's body weight change is 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 at intervals of more than 14 days). Exemplary panitumumab dose reductions are listed in the table below.

[0392] [Table 32]

[0393] If administration of panitumumab is withheld, administration of sotrasib may be continued if the principal investigator determines it is clinically safe.

[0394] The following table provides exemplary guidelines for adjusting the dose of panitumumab due to skin toxicity.

[0395] [Table 33]

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

[0397] Patients initiating panitumumab should, if feasible, begin prophylaxis before the first dose of panitumumab. Clinically necessary prophylaxis should include skin moisturizers, sunscreen (SPF > 15 UVA and UVB), topical steroid creams (1% hydrocortisone or less), and oral antibiotics (doxycycline 100 mg BID or minocycline 100 mg QD) (Lacouture et al, 2010). Details regarding the frequency and application sites of these prophylactic measures are described in the panitumumab prescribing information and information pamphlet.

[0398] Treatment of skin reactions should be based on their severity and may include moisturizers, sunscreens (SPF > 15 UVA and UVB), topical steroid creams (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 the facility's guidelines for managing skin toxicity.

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

[0400] ocular toxicity Patients who develop ocular toxicity during panitumumab administration should be monitored for evidence of keratitis or ulcerative keratitis. If a diagnosis of ulcerative keratitis is confirmed, treatment with panitumumab 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 keratitis, such as acute or exacerbating keratitis: Patients presenting with eye inflammation, tearing, photosensitivity, blurred vision, eye pain, and / or redness should be immediately referred to an ophthalmologist.

[0401] Hypersensitivity reaction Depending on the severity and / or persistence of the hypersensitivity reaction (e.g., bronchospasm, edema, angioedema, hypotension, need for parenteral medication, or presence of anaphylaxis), panitumumab should be permanently discontinued.

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

[0403] Injection reaction Infusion reactions may manifest as fever, chills, difficulty breathing, bronchospasm, or hypotension. - In patients experiencing a mild or moderate (grade 1 or 2) infusion reaction, the infusion rate should be reduced by 50% during the infusion period. If necessary, subsequent infusions may be administered at the reduced rate. - In patients experiencing a severe infusion reaction, discontinue the infusion. Depending on the severity and / or persistence of the reaction, permanently discontinue panitumumab.

[0404] Criteria for retreatment with panitumumab In cases of toxicity other than cutaneous toxicity: If panitumumab is withheld, administration may be resumed when the adverse event improves to grade 1 or less, or when the adverse event returns to baseline.

[0405] Trifluridine and Tipiracil The dosage of trifluridine and tipiracil is calculated on day 1 of cycle 1 based on body surface area (BSA). If body weight changes by more than 10% at the start of subsequent cycles, the BSA should be recalculated and used for administration.

[0406] Complete blood counts are taken before day 15 of each cycle and on day 15.

[0407] Do not start a trifluridine and tipiracil cycle until the following point: - ANC is 1500 / mm 3 The above, or the febrile neutropenia resolves. - Platelet count: 75,000 / mm³ 3 That's all. - Grade 3 or 4 non-hematological adverse reactions improve to Grade 0 or 1.

[0408] During the treatment cycle, withhold the use of trifluridine and tipiracil in any of the following cases: - ANC is 500 / mm 3 Less than or febrile neutropenia - Platelet count is 50,000 / mm³ 3 less than - Grade 3 or 4 non-hematological adverse reactions

[0409] If any of the following occurs after recovery, increase the dose level by 5 mg / m² from the previous dose level. 2 After reducing the dose by only one portion, restart trifluridine and tipiracil. -Fever neutropenia - Uncomplicated grade 4 neutropenia (1,500 / mm³) causing a delay of more than one week in starting the next cycle. 3(Recovery above) or thrombocytopenia (75,000 / mm³) 3 (Recovered beyond this point) - Non-hematological 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 drugs.

[0410] If the principal investigator determines that a more severe dose reduction or dose retention is necessary, this is permissible.

[0411] Minimum dose 20mg / m twice a day 2 Up to three dose reductions are permitted. Do not increase the dose of trifluridine and tipiracil after a dose reduction.

[0412] Legolafenib In clinical trials, severe, sometimes fatal, hepatotoxicity occurred (see regorafenib USPI). Monitor liver function before and during treatment. If hepatotoxicity is evident due to elevated liver function test values ​​or hepatocyte necrosis, discontinue regorafenib, and then reduce or discontinue the dose, depending on the severity and duration.

[0413] If a dose change is necessary, the dose should be reduced by 40 mg (1 tablet) at a time. If the principal investigator determines that a more severe dose reduction or dose maintenance is necessary, this is permissible. The minimum recommended daily dose of regorafenib is 80 mg per day.

[0414] Discontinue regorafenib administration in the following cases: - Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that has recurred or does not improve within 7 days despite dose reduction; in the case of grade 3 HFSR, discontinue therapy for at least 7 days. - Symptomatic grade 2 hypertension - Any Grade 3 or 4 adverse reaction - Worsening of infections of all grades

[0415] The dose of regorafenib will be reduced to 120 mg. - When Grade 2 HFSR occurs for the first time, regardless of duration - After recovery from grade 3 or 4 adverse reactions, excluding infection. - In cases of Grade 3 AST / ALT elevation, restart only if the potential benefits outweigh the risks of hepatotoxicity.

[0416] The dose of regorafenib will be reduced to 80 mg. - If Grade 2 HFSR recurs at a dose of -120 mg - After recovery from a Grade 3 or 4 adverse reaction (excluding hepatotoxicity or infection) at a dose of 120 mg.

[0417] Permanently discontinue regorafenib in the following cases: - Unable to tolerate a dose of 80 mg - Occurrence of AST or ALT exceeding 20 times ULN - Simultaneous production of AST or ALT at more than 3 times the ULN level, and bilirubin at more than 2 times the ULN level. Despite dose reduction to -120 mg, recurrence of AST or ALT more than 5 times the ULN. - In case of a Grade 4 adverse reaction; resume only if the potential benefits outweigh the risks.

[0418] Effectiveness evaluation The severity of the disease is assessed by contrast-enhanced CT / MRI according to RECIST 1.1 (discussed below). All radiological imaging is performed as instructed in the facility's radiological imaging manual provided by the center's radiological imaging core laboratory. Low-dose CT should be used whenever possible to reduce radiation exposure to the patient.

[0419] Screening scans must be performed within 28 days prior to day 1 of cycle 1. If multiple screening scans are available, the scan closest to day 1 of cycle 1 will be used as the baseline. Imaging tests performed as part of standard care prior to signing informed consent may be used if they are performed within 28 days of the start of the trial and can be submitted to the center's core imaging examination period.

[0420] Radiographic evaluation must include CT / MRI of the chest, abdomen, and pelvis, as well as evaluation of all other known sites of the disease, as detailed in the facility's imaging diagnostic manual.

