Sotorasib Dosing Regimen

Abstract

Provided herein is a method of administering a total daily dose of 240 mg sotorasib to a patient suffering from a cancer with a KRAS G12C mutation.Also provided herein is a method of treating a KRAS G12C mutant cancer in a patient, comprising administering a total daily dose of 960 mg sotorasib to the patient, and reducing the total daily dose of sotorasib to 480 mg in patients experiencing adverse events to the 960 mg dose of sotorasib.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 162,273, filed March 17, 2021, U.S. Provisional Patent Application No. 63 / 185,054, filed May 6, 2021, and U.S. Provisional Patent Application No. 63 / 190,096, filed May 18, 2021, all of which are incorporated by reference in their entireties herein. [Background technology]

[0002] The rat sarcoma (RAS) proto-oncogene has been identified as an oncogenic driver of tumorigenesis in cancers such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The RAS family consists of three closely related genes expressing guanosine triphosphate (GTP)ases involved in regulating cell proliferation and survival. The RAS proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS), can be mutationally activated at codons 12, 13, or 61 to cause human cancers. Different tumor types are associated with mutations in specific isoforms of RAS, with KRAS being the most frequently mutated isoform in the majority of cancers. The role of KRAS mutations in human cancers has been known for decades, but until recently, anti-cancer therapies that specifically target KRAS mutations have not been successfully developed because the protein has generally been considered difficult to inhibit with small molecules. Summary of the Invention [Means for solving the problem]

[0003] Provided herein is a method of treating cancer in a patient, comprising administering to the patient a total daily dose of 240 mg of sotorasib, wherein the cancer is a KRAS G12C mutant cancer.

[0004] Also provided herein is a method of treating cancer in a patient, comprising administering to the patient an initial total daily dose of 960 mg of sotorasib, and if the patient experiences an adverse event to the initial total daily dose, administering a reduced total daily dose of sotorasib to 480 mg, wherein the cancer is a KRAS G12C mutant cancer. In some embodiments, the method further comprises administering a second reduced total daily dose of sotorasib of 240 mg if the patient experiences an adverse event to the reduced total daily dose.

[0005] In various embodiments, sotorasib is administered once a day. In various embodiments, sotorasib is administered orally. In various embodiments, the patient is administered sotorasib for at least one month. In various embodiments, the patient is administered sotorasib for at least three months. In various embodiments, the patient is administered sotorasib for at least six months.

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

[0007] In various embodiments, the patient has received at least one other systemic cancer therapy prior to the initiation of sotorasib therapy. In various embodiments, the patient has received at least two other systemic cancer therapies. In various embodiments, the at least one systemic cancer therapy is selected from anti-PD1 immunotherapy, anti-PDL1 immunotherapy, and platinum-based chemotherapy. In various embodiments, the patient has previously received (i) anti-PD1 therapy or anti-PDL1 therapy, unless contraindicated, or (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK, or ROS1. In various embodiments, the patient has previously received (i) anti-PD1 therapy or anti-PDL1 therapy, unless contraindicated, and (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK, or ROS1.

[0008] In various embodiments, the patient has no active brain metastases within 4 weeks of initiating sotorasib therapy. In various embodiments, the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

[0009] In various embodiments, patients exhibit stable disease (SD) as measured by RECIST 1.1 protocol after at least 1, 3, or 6 months of sotorasib therapy. In various embodiments, stable disease is neither shrinking enough to qualify as a partial response (PR) nor expanding enough to qualify as progressive disease (PD).

[0010] In various embodiments, the patient exhibits at least a partial response (PR) as measured by RECIST 1.1 protocol after 1, 3, or 6 months of sotorasib therapy. In various embodiments, a partial response is at least a 30% reduction in the sum of the diameters of the target lesions.

[0011] In various embodiments, the patient exhibits a progression free survival (PFS) of at least 3 months. In various embodiments, the patient exhibits a PFS of at least 6 months.