[0421] All subjects with a history of brain metastases must undergo brain MRI. All brain scans of subjects with brain metastases must be MRI unless MRI is contraindicated, followed by contrast-enhanced CT, which 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 using the same method as the screening (e.g., the same contrast, MRI field intensity), preferably on the same scanner. If it becomes necessary to change the imaging modality (e.g., for unplanned evaluations), it is recommended to consult with Amgen's medical monitor.

[0423] During treatment and follow-up, radiographic imaging of the chest, abdomen, pelvis, and all other known sites of the disease will be performed regardless of the treatment cycle. Imaging may also be performed more frequently if clinically necessary, at the discretion of the attending physician. Confirmed radiographic response (complete response, PR) requires confirmation by a rescan at least four weeks after the initial response recording, although this may be done later in the next scheduled scan. Radiographic and tumor evaluations will continue until the initiation of another chemotherapy treatment, withdrawal of consent, inability to follow up, or death, whichever comes first.

[0424] Scans are submitted to the center's diagnostic imaging core laboratory for archival data, response assessment including RECIST 1.1, and / or exploratory analysis (e.g., volumetric and viable tumor measurements). BICR continues to perform tumor assessments on acquired scans until the progression assessed by the initial BICR is achieved. Scans acquired after the progression assessed by the initial BICR are not periodically evaluated by BICR.

[0425] Criteria for evaluating the effectiveness of solid tumor treatment, version 1.1 (RECIST 1.1) Definition: Measurable lesions Measurable non-lymph node tumor lesions Non-lymph node lesions with clearly defined boundaries that can be accurately measured in at least one dimension, and with a maximum diameter of ≥10 mm in 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 lesions Lymph node lesions – Lymph nodes are considered measurable if they are ≥15 mm in the short axis when evaluated by CT / MRI (scan slice thickness of 5 mm or less is recommended). Only the short axis is measured and tracked at baseline and follow-up.

[0427] Cystic lesions Cystic lesions that are 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 identifiable soft tissue components that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered measurable lesions if the soft tissue components meet the definition of measurability described above for non-lymph node lesions.

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

[0430] Radiation-treated lesions Tumor lesions located in areas previously irradiated or treated with other local therapies are unmeasurable unless measurable progression of the lesion has been demonstrated prior to registration.

[0431] Unmeasurable 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 unmeasurable. (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 unmeasurable include: • Previously treated lesions: Tumor lesions located in areas previously irradiated or subjected to other local therapies should not be considered measurable unless progression of the lesion has been demonstrated. • Classification-wise, clusters of small lesions, bone lesions without soft tissue components, inflammatory breast disease, ascites, pleural effusion / pericardial effusion, cutaneous lymphangitis / pneumonia, and leptomeningeal diseases are unmeasurable.

[0433] Measurement method All lesions should be evaluated using CT / MRI-contrast-enhanced CT or MRI. Optimal visualization and measurement of metastases in solid tumors require consistent administration (dosage and rate) of IV contrast agent and timing of scans. CT and MRI should be performed on adjacent slices ≤5 mm thick.

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

[0435] Baseline evaluation of "targeted" and "non-targeted" lesions Target lesions—all measurable lesions, up to two per organ and a total of up to five lesions, 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 (the lesion with the longest diameter) and their suitability for accurate, repeated measurements.

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

[0438] A lymph node is considered a single 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, short axis for lymph node lesions) is calculated and reported as the baseline sum of diameters. The baseline sum of diameters is used as a criterion to characterize objective tumor response.

[0440] Non-target lesions—all other lesions (or sites of disease), including pathological lymph nodes, should be identified as non-target lesions and recorded at baseline. Measurement of these lesions is not required, and they should be tracked as “present,” “absent,” or “obvious progression” throughout the study. In addition, multiple non-target lesions involving the same organ can be recorded as a single item on the case report form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).

[0441] Criteria for determining effectiveness Evaluation of target lesions

[0442] [Table 34]

[0443] Evaluation of non-target lesions

[0444] [Table 35]

[0445] Best overall response rating The allocation of the best response to a subject depends on findings in both the target and non-target diseases, taking into account the appearance of new lesions and confirmation of responses. The best overall response (BOR) is the best response recorded based on all post-baseline disease assessments performed before disease progression and subsequent initiation of anticancer treatment. To allocate the best overall response to stable disease (SD), at least 7 weeks must have passed without radiological disease progression from the first dose of the investigational drug for tumor assessment to meet the minimum criteria for the duration of SD. In general, subjects who cannot be classified into the RECIST 1.1 response category due to insufficient data or early death are classified as not evaluable for BOR (NE), but are counted in the denominator of all response rate calculations.

[0446] [Table 36]

[0447] [Table 37]

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

[0449] Novel Lesions - The term "novel lesion" always refers to the presence of a new finding that is clearly a tumor. If 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 clearly considered a tumor. New findings that are not definitively tumorous but may be benign (e.g., infection, inflammation) are not selected as novel lesions until they are confirmed to be tumors through review. For example, if a new lesion is uncertain due to its small size, continued therapy and follow-up evaluation will clarify whether it actually becomes a new disease. If additional imaging confirms the clear presence of a new lesion, the progression should be reported using the date of the initial scan. - Lesions identified in follow-up studies at anatomical locations not scanned at baseline are considered novel lesions and will indicate disease progression, regardless of any response observed in target or non-target lesions that were present from baseline.

[0450] Local area therapy not permitted by the protocol: - Subjects who receive local area therapy not permitted by the protocol during a trial directly affecting one or more target lesions selected at baseline will be considered unevaluable for all disease assessments conducted after the day of local area therapy, except in cases of disease progression. However, subjects are evaluable for reported zero-dimensional responses, even if the pathology is benign and the lesion is completely resected. -When localized therapy is performed on a non-target lesion, the lesion is always considered to be present unless the pathology is benign.

[0451] If a non-lymph node lesion fragments or fuses during treatment, the longest diameters of the fragmented portions should be added together to calculate the total diameter of the target lesion and identify it as a fragment of the original lesion. Similarly, when lesions fuse, a plane between the lesions may be maintained, which can be helpful in obtaining the maximum diameter measurement of the individual lesions. If the lesions have truly fused and become inseparable, the longest diameter vector in this case should be the maximum diameter of the "fused lesion". - "Worsening of symptoms" alone is not sufficient to recognize objective progression. If objective progression has not been previously recorded, every effort should be made to record objective progression, even after treatment has been discontinued. -Under certain circumstances, it may be difficult to distinguish residual disease from scar or normal tissue. When the assessment of complete response (CR) depends on this decision, it is recommended to further investigate the residual lesion by fine-needle aspiration / biopsy to confirm the CR status. - If a lesion disappears and then reappears at a later point, measurements should be continued. However, the patient's response at the time of lesion recurrence depends on the status of the patient's other lesions. For example, if a patient's tumor has reached CR and the lesion recurs, the patient will be considered PD at the time of recurrence. In contrast, if the tumor status is PR or SD and one lesion that had disappeared reappears, its largest diameter should be added to the sum of the remaining lesions to calculate the effect. In other words, the recurrence of a single lesion that had clearly "disappeared" while many other lesions remain is not sufficient to classify it as PD. The sum of all lesions is required to meet the PD criteria.

[0452] Confirmation measurement / response period Confirmation of CR and PR is required and must be performed at least four weeks after the initial confirmation of CR or PR. If CR is pending confirmation and one or more NE and / or PR evaluations follow in subsequent evaluations, and the target lesion response is designated as CR and the non-target lesion response as NE, then CR may be confirmed if the target lesion response returns to CR. Similarly, if PR is pending confirmation and designated in a certain evaluation, followed by one or more NE and / or SD evaluations, then PR may be confirmed thereafter. Subsequent target lesion responses following CR are limited to CR, PD, or NE; PD of the target lymph node is only met if the short-axis measurement of the lymph node target lesion reaches 15 mm or more.

[0453] ECOG Performance and NYHA Classification

[0454] [Table 38]

[0455] Functional classification of the New York Heart Association Class I: No restrictions on physical activity. Normal physical activity does not cause excessive fatigue, palpitations, or shortness of breath. Class II: Mild limitation of physical activity. Comfortable at rest, but fatigue, palpitations, or shortness of breath occur with normal physical activity. Class III: Significant limitation of physical activity. While comfortable at rest, fatigue, palpitations, or shortness of breath occur with less activity than usual. Class IV: No physical activity can be performed without discomfort. Symptoms of heart failure may appear even at rest. Discomfort increases with any physical activity.

[0456] Example 3 - Pharmacokinetic analysis of sotrasib at 960 mg, 360 mg, 180 mg, and 240 mg doses. Preliminary pharmacokinetic (PK) data are available for patients with progressive solid tumors with specific KRAS G12C mutations at doses ranging from 180 to 960 mg PO QD (Study 20170543; https: / / clinicaltrials.gov / ct2 / show / NCT03600883; CodeBreaK 100). An increase in dose correlation was observed from 180 to 960 mg PO QD in day 1 exposure. The increase in exposure was smaller than the dose ratio on day 1. There was no accumulation with multiple PO QD administrations over 8 days. The change in exposure from 180 to 960 mg PO QD was smaller than the dose ratio on day 8. Rapid absorption was observed by tmax 1–2 hours after PO administration. Figure 1 shows the mean plasma concentration-time profiles after oral administration of 180, 360, 720, or 960 mg of sotrasib on day 1. Figure 2 shows the concentrations after 8 days of once-daily administration (day 8). The table below provides pharmacokinetic parameters and AUC. 0~24h This is the area under the concentration-time curve from zero to 24 hours after administration; C max This is the highest drug concentration during the dosing interval; t 1 / 2,z This is the terminal phase disappearance half-life; t max C max This is the time it takes to reach [the specified value]. The reported data are reported as the median (range) and arithmetic mean (SD), respectively. max and t 1 / 2 Except for , the values ​​are expressed as geometric mean (arithmetic CV%). The values ​​are reported to 0 and 2 significant figures, respectively, for CV% and t. max Except for [specific case], the report is given to three significant digits.

[0457] [Table 39]

[0458] Example 4 - Contraindications of simultaneous administration of antacids and sotrasib under fasting conditions This Phase 1, open-label, fixed-sequence trial enrolled 14 healthy subjects. Subjects received 960 mg of omeprazole on day 1, 40 mg once daily from days 4 to 8, and 960 mg of sotrasib on day 9, following 40 mg of omeprazole. All doses were administered under fasting conditions. Blood samples for sotrasib PK were collected pre-administration and up to 48 hours after sotrasib administration. Plasma PK parameters for sotrasib were estimated using a non-compartment method.

[0459] Co-administration of sotrasib and omeprazole may increase the maximum plasma concentration of sotrasib (t max The time to ) was delayed by 0.75 hours. The mean terminal half-life (t) of sotrasib 1 / 2 The geometric mean sotrab AUC after co-administration of sotrasib and omeprazole was similar compared to administration of sotrasib alone. inf (Area under the curve from zero to infinity) and C max Maximum plasma concentrations (17,000 h⁻¹ ng / mL and 3,100 ng / mL, respectively) were lower compared to sotrasib monotherapy (29,300 h⁻¹ ng / mL and 7,200 ng / mL, respectively). Sotrasib was safe and well-tolerated when administered co-administered with 40 mg of omeprazole or alone to healthy subjects.

[0460] The results showed that co-administration of sotrasib and omeprazole in a fasted state resulted in a higher AUC of sotrasib compared to sotrasib alone. inf 42% and C max It showed a 57% reduction.

[0461] Example 5 - Contraindications of simultaneous administration of postprandial antacids and sotrasib This was a Phase 1, open-label, fixed-sequence, crossover, single-center trial exploring mitigation strategies to limit the impact of antacids on sotrasib exposure. The trial evaluated the pharmacokinetics (PK) of sotrasib administered alone and in combination with famotidine or omeprazole in healthy men and women (14 subjects in total) after meals. Subjects received a single dose of sotrasib on day 1, an evening dose of famotidine on day 3 (10 hours prior to sotrasib administration), a single dose of sotrasib followed by a read-up of famotidine 2 hours later on day 4, daily doses of omeprazole from days 6 to 10, and single doses of both omeprazole and sotrasib on day 11. All sotrasib administrations were performed after the consumption of a standard calorie, moderate-fat meal. Blood samples were collected at pre-specified time points to characterize plasma concentrations of sotrasib. Safety and tolerability monitoring was performed throughout the trial.

[0462] A total of 15 healthy subjects (1 woman and 13 men) were enrolled in the study. Of the 14 subjects, 13 received all treatments and completed the study.

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

[0464] In summary, co-administration of a single dose of famotidine (an H2 receptor antagonist) 10 hours before and 2 hours after a single dose of sotrasib after a meal is effective against sotrasib's C maxIt reduced C15% and AUC by 38%. In addition, simultaneous administration of a single dose of sotrasib and repeated doses of omeprazole (PPI) after meals reduced the C15% of sotrasib. max This reduced the coefficient of interest by 65% ​​and the AUC by 57%.

[0465] Example 6 - Contraindications of simultaneous administration of a potent CYP34A4 inducer and sotracib This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 960 mg of sotrasib on days 1, 3, and 18, and 600 mg of rifampin on days 3 and 5–19. Blood samples for sotrasib PK were collected pre-administration and up to 48 hours after sotrasib administration. Plasma PK parameters for sotrasib were estimated using a non-compartment method.