[0012] In various embodiments, the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of 1-49%. In various embodiments, the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of less than 1%. In various embodiments, the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of 50-100%. In various embodiments, the cancer further comprises an STK11 mutation. In various embodiments, the cancer further comprises a KEAP1 mutation. In various embodiments, the cancer further comprises an STK11 wild type. In various embodiments, the cancer further comprises a KEAP1 wild type. [Brief description of the drawings]

[0013] [Figure 1] 1 shows the mean plasma concentration-time profiles following once-daily oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1, where N indicates the number of observations across data points. [Diagram 2] 1 shows the mean plasma concentration-time profiles following once-daily oral administration of 180, 360, 720, or 960 mg sotorasib on day 8, where N indicates the number of observations across data points. [Diagram 3] Figure 1 shows box plots of best tumor shrinkage in patients with non-small cell lung cancer given sotorasib 180 mg QD, 360 mg QD, 720 mg QD, or 960 mg QD, where n is the number of patients. Percent change from baseline in sum of diameters considers only tumor assessments prior to the first assessment where the response at time point was progressive disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Provided herein is a method of administering sotorasib to a patient having a cancer with a KRAS G12C mutation. G12CIt is a small molecule that irreversibly inhibits mutant proteins. Sotorasib is also AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one, and has the following structure: [ka]

[0015] Sotorasib binds to the P2 pocket and nucleotide-binding pocket of KRAS adjacent to the mutant cysteine ​​at position 12. The inhibitor covalently modifies the cysteine ​​residue, inhibiting KRAS in the inactive guanosine diphosphate (GDP)-bound conformation. G12C It contains a thiol-reactive moiety that locks the KRAS receptor activator (CRC) in the target cell. This prevents downstream signaling, including extracellular signal-regulated kinase (ERK) phosphorylation, by blocking KRAS interaction with effectors such as rapidly progressing fibrosarcoma (RAF) (Cully and Downward, 2008; Ostrem et al., 2013; Simanshu et al., 2017). Inactivation of KRAS by RNA interference (RNAi) or small molecule inhibition has previously demonstrated inhibition of cell proliferation and induction of apoptosis in tumor cell lines and xenografts harboring KRAS mutations, including the KRAS G12C mutation (Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016). Studies with sotorasib confirmed these in vitro findings, similarly demonstrating inhibition of growth and regression of cells and tumors harboring the KRAS G12C mutation (Canon et al., 2019).

[0016] In various embodiments of the present disclosure, the patient is administered a total daily dose of 240 mg of sotorasib. In some embodiments, sotorasib is administered once a day. In various embodiments, sotorasib is administered orally. In various embodiments, sotorasib is administered with a meal. In various embodiments, sotorasib is administered without a meal.

[0017] In various embodiments, the patient further requires treatment with an antacid. Antacids include, but are not limited to, proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and topical antacids. In one embodiment, the patient further requires treatment with a PPI or H2RA. Exemplary PPIs include, but are not limited to, esomeprazole, lansoprazole, rabeprazole, and dexlansoprazole. Exemplary PPIs include, but are not limited to, omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. Exemplary H2RAs include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine, roxatidine, and lafutidine. Exemplary topical antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide. In some embodiments, the patient is not administered a proton pump inhibitor or an H2 receptor antagonist in combination with sotorasib. In some embodiments, in conditions where the patient further requires treatment with an antacid, sotorasib is administered about 4 hours before or about 10 hours after the locally acting antacid.

[0018] In various embodiments, the patient further requires treatment with a CYP3A4 inducer. In some embodiments, the patient is not administered a CYP3A4 inducer in combination with sotorasib. Exemplary CYP3A4 inducers include, but are not limited to, barbiturates, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, and troglitazone. See, e.g., Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), www.drug-interactions.medicine.iu.edu, accessed May 2021. In some embodiments, the patient is not administered a strong CYP3A4 inducer in combination with sotorasib. Exemplary strong CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. See, e.g., www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed May 2021.

[0019] In various embodiments, the patient further requires treatment with a CYP3A4 substrate. In some embodiments, the patient is not administered a CYP3A4 substrate in combination with sotorasib. Exemplary CYP3A4 substrates include abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilonate, cyclosporine ... Stazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib, cyclosporine, dabrafenib, daclatasvir, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, dolutegravir, domperidone, doxepin, elagolix, elbasvir / grazoprevir, eliglustat, enzalutamide, eplerenone, erythro Mycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, Gleevec, haloperidol, hydrocortisone, ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isavuconazonium, ivabradine, ivacaftor, lansoprazole, lenvatinib, lercanidipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, midazolam, naldemedine, naloxegol, nate Glinides, Nelfinavir, Neratinib, Netupitant / Palonosetron, Nevirapine, Nifedipine, Nisoldipine, Nitrendipine, Olaparib, Omeprazole, Ondansetron, Osimertinib, Ospemifene, Palbociclib, Panobinostat, Pantoprazole, Perampanel, Pimavanserin, Pimozide, Pomalidomide, Ponatinib, Progesterone, Propranolol, Quetiapine, Quinidine, Quinine, Regorafenib, Ribociclib, Rilpivirine, Risperidone, Ritonavir,These include, but are not limited to, rivaroxaban, roflumilast, rolapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus, sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus (fk506), tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, vilazodone, vincristine, vorapaxar, voriconazole, zaleplon, and ziprasidone. See, for example, Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), https: / / drug-interactions.medicine.iu.edu, accessed May 2021.

[0020] In some embodiments, the patient is not administered a CYP3A4 substrate in combination with sotorasib, and the CYP3A4 substrate is a CYP3A4 substrate with a narrow therapeutic index. Exemplary CYP3A4 substrates with narrow therapeutic indexes include, but are not limited to, alfentanil, fentanyl, cyclosporine, pimozide, dihydroergotamine, quinidine, ergotamine, cyclosporine, everolimus, and tacrolimus.

[0021] In various embodiments, the patient further requires treatment with a P-glycoprotein (P-gp) substrate. In some embodiments, the patient is not administered a P-gp substrate in combination with sotorasibe. Exemplary P-gp substrates include, but are not limited to, dabigatran etexilate, digoxin, and fexofenadine. 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, the patient is not administered a P-gp substrate in combination with sotorasibe, and the P-gp substrate is a P-gp substrate with a narrow therapeutic index. Exemplary P-gp substrates with a narrow therapeutic index include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, tacrolimus, and vincristine. P-gp substrates with narrow therapeutic indices are compounds for which minimal concentration changes can cause significant toxicity.

[0022] In various embodiments, the patient has KRAS prior to administration of sotorasib as disclosed herein. G12C have a cancer determined to have one or more cells that express a mutant KRAS protein. G12C Determination of mutant proteins may be assessed as described elsewhere in this disclosure.

[0023] The patient to whom 240 mg of sotorasib is administered in the methods disclosed herein may have been previously treated with a systemic cancer therapy, for example, at least one other systemic cancer therapy, such as one, or two, or three. In some embodiments, the patient to whom sotorasib is administered in the methods described herein has not been previously treated with a systemic cancer therapy. In some embodiments, the patient has been previously treated with one other systemic cancer therapy, such that sotorasib therapy is a second-line therapy. In some embodiments, the patient has been previously treated with two other systemic cancer therapies, such that sotorasib therapy is a third-line therapy.

[0024] In some embodiments, the prior systemic cancer therapy is G12C In some embodiments, the prior systemic cancer therapy is a therapy with a KRAS inhibitor. G12C In certain embodiments, the patient is not a patient with KRAS inhibitor therapy. G12C In some embodiments, the patient exhibits reduced sensitivity to therapy with a KRAS inhibitor. G12C In some embodiments, the KRAS G12C The inhibitor is sotorasib, adagrasib, GDC-6036, D-1553, JDQ443, LY3537982, BI1823911, JAB-21822, RMC-6291, or APG-1842. G12C In certain embodiments, the KRAS inhibitor is sotorasib. G12C The inhibitor is adagrasib. In some embodiments, the therapy is monotherapy. In one embodiment, the KRAS G12C In another embodiment, the inhibitor therapy is sotorasib monotherapy. G12C Inhibitor therapy is monotherapy with adagrasib.