[0466] result Geometric mean sotrasib AUC after co-administration of a single dose of sotrasib 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 sotrasib alone (25600 h*ng / mL and 6350 ng / mL, respectively). Geometric mean sotrasib AUC after multiple doses of sotrasib and rifampin. inf and C max The levels (12400 h*ng / mL and 4110 ng / mL, respectively) were lower compared to sotrasib alone (25600 h*ng / mL and 6350 ng / mL, respectively).

[0467] Sotrasib was safe and well-tolerated when administered co-administered with 600 mg of rifampin or alone to healthy subjects. A single dose of rifampin did not have a clinically significant effect on the pharmacokinetics of sotrasib, indicating that sotrasib is not a substrate of OATP1B1. Multiple doses of rifampin did not affect the AUC of sotrasib. inf 51%, C maxIt reduced the amount by 35%, indicating that sotracib is a CYP3A4 substrate, which is consistent with in vitro data.

[0468] Example 7 - Contraindications of simultaneous administration of CYP34A substrate and sotracib This Phase 1, open-label, fixed-sequence trial enrolled five subjects with previously untreated NSCLC. They received a single oral dose of 2 mg of midazolam alone one day prior to administration, 960 mg of sotrasib orally from day 1 to day 14, and a single oral dose of 2 mg of midazolam almost simultaneously with the oral administration of 960 mg of sotrasib on day 15. Blood samples for sotrasib PK were collected before administration and up to 48 hours after sotrasib administration. Plasma PK parameters for sotrasib were estimated using a non-compartment method.

[0469] Plasma PK data for single-dose midazolam were obtained from five subjects who received midazolam alone and midazolam co-administered with sotrasib, after 14 days of multiple daily sotrasib administrations. The results showed that exposure to midazolam decreased when co-administered with sotrasib after multiple daily sotrasib administrations. Co-administration of midazolam (highly sensitive CYP3A4 substrate) and sotrasib reduced midazolam's C150 PK levels. max This reduced airborne load by 48% and AUV by 53%.

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

[0471] Time to reach maximum plasma concentration of digoxin (tmax ) and mean terminal half-life (t 1 / 2 The geometric mean digoxin AUC after co-administration of sotrasib and digoxin was similar compared to digoxin alone. 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). Geometric mean digoxin C after simultaneous administration of sotrasib and digoxin. max The maximum plasma concentration (3.64 ng / mL) was higher (1.90 ng / mL) compared to digoxin alone. A single dose of 0.5 mg of digoxin was safe and well-tolerated when administered alone or concurrently with 960 mg of sotrasib.

[0472] The results showed that a single dose of sotrasib combined with digoxin resulted in a higher AUC compared to digoxin alone. inf and C max This showed an increase of approximately 21% and 91%, respectively.

[0473] Example 9 - Panitumumab and sotracib, optionally combined with FOLFIRI, in treatment-naive patients with metastatic colorectal cancer, compared to 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 sotracib, panitumumab, and FOLFIRI, or FOLFOX or FOLFIRI with or without bevacizumab-awwb, in treatment-naive patients with metastatic colorectal cancer (mCRC) bearing the KRAS G12C mutation.

[0474] This trial consists of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Approximately 450 treatment-naive mCRC patients with KRAS G12C mutations will be enrolled and randomized in a 1:1 ratio to receive either sotracib, panitumumab, or FOLFIRI, or chemotherapy (FOLFOX or FOLFIRI) with or without bevacizumab-awwb.

[0475] The subjects are stratified by region, the number of organ sites affected by metastatic disease (1 vs > 1), and age (< 70 years vs ≥ 70 years).

[0476] Day 1 of Cycle 1 is defined as the first day a subject receives the study drug; tumor assessment will be performed at 8-week + / - 1-week intervals (by MRI and / or CT) until baseline, progression as assessed by BICR, initiation of another anticancer drug therapy, withdrawal of consent, failure to follow, or death, whichever comes first. Tumor assessment and response will be 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 anticancer 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 during subsequent therapy, and survival data. Subjects who discontinued treatment before RECIST 1.1 disease progression (e.g., due to unacceptable toxicity) will be followed by radiography until disease progression, withdrawal of consent, or initiation of another anticancer therapy, and thereafter will undergo further long-term follow-up by telephone or clinic visit for survival assessment and anticancer treatment record-keeping. Subjects will be followed for 5 years from the last subject's randomization, or until withdrawal of consent, loss of follow-up, or death of the subject, whichever comes first. The evaluations performed in this trial are described below and will be performed at the times specified in the Evaluation Schedule (SOA).

[0478] Disease progression is assessed using the BICR-based criteria for evaluating the response to solid tumors, version 1.1 (RECIST v1.1).

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

[0480] Clinical safety tests include hematology, blood chemistry, and urinalysis. Vital signs are assessed, including blood pressure and pulse rate; additional vital signs are collected only when clinically appropriate.

[0481] The sample is collected for sotracib PK analysis.

[0482] Patient-reported results (PROs) and quality of life (QOL) assessments are evaluated.

[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 - Participants must either provide stored tumor tissue samples (formalin-fixed, paraffin-embedded [FFPE] samples recovered within the last 5 years) or undergo a pre-treatment tumor biopsy before registration. - Diseases measurable according to RECIST 1.1 criteria. Lesions previously treated with radiation are not considered measurable unless they have progressed since radiation exposure. - Age 18 or older -≤1 in the US East Coast Cancer Clinical Trials Group (ECOG) performance status. ->Average life expectancy of 6 months - If you have previously received adjuvant therapy for a non-metastatic disease, you must have completed adjuvant therapy at least 6 months prior to the identification of the metastatic disease. - Within 10 days prior to randomization, adequate blood and peripheral organ function as defined below: - ANC ≥ 1500 cells / μL (without granulocyte colony-stimulating factor support within 2 weeks of the clinical test used to determine eligibility) - Hemoglobin ≥ 9.0 g / dl (no blood transfusions within 2 weeks of the clinical test used to determine eligibility) - Platelet count ≥ 100,000 / μl (no blood transfusions within 2 weeks of the clinical test used to determine eligibility) - Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels ≤ 2.5 times the upper limit of the normal range (ULN). -Serum bilirubin ≤ 1.0 × ULN - International normalized ratio (INR) and activated partial thromboplastin time ≤ 1.5 × ULN - Serum creatinine ≤ 1.5 × ULN or creatinine clearance > 30 mL / min, based on the Cockcroft-Gault formula or 24-hour urine collection. - QTcF ≤ 470 milliseconds for females, ≤ 450 milliseconds for males. - You are able to take oral medication and are willing to record daily adherence to the investigational product.

[0486] Exclusion criteria: - Previous systemic therapies for metastatic diseases - Active brain metastases. As used herein, the term “active brain metastases” refers to cancer that has spread from the original (primary, non-brain) tumor to the brain. Active brain metastases can be assessed by the presence of intracranial lesions. Although “metastases” is plural, it should be understood that a patient exhibiting only one intracranial lesion under the criteria set forth below is considered to have “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 has completed radiotherapy at least four weeks prior to day 1 of the study, the patient is not considered to have active brain metastases and is eligible if all of the following criteria are met: a) residual neurological symptoms of grade ≤ 2; b) administration of a stable dose or equivalent of dexamethasone, where applicable, for at least two weeks; and c) follow-up MRI performed within 28 days of day 1 shows no progression or appearance of new lesions. For the determination of the grade of any neurological symptoms resulting from 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 whole. -Leptomeningeal disease. - The tumor is known to have the BRAF V600E mutation. - The tumor is known to be MSI-H. - Unresolved toxicity (any grade is acceptable), neurological disorders (up to grade 2 is acceptable), or toxicity from previous antitumor therapy that is considered irreversible (defined as present for more than 6 months and stable), as defined in the eligibility criteria of CTCAE version 5.0, excluding grade 0 or 1 or alopecia. Endocrine AEs that are stably maintained by appropriate replacement therapy. For the determination of the grade of any neurological symptoms resulting from intracranial lesions, 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 whole. - Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormone therapy [excluding subjects receiving long-term adjuvant endocrine therapy or those with a history of complete mastectomy for breast cancer without active disease for more than 5 years] or investigational drug) within 4 weeks of day 1 of the trial); note that bisphosphonate or anti-RANKL antibody therapy is permitted if necessary for the management of hypercalcemia or the prevention of bone-related events. - Therapeutic or symptomatic radiotherapy within two weeks of day 1 of the trial. Participants must have recovered from radiotherapy-related toxicity of CTCAE version 5.0 grade 1 or lower, excluding alopecia (alopecia of any grade is acceptable). - You are currently receiving treatment through another investigational medical device or investigational drug trial, or less than four weeks have passed since the completion of another investigational medical device or investigational drug trial. -Other clinical trial procedures are excluded. -KRAS G12C Previous treatment with inhibitors. - More than 25% of the bone marrow was subjected to cumulative radiation. - Known dihydropyrimidine dehydrogenase deficiency - Known UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease - Known susceptibility to any of the products or components that will be administered during treatment. -To the best of the investigator's knowledge, the subjects have previously required dose reduction or dose postponement of either 5-fluorouracil or irinotecan in their chemotherapy regimens due to toxicity. - Use of known cytochrome P450 (CYP) 3A4 sensitive substrates and P-gp substrates (with a narrow therapeutic range) within 14 days prior to day 1 of the trial, or within 5 half-lives of the drug or its major active metabolite, whichever is longer, if the use has not been reviewed and approved by the principal investigator and medical monitor. - Use of potent CYP3A4 inducers (including herbal nutritional supplements such as St. John's wort) within 14 days prior to day 1 of the trial or within 5 half-lives (whichever is longer) without review and approval by the principal investigator and medical monitor. - Use of a known CYP3A4 or UGT1A1 inhibitor at least one week prior to initiating irinotecan therapy, unless reviewed and approved by the principal investigator and medical monitor. - Use of antiretroviral or viral drugs that may interact with the investigational drug, unless reviewed and approved by the principal investigator and medical monitor. - For women of potential pregnancy who do not wish to use the contraceptive methods specified in the protocol during treatment and / or for the following periods: - 7 days after the last dose of sotrasib - 2 months after the last dose of panitumumab - 6 months after the last dose of FOLFIRI -9 months after the last dose of FOLFOX - 6 months after the last dose of bevacizumab - For women who are breastfeeding or plan to breastfeed from the start of the trial until the following period: - 7 days after the last dose of sotrasib - 2 months after the last dose of panitumumab - 6 months after the last dose of FOLFIRI - 3 months after the last dose of FOLFOX - 6 months after the last dose of bevacizumab - For women who are expected to become pregnant during the following period: - 7 days after the last dose of sotrasib - 2 months after the last dose of panitumumab - 6 months after the last dose of FOLFIRI -9 months after the last dose of FOLFOX - 6 months after the last dose of bevacizumab - This program is for women who may be pregnant and who have a positive pregnancy test result using a highly sensitive urine or serum pregnancy test at the time of screening or on day 1. - For men who practice sexual abstinence (refraining from heterosexual intercourse) during treatment and for the following periods, or who have a female partner who does not wish to use contraception or who may become pregnant: - 7 days after the last dose of sotrasib - 6 months after the last dose of FOLFIRI - 6 months after the last dose of FOLFOX - 6 months after the last dose of bevacizumab - For men with a pregnant partner who does not wish to abstain from sex or use condoms during treatment and / or for the following periods: - 7 days after the last dose of sotrasib - 6 months after the last dose of FOLFIRI - 6 months after the last dose of FOLFOX - 6 months after the last dose of bevacizumab - For men who do not wish to refrain from sperm donation during the trial and / or the following periods: - 7 days after the last dose of sotrasib - 6 months after the last dose of FOLFIRI - 6 months after the last dose of FOLFOX - 6 months after the last dose of bevacizumab - Use of warfarin. Other anticoagulants may be permitted with the approval of the medical monitor. - Known HIV with CD4+ T cell count <350 cells / μl - History of opportunistic infections defining acquired immunodeficiency syndrome within the past 12 months - Known hepatitis B with detectable viral load, or hepatitis C with detectable viral load - Malignant tumors other than CRC within 5 years prior to randomization, excluding those treated with appropriate treatment for cervical carcinoma in situ, basal cell carcinoma, cutaneous squamous cell carcinoma, localized prostate cancer treated for the cure, or ductal carcinoma in situ surgically treated for the cure, where the risk of metastasis or death is negligible and a curative outcome is expected (e.g., appropriately treated cervical carcinoma in situ, basal cell carcinoma, cutaneous squamous cell carcinoma, localized prostate cancer treated for the cure, or ductal carcinoma in situ surgically treated for the cure). - Major surgery within 28 days of the first day of the exam - In the opinion of the principal investigator, there are uncontrolled serious complications that could affect adherence to the protocol or interpretation of results, or that could pose a risk to the safety of the subjects. - Severe gastrointestinal disorders causing severe malabsorption, need for intravenous nutritional support, or inability to take oral medications. - A history of interstitial pneumonia or pulmonary fibrosis, or evidence of interstitial pneumonia or pulmonary fibrosis on a baseline CT scan. -Unless agreed upon with a medical monitor and meeting the following criteria, a history of evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not permitted: - Testing for SARS-CoV-2 by local standard care within 72 hours of the first dose of sotrasib is negative. - No acute symptoms of coronavirus infection 2019 (COVID-19) within 10 days prior to the first dose of sotrasib. - New York Heart Association (Class II or higher), myocardial infarction, unstable arrhythmia, or unstable angina within 6 months prior to randomization, or other significant cardiovascular disease. - If the subject is randomly assigned to an arm of the investigator's choice, the investigator will select the subject with uncontrolled hypertension (SBP > 140 or DB > 90) who is scheduled to receive bevacizumab. - Peripheral neuropathy ≥ Grade 2 in patients selected by the principal investigator for FOLFOX or FOLFOX and bevacizumab. - Oral or intravenous administration of therapeutic antibiotics within two weeks prior to randomization. Prophylactic use of antibiotics is permitted.