[0025] As used herein, "sensitivity" refers to the manner in which a cancer responds to a drug, e.g., sotorasib. In an exemplary embodiment, "sensitivity" means "responsive to treatment," and the concepts of "sensitivity" and "responsiveness" show a positive association in that a cancer or tumor that responds to a drug treatment is said to be sensitive to that drug. "Sensitivity" in the exemplary case is defined as the ability of a population, individual, or tissue, compared to the other's ability, to respond in a qualitatively normal way to a particular drug dose, according to Pelikan, Edward, Glossary of Terms and Symbols used in Pharmacology (Pharmacology and Experimental Therapeutics Department Glossary at Boston University School of Medicine). The lower the dose required to produce an effect, the more sensitive the responsive system is. "Sensitivity" may be quantitatively measured or described with reference to the intersection of the dose-effect curve with the axis of the abscissa value or a line parallel to it; such a point corresponds to the exact dose required to produce a given degree of effect. Similarly, the "sensitivity" of a measurement system is defined as the minimum input (minimum amount) required to produce a given degree of output (effect). In an exemplary embodiment, "sensitivity" is the opposite of "resistance," and the concept of "resistance" is negatively related to "sensitivity."

[0026] For example, a cancer that is resistant to drug treatment is either not sensitive or responsive to the drug, or was initially sensitive to the drug and is no longer sensitive upon acquiring resistance; the drug is no longer an effective treatment for the tumor or cancer cells, or is no longer an effective treatment.

[0027] Previous systemic cancer therapy includes, but is not limited to, chemotherapy and immunotherapy.Particularly considered previous systemic cancer therapy includes anti-PD1 therapy, anti-PDL1 therapy, platinum-based chemotherapy, and anti-EGFR therapy.Some examples of anti-PD1 therapy and anti-PDL1 therapy include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, tisielizumab, toripalimab, aspartalizumab, dostarlimab, retifanlimab, simtilimab, pidilizumab, atezolizumab, avelumab, and durvalumab. In some embodiments, the anti-PD1 therapy or anti-PDL1 therapy is valstilimab, budigalimab, kadonilimab, camrelizumab, cetrelimab, cemiplimab, dostarlimab, ezabenlimab, phytonlimab, nivolumab, penprimab, pembrolizumab, pucotenlimab, retifanlimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, toripalimab, zelvalimab (AMG 404), and zimberelimab. In certain embodiments, the anti-PD1 therapy or antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab. Some examples of anti-PDL1 therapy or antibody include, but are not limited to, adebulimab, atezolizumab, avelumab, cosibelimab, durvalumab, embafolimab, erfonrilimab, garivulimab, lodapolimab, opucolimab, sugemalimab, socazolimab, and tagitanlimab. In some embodiments, the anti-PDL1 therapy or antibody is atezolizumab, avelumab, or durvalumab. Some examples of platinum-based chemotherapy include, but are not limited to, carboplatin, oxaliplatin, cisplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin, ProLindac™ (AP5346), and aroplatin.Some examples of anti-EGFR therapies include, but are not limited to, cetuximab and panitumumab.

[0028] In some embodiments, the patient has previously been administered a systemic cancer therapy that is a targeted therapy when the cancer is identified to have a therapeutic oncogenic driver mutation in the epidermal growth factor receptor gene (EGFR), anaplastic lymphoma kinase gene (ALK), and / or ROS proto-oncogene 1 (ROS1). Targeted therapies for EGFR mutations include, but are not limited to, cetuximab, panitumumab, erlotinib, gefitinib, and afatinib. Targeted therapies for ALK mutations include, but are not limited to, crizotinib, entrectinib, lorlatinib, repotrectinib, brigatinib, alkotinib, alectinib, ensartinib, and ceritinib. Targeted therapies for ROS1 mutations include, but are not limited to, crizotinib, entrecetinib, ensartinib, alkotinib, brigatinib, taretrectinib, cabozantinib, repotrectinib, lorlatinib, and ceritinib.