[0487] Test product: - Sotrasib 960 mg or 240 mg orally, once daily. - Panitumumab 6 mg / kg IV once every two weeks -Bevacizumab-awwb 5mg / kg IV once every two weeks

[0488] FOLFIRI: - Irinotecan 180 mg / m² once every two weeks 2 IV - Leucovorin 400 mg / m² once every two weeks 2 IV -5-Fluorouracil 400 mg / m² 2 IV bolus once every two weeks -5-Fluorouracil 2400 mg / m² 2 IVCI is administered every two weeks over a period of 46-48 hours.

[0489] FOTABLEOX: -Oxaliplatin 85 mg / m² 2 IV once every two weeks - Leucovorin 400 mg / m² once every two weeks 2 IV -5-Fluorouracil 400 mg / m² 2 IV bolus once every two weeks -5-Fluorouracil 2400 mg / m² 2 IVCI is administered every two weeks over a period of 46-48 hours.

[0490] Objectives / Evaluation Items:

[0491] [Table 40]

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

[0493] This trial consists of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Approximately 350 previously treated mCRC patients with KRAS G12C mutations will be enrolled and randomized in a 1:1 ratio to receive either sotracib, panitumumab, or FOLFIRI, or FOLFIRI with or without bevacizumab-awwb.

[0494] The subjects are stratified by region, the number of organ sites affected by metastatic disease (1 vs > 1), and age (< 70 years vs ≥ 70 years).

[0495] Day 1 of Cycle 1 is defined as the first day a subject receives the study drug; tumor assessment will be performed at 8-week + / - 1-week intervals (by MRI and / or CT) until baseline, progression as assessed by BICR, initiation of another anticancer drug therapy, withdrawal of consent, failure to follow, or death, whichever comes first. Tumor assessment and response will be 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 anticancer 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 during subsequent therapy, and survival data. Subjects who discontinued treatment before RECIST 1.1 disease progression (e.g., due to unacceptable toxicity) will be followed by radiography until disease progression, withdrawal of consent, or initiation of another anticancer therapy, and thereafter will be further long-term follow-up by telephone or clinic visit for survival assessment and recording of anticancer treatment. Subjects will be followed for 5 years from the last subject's randomization, or until withdrawal of consent, loss of follow-up, or death of the subject, whichever comes first.

[0497] The assessments performed in this test are described below and will be conducted at the times specified in the Assessment Schedule (SOA). - Disease progression is assessed using the solid tumor response criteria, version 1.1 (RECIST v1.1), as evaluated by BICR. - Safety is monitored by evaluating serious and non-serious adverse events (AEs), safety clinical trials, and vital signs. The incidence, nature, and severity of all AEs are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0). Clinical safety tests include hematology, blood chemistry, and urinalysis. Vital signs assessment includes blood pressure and pulse rate; additional vital signs are collected only when clinically appropriate. - The sample is collected for sotracib PK analysis. - Patient-reported results (PROs) and quality of life (QOL) assessments are evaluated. - The sample is collected for sotracib PK analysis. - Samples are collected for tumor markers. - 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 previously identified KRAS G12C mutations via local testing. - Participants must either provide stored tumor tissue samples (formalin-fixed, paraffin-embedded [FFPE] samples recovered within the last 5 years) or undergo a pre-treatment tumor biopsy before registration. - Diseases measurable according to RECIST 1.1 criteria. Lesions previously treated with radiation are not considered measurable unless they have progressed since radiation exposure. - Age 18 or older -≤1 in the US East Coast Cancer Clinical Trials Group (ECOG) performance status. ->Average life expectancy of 6 months - Patients must have previously received only one line of systemic therapy for metastatic disease and have progressed during or after that therapy. If adjuvant therapy has been previously administered for non-metastatic disease, it will be counted as a line of therapy for metastatic disease if metastatic disease is identified within six months of the completion of adjuvant therapy. If the tumor is MSI-H, patients must have received checkpoint inhibitors for metastatic disease, if available in their region or country, and they must not have any medical contraindications to that therapy. - Within 10 days prior to randomization, adequate blood and peripheral organ function as defined below: - ANC ≥ 1500 cells / μL (without granulocyte colony-stimulating factor support within 2 weeks of the clinical test used to determine eligibility) - Hemoglobin ≥ 9.0 g / dl (no blood transfusions within 2 weeks of the clinical test used to determine eligibility) - Platelet count ≥ 100,000 / μl (no blood transfusions within 2 weeks of the clinical test used to determine eligibility) - Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels ≤ 2.5 times the upper limit of the normal range (ULN). -Serum bilirubin ≤ 1.0 × ULN - International normalized ratio (INR) and activated partial thromboplastin time ≤ 1.5 × ULN - Serum creatinine ≤ 1.5 × ULN or creatinine clearance > 30 mL / min, based on the Cockcroft-Gault formula or 24-hour urine collection. - QTcF ≤ 470 milliseconds for females, ≤ 450 milliseconds for males. - You are able to take oral medication and are willing to record daily adherence to the investigational product.

[0499] Exclusion criteria: - Active brain metastases. As used herein, the term “active brain metastases” refers to cancer that has spread from the original (primary, non-brain) tumor to the brain. Active brain metastases can be assessed by the presence of intracranial lesions. Although “metastases” is plural, it should be understood that a patient exhibiting only one intracranial lesion under the criteria set forth below is considered to have “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 has completed radiotherapy at least four weeks prior to day 1 of the study, the patient is not considered to have active brain metastases and is eligible if all of the following criteria are met: a) residual neurological symptoms of grade ≤ 2; b) administration of a stable dose or equivalent of dexamethasone, where applicable, for at least two weeks; and c) follow-up MRI performed within 28 days of day 1 shows no progression or appearance of new lesions. For the determination of the grade of any neurological symptoms resulting from 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 whole. -Leptomeningeal disease. - The tumor is known to have the BRAF V600E mutation. - Unresolved toxicity (any grade is acceptable), neuropathy (up to grade 2 is acceptable), or toxicity from previous antitumor therapy that is considered irreversible (defined as having been present for more than 6 months and being stable), as defined in the eligibility criteria of CTCAE version 5.0, excluding grade 0 or 1 or alopecia. - Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormone therapy [excluding subjects receiving long-term adjuvant endocrine therapy or those with a history of complete mastectomy for breast cancer without active disease for more than 5 years] or investigational drug) within 4 weeks of day 1 of the trial); note that bisphosphonate or anti-RANKL antibody therapy is permitted if necessary for the management of hypercalcemia or the prevention of bone-related events. - Therapeutic or symptomatic radiotherapy within two weeks of day 1 of the trial. Participants must have recovered from radiotherapy-related toxicity of CTCAE version 5.0 grade 1 or lower, excluding alopecia (alopecia of any grade is acceptable). - You are currently receiving treatment through another investigational medical device or investigational drug trial, or less than four weeks have passed since the completion of another investigational medical device or investigational drug trial. -Other clinical trial procedures are excluded. -KRAS G12C Previous treatment with inhibitors. - More than 25% of the bone marrow was subjected to cumulative radiation. - Known dihydropyrimidine dehydrogenase deficiency - Known UDP-glucuronosyltransferase 1A1 (UGT1A1)*28 homozygosity or Gilbert's disease - Known susceptibility to any of the products or components that will be administered during treatment. -To the best of the investigator's knowledge, the subjects have previously required dose reduction or dose postponement of either 5-fluorouracil or irinotecan in their chemotherapy regimens due to toxicity. -The patient has previously received treatment with irinotecan for metastatic disease. - Use of known cytochrome P450 (CYP) 3A4 sensitive substrates and P-gp substrates (with a narrow therapeutic range) within 14 days prior to day 1 of the trial, or within 5 half-lives of the drug or its major active metabolite, whichever is longer, if the use has not been reviewed and approved by the principal investigator and medical monitor. - Use of potent CYP3A4 inducers (including herbal nutritional supplements such as St. John's wort) within 14 days prior to day 1 of the trial or within 5 half-lives (whichever is longer) without review and approval by the principal investigator and medical monitor. - Use of a known CYP3A4 or UGT1A1 inhibitor at least one week prior to initiating irinotecan therapy, unless reviewed and approved by the principal investigator and medical monitor. - Use of antiretroviral or viral drugs that may interact with the investigational drug, unless reviewed and approved by the principal investigator and medical monitor. - For women of potential pregnancy who do not wish to use the contraceptive methods specified in the protocol during treatment and / or for the following periods: - 7 days after the last dose of sotrasib - 2 months after the last dose of panitumumab - 6 months after the last dose of FOLFIRI - 6 months after the last dose of bevacizumab - For women who are breastfeeding or plan to breastfeed from the start of the trial until the following period: - 7 days after the last dose of sotrasib - 2 months after the last dose of panitumumab 7 days after the last dose of FOLFIRI - 6 months after the last dose of bevacizumab - For women who are expected to become pregnant during the following period: - 7 days after the last dose of sotrasib - 2 months after the last dose of panitumumab - 6 months after the last dose of FOLFIRI - 6 months after the last dose of bevacizumab - This program is for women who may be pregnant and who have a positive pregnancy test result using a highly sensitive urine or serum pregnancy test at the time of screening or on day 1. - For men who practice sexual abstinence (refraining from heterosexual intercourse) during treatment and for the following periods, or who have a female partner who does not wish to use contraception or who may become pregnant: - 7 days after the last dose of sotrasib - 6 months after the last dose of FOLFIRI - 6 months after the last dose of bevacizumab - For men with a pregnant partner who does not wish to abstain from sex or use condoms during treatment and / or for the following periods: - 7 days after the last dose of sotrasib - 6 months after the last dose of FOLFIRI - 6 months after the last dose of bevacizumab - For men who do not wish to refrain from sperm donation during the trial and / or the following periods: - 7 days after the last dose of sotrasib - 6 months after the last dose of FOLFIRI - 6 months after the last dose of bevacizumab - Use of warfarin. Other anticoagulants may be permitted with the approval of the medical monitor. - Known HIV with CD4+ T cell count <350 cells / μl - History of opportunistic infections defining acquired immunodeficiency syndrome within the past 12 months - Known hepatitis B with detectable viral load, or hepatitis C with detectable viral load - Malignant tumors other than CRC within 5 years prior to randomization, excluding those treated with appropriate treatment for cervical carcinoma in situ, basal cell carcinoma, cutaneous squamous cell carcinoma, localized prostate cancer treated for the cure, or ductal carcinoma in situ surgically treated for the cure, where the risk of metastasis or death is negligible and a curative outcome is expected (e.g., appropriately treated cervical carcinoma in situ, basal cell carcinoma, cutaneous squamous cell carcinoma, localized prostate cancer treated for the cure, or ductal carcinoma in situ surgically treated for the cure). - Major surgery within 28 days of the first day of the exam - In the opinion of the principal investigator, there are uncontrolled serious complications that could affect adherence to the protocol or interpretation of results, or that could pose a risk to the safety of the subjects. - Severe gastrointestinal disorders causing severe malabsorption, need for intravenous nutritional support, or inability to take oral medications. - A history of interstitial pneumonia or pulmonary fibrosis, or evidence of interstitial pneumonia or pulmonary fibrosis on a baseline CT scan. -Unless agreed upon with a medical monitor and meeting the following criteria, a history of evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not permitted: - Testing for SARS-CoV-2 by local standard care within 72 hours of the first dose of sotrasib is negative. - No acute symptoms of coronavirus infection 2019 (COVID-19) within 10 days prior to the first dose of sotrasib. - New York Heart Association (Class II or higher), myocardial infarction, unstable arrhythmia, or unstable angina within 6 months prior to randomization, or other significant cardiovascular disease. - If the subject is randomly assigned to an arm of the investigator's choice, the investigator will select the subject with uncontrolled hypertension (SBP > 140 or DB > 90) who is scheduled to receive bevacizumab. - Oral or intravenous administration of therapeutic antibiotics within two weeks prior to randomization. Prophylactic use of antibiotics is permitted.

[0500] Test product: - Sotrasib 960 mg or 240 mg orally, daily - Panitumumab 6 mg / kg IV once every two weeks -Bevacizumab-awwb 5mg / kg IV once every two weeks

[0501] FOLFIRI: - Irinotecan 180 mg / m² once every two weeks 2 IV - Leucovorin 400 mg / m² once every two weeks 2 IV -5-Fluorouracil 400 mg / m² 2 IV bolus once every two weeks -5-Fluorouracil 2400 mg / m² 2 IVCI is administered every two weeks over a period of 46-48 hours.

[0502] Objectives / Evaluation Items:

[0503] [Table 41]

[0504] All publications and patent applications referenced herein represent the level of art of those skilled in the art relating to the present invention. All publications and patent applications are incorporated herein by reference in the same way that each individual publication or patent application is specifically and individually indicated to be incorporated by reference.