[0029] In various embodiments, the patient does not exhibit active brain metastases. In some embodiments, the patient does not exhibit brain metastases within 4 weeks of initiating sotorasib therapy as disclosed herein.

[0030] In various embodiments, the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see, e.g., Zubrod et al., 1960). Status 0 indicates fully active and able to continue all pre-disease activities without limitations. Status 1 indicates limitations in physically strenuous activities, but ambulatory and able to perform light or sedentary tasks. Status 2 indicates ambulatory and full self-care, but unable to work; up and moving about more than 50% of the day. Status 3 indicates limited self-care, and more than 50% of the day spent in bed or chair. Status 4 indicates complete inability to move, unable to perform any self-care, and entirely confined to bed or chair. Status 5 indicates death.

[0031] Dose Modification Scheme Also provided herein is a method of treating cancer in a patient, comprising administering to the patient an initial total daily dose of 960 mg of sotorasib, and if the patient experiences an adverse event to the initial total daily dose, administering a reduced total daily dose of 480 mg of sotorasib, wherein the cancer is a KRAS G12C mutant cancer. In some embodiments, the method further comprises administering a second reduced total daily dose of 240 mg of sotorasib if the patient experiences an adverse event to the reduced total daily dose.

[0032] The term "adverse event or (AE)" as used herein refers to any unfavorable and unintended sign (including abnormal clinical laboratory findings), symptom, or disease that is temporally associated with the use of a medical treatment or procedure that can be considered related to the medical treatment or procedure.

[0033] In some embodiments, the adverse event is hepatotoxicity (e.g., elevated liver enzymes), diarrhea, and / or nausea / vomiting. In some embodiments, the adverse event is hepatotoxicity (e.g., elevated liver enzymes), interstitial lung disease / pneumonitis, diarrhea, and / or nausea / vomiting.

[0034] hepatotoxicity In some embodiments, the adverse event is hepatotoxicity. The term "hepatotoxicity" as used herein refers to a patient having abnormal laboratory values ​​of liver biomarkers (e.g., alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and / or total bilirubin (TBL)) when the patient had a baseline level of the liver biomarker that was not abnormal laboratory value before administration of sotorasib or was lower than that measured after administration of sotorasib.

[0035] Alanine transaminase (ALT), also called serum glutamate pyruvic transaminase (SGPT) or alanine aminotransferase (ALAT), catalyzes the transfer of an amino group from alanine to α-ketoglutarate to produce pyruvate and glutamate. When the liver is damaged, the level of ALT in the blood can be elevated due to leakage of ALT from damaged or necrotic liver cells into the blood.

[0036] Aspartate transaminase (AST), also called serum glutamic oxaloacetic transaminase (SGOT or GOT) or aspartate aminotransferase (ASAT), catalyzes the transfer of an amino group from aspartate to α-ketoglutarate to produce oxaloacetate and glutamate. AST can be increased in response to liver injury. Elevated AST can also result from injury to other sources, including red blood cells, cardiac muscle, skeletal muscle, kidney tissue, and brain tissue. The ratio of AST to ALT can be used as a biomarker of liver injury.

[0037] Bilirubin is a catabolic product of heme that is eliminated from the body by the liver. Conjugation of bilirubin to glucuronic acid by hepatocytes produces direct bilirubin, a water-soluble product that is easily eliminated from the body. Indirect bilirubin is unconjugated, and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin may indicate liver dysfunction.

[0038] Alkaline phosphatase (ALP) hydrolyzes phosphate groups from a variety of molecules and is present in cells lining the bile ducts of the liver. Plasma ALP levels can be elevated in response to liver injury and are higher in growing children and older patients with Paget's disease. However, elevated ALP levels usually reflect biliary tree disease.

[0039] In some embodiments, the patient is not suffering from a disorder that results in an elevation of the liver biomarker. Disorders associated with elevation of liver biomarkers (such as AST / ALT and / or TBL levels) include hepatobiliary disease; viral hepatitis (e.g., Hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, chickenpox, toxoplasmosis, and parvovirus); any cause of hypoxia to the liver that results in right heart failure, hypotension, or ischemia; exposure to hepatotoxic agents / drugs or hepatotoxins, including herbal and dietary supplements, plants, and mushrooms. genetic disorders causing impaired glucuronidation (e.g., Gilbert syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); alpha-1-antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson's disease and hemochromatosis; non-alcoholic fatty liver disease including steatohepatitis; and / or extrahepatic causes (e.g., rhabdomyolysis, hemolysis).

[0040] Prior to receiving sotorasib, the patient's baseline liver function may be assessed by various means known in the art, such as blood chemistry tests that measure biomarkers of liver function. In some embodiments, the methods described herein include monitoring liver biomarkers in patients and withholding sotorasib administration in patients with abnormal liver function > Grade 2 as measured by AST and / or ALT levels. In such embodiments, sotorasib administration is suspended until the AST and / or ALT levels in the patient improve to Grade 1 or lower (baseline).

[0041] Adverse effect grades for abnormal liver function are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 1. See 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.

[0042] [Table 1]

[0043] Grade 0 levels are characterized by biomarker levels within the normal range (WNL). "Normal" liver function, as used herein, refers to grade 0 adverse effects. "Abnormal" liver function, as used herein, refers to grade 1 or higher adverse effects.

[0044] "Grade 1 liver function abnormality" includes an elevation in ALT or AST greater than ULN and less than or equal to 3 times the ULN if the baseline was normal; 1.5-3.0 x baseline if the baseline was abnormal. Grade 1 liver function abnormality also includes an elevation in bilirubin levels greater than ULN and less than or equal to 1.5 times the ULN if the baseline was normal; >1.0-1.5 x baseline if the baseline was abnormal. Grade 1 liver function abnormality also includes an elevation in ALP greater than ULN and less than or equal to 2.5 times the ULN if the baseline was normal; >2.0-2.5 x baseline if the baseline was abnormal.

[0045] "Grade 2 liver function abnormalities" include elevations in ALT or AST greater than 3 times and less than or equal to 5 times the upper limit of normal (ULN) if the baseline was normal; >3.0-5.0 x baseline if the baseline was abnormal. Grade 2 liver function abnormalities also include elevations in bilirubin levels greater than 1.5 times and less than or equal to 3 times the ULN if the baseline was normal; >1.5-3.0 x baseline if the baseline was abnormal. Grade 2 liver function abnormalities also include elevations in ALP greater than 2.5 times and less than or equal to 5 times the ULN if the baseline was normal; >2.5-5.0 x baseline if the baseline was abnormal.

[0046] "Grade 3 liver function abnormalities" include elevations in ALT, AST, or ALP greater than 5 times the ULN and less than or equal to 20 times the ULN if baseline was normal; >5.0 to 20.0 x baseline if baseline. Grade 3 liver function abnormalities also include elevations in bilirubin levels greater than 3 times the ULN and less than or equal to 10 times the ULN if baseline was normal; >3.0 to 10 x baseline if baseline was abnormal.

[0047] "Grade 4 liver function abnormalities" include elevations in ALT, AST, or ALP greater than 20 times the ULN if baseline was normal; >20× baseline if baseline was abnormal. Grade 4 liver function abnormalities also include elevations in bilirubin levels greater than 10 times the ULN if baseline was normal; >10.0× baseline if baseline was abnormal.

[0048] The ULN for various indicators of liver function depends on the assay used, the patient population, and the respective clinical laboratory normal range of values ​​for the designated biomarker, but can be easily determined by those skilled in the art. Exemplary values ​​for normal ranges for a healthy adult population are listed in Table 2 below. See Cecil Textbook of Medicine, pp.2317-2341, WB Saunders & Co. (1985).

[0049] [Table 2]

[0050] In any of the methods described herein, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when AST and / or ALT levels in a patient rise to, for example, Grade 2 or Grade 3 levels, and the patient's baseline AST and / or ALT levels were below Grade 2 or below Grade 3. In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when AST and / or ALT levels in a patient rise to Grade 1 levels, and the patient's baseline AST and / or ALT levels were below Grade 1 levels.

[0051] Alternatively, in any of the methods disclosed herein, the total daily dose of sotorasib is decreased (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when (1) the AST and bilirubin levels in the patient are elevated, or (2) the AST or ALP levels in the patient are elevated, or (3) the ALT and bilirubin levels in the patient are elevated, or (4) the ALT and ALP levels in the patient are elevated, or (5) the bilirubin and ALP levels in the patient are elevated, e.g., to grade 1, grade 2, grade 3, or grade 4 levels, and the patient's baseline AST, bilirubin, ALP, and / or ALT levels were at levels 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 and AST and bilirubin, or ALT and AST and ALP, may be elevated to grade 1, grade 2, grade 3, or grade 4 levels in a patient, and the patient's baseline biomarker levels were less than grade 1, less than grade 2, less than grade 3, or less than grade 4, respectively.

[0052] In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the levels of ALT and / or AST are greater than about 3-fold increase compared to the upper limit of normal (ULN). In related embodiments, the abnormal levels of ALT and / or AST are greater than about 3-fold to about 5-fold increase compared to the upper limit of normal (ULN) (i.e., "grade 2 abnormality"). In some embodiments, if the patient has an abnormal baseline, a grade 2 abnormality is an abnormal level of ALT and / or AST greater than about 3-fold to about 5-fold increase compared to baseline. In some embodiments, the abnormal level of ALP is greater than about 2.5-fold to about 5-fold increase compared to the upper limit of normal (ULN) (i.e., "grade 2 abnormality"). In some embodiments, if the patient has an abnormal baseline, a grade 2 abnormality is an abnormal level of ALP greater than about 2.5-fold to about 5-fold increase compared to baseline. In some embodiments, the abnormal level of bilirubin is greater than about a 1.5 to about a 3-fold increase compared to the upper limit of normal (ULN) (i.e., a "Grade 2 abnormality"). In some embodiments, if a patient has an abnormal baseline, a Grade 2 abnormality is an abnormal level of bilirubin that is greater than about a 1.5 to about a 3-fold increase compared to the baseline.

[0053] In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the levels of ALT and / or AST are greater than about 5-fold increase compared to the upper limit of normal (ULN). In some embodiments, the total daily dose is reduced when the levels of ALT, AST, or ALP are greater than about 5-fold to about 20-fold increase compared to the upper limit of normal (ULN) (i.e., "grade 3 abnormality"). In some embodiments, if the patient has an abnormal baseline, a grade 3 abnormality is an abnormal level of ALT and / or AST greater than about 5-fold to about 20-fold increase compared to baseline. In some embodiments, an abnormal level of ALP is greater than about 5-fold to about 20-fold increase compared to the upper limit of normal (ULN) (i.e., "grade 3 abnormality"). In some embodiments, if the patient has an abnormal baseline, a grade 3 abnormality is an abnormal level of ALP greater than about 5-fold to about 20-fold increase compared to baseline. In some embodiments, the total daily dose is reduced when the bilirubin level is greater than about a 3-fold to about a 10-fold increase compared to the upper limit of normal (ULN) (i.e., "Grade 3 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 3 abnormality is an abnormal level of bilirubin that is greater than about a 3-fold to about a 10-fold increase compared to baseline.

[0054] In some embodiments, the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when ALT and / or