[0505] Although the above invention has been described in some detail by examples and embodiments for the sake of clarity, it will be apparent that certain changes and modifications may be made within the scope of the attached 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 (registered trademark) 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. A method for treating cancer containing the KRAS G12C mutation in a patient, comprising administering to the patient an effective amount of (a) sotrasib and (b) an anti-epidermal growth factor receptor (EGFR) antibody for treating the cancer.

2. The method according to claim 1, comprising administering 960 mg of sotrasib to the patient daily.

3. The method according to claim 1, comprising administering 240 mg of sotrasib to the patient daily.

4. The method according to any one of claims 1 to 3, comprising administering sotrasib to the patient once daily.

5. The method according to any one of claims 1 to 3, comprising administering sotrasib to the patient twice a day.

6. The method according to any one of claims 1 to 5, wherein the anti-EGFR antibody is panitumumab.

7. The method according to claim 6, comprising administering 6 mg / kg of panitumumab to the patient.

8. (a) 960 mg of sotrasib daily; and (b) Panitumumab 6 mg / kg administered IV every two weeks The method according to claim 6 or claim 7, comprising administering to the patient.

9. (a) 240 mg of sotrasib daily; and (b) Panitumumab 6 mg / kg administered IV every two weeks The method according to claim 6 or claim 7, comprising administering to the patient.

10. The method according to any one of claims 1 to 13, further comprising administering (c) irinotecan, (d) 5-FU, and (e) leucovorin or levoleucovorin to the patient.

11. IV administration of 400 mg / m² ２ The method according to claim 10, comprising administering leucovorin to the patient.

12. IV administration of 200 mg / m² ２ The method according to claim 10, comprising administering levoleucovorin to the patient.

13. IV administration of 180 mg / m² ２ The method according to any one of claims 10 to 12, comprising administering irinotecan to the patient.

14. IV administration of 400 mg / m² ２ The method according to any one of claims 10 to 13, comprising administering 5-FU to the patient.

15. IV administration resulted in 180 mg / m² ２ Irinotecan, 400 mg / m² ２ Leucovorin, and 400 mg / m² ２ Administer 5-FU to the patient every two weeks as an IV bolus, and 2400 mg / m² ２ The method according to claim 10, comprising administering 5-FU to the patient by continuous IV infusion over a period of 46 to 48 hours.

16. By intravenous administration, irinotecan at 180 mg / m ２ , leucovorin at 200 mg / m ２ , and an IV bolus of 5-FU at 400 mg / m ２ , as well as a 46- to 48-hour IV continuous infusion of 5-FU at 2400 mg / m ２ are administered to the patient every two weeks, the method according to claim 10, comprising this.

17. The method according to any one of claims 1 to 16, wherein the cancer is a solid tumor.

18. The method according to any one of claims 1 to 17, wherein the cancer is non-small cell lung cancer (NSCLC).

19. The method according to any one of claims 1 to 17, wherein the cancer is metastatic pancreatic cancer.

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

21. The method according to any one of claims 1 to 17, wherein the cancer is metastatic colorectal cancer (mCRC).

22. The method according to any one of claims 1 to 36, wherein the patient has received at least one prior systemic cancer therapy.

23. The method according to any one of claims 1 to 36, wherein the patient has received at least two prior systemic cancer therapies.

24. The method according to claim 22 or claim 23, wherein the systemic cancer therapy comprises administering a fluoropyrimidine, irinotecan, and oxaliplatin to the patient.

25. The method according to any one of claims 21 to 24, wherein the mCRC is determined to be MSI-H, and the systemic cancer therapy is a therapy comprising administering a checkpoint inhibitor to the patient.

26. The method according to any one of claims 21 to 25, wherein the mCRC comprises the BRAF V600E mutation, and the systemic cancer therapy comprises administering encorafenib and cetuximab to the patient.

27. The method according to any one of claims 21 to 26, wherein the patient exhibits an ECOG performance status of 2 or less.

28. The method according to any one of claims 21 to 27, wherein the patient does not have active brain metastases.

29. The aforementioned systemic therapy is KRAS Ｇ１２Ｃ A method according to any one of claims 22 to 28, wherein the therapy does not involve administering an inhibitor to the patient.

30. The method according to any one of claims 1 to 21, wherein the patient has not received prior systemic cancer therapy.

31. The method according to claim 30, wherein the patient does not have active brain metastases.

32. The method according to claim 30 or claim 31, wherein the mCRC does not contain the BRAF V600E mutation.

33. The method according to any one of claims 30 to 32, wherein the mCRC is determined not to be MSI-H.

34. The aforementioned systemic therapy is KRAS Ｇ１２Ｃ The method according to any one of claims 30 to 33, comprising administering an inhibitor to the patient.

35. The method according to any one of claims 30 to 34, wherein the patient exhibits an ECOG performance status of 1 or less.

36. The method according to any one of claims 1 to 21, wherein the patient has received one prior systemic cancer therapy.

37. The method according to claim 36, wherein, if the cancer is determined to be MSI-H, the systemic cancer therapy is a checkpoint inhibitor.

38. The method according to claim 36 or claim 37, wherein the patient is receiving the systemic cancer therapy and the disease progresses during or after the therapy.

39. The aforementioned systemic therapy is KRAS Ｇ１２Ｃ The method according to any one of claims 36 to 38, wherein the therapy does not involve administering an inhibitor to the patient.

40. The method according to any one of claims 36 to 38, wherein the systemic therapy is not a therapy that includes the administration of irinotecan.

41. The method according to any one of claims 36 to 40, wherein the patient exhibits an ECOG performance status of 1 or less.

42. The method according to any one of claims 36 to 41, wherein the patient does not have active brain metastases.

43. The method according to any one of claims 36 to 42, wherein the mCRC does not contain the BRAF V600E mutation.

44. The method according to any one of claims 1 to 43, wherein the patient exhibits at least stable disease (SD) one, three, or six months after sotrasib and panitumumab therapy, as measured by the RECIST 1.1 protocol.

45. The method according to any one of claims 1 to 43, wherein the patient exhibits at least a partial response (PR) one, three, or six months after sotrasib and panitumumab therapy, as measured by the RECIST 1.1 protocol.

46. The method according to any one of claims 1 to 45, wherein the patient further requires treatment with an antacid.

47. The method according to claim 46, wherein the antacid is a proton pump inhibitor (PPI), an H2 receptor antagonist (H2RA), or a topical antacid.

48. The method according to claim 46 or claim 47, wherein the antacid is a topical antacid, and sotrasib is administered about 4 hours before or about 10 hours after the topical antacid.

49. The method according to any one of claims 1 to 48, wherein the patient further requires treatment with a proton pump inhibitor (PPI) or an H2 receptor antagonist (H2RA).

50. The method according to claim 49, wherein the patient is not administered a PPI or H2RA in combination with sotrasib.

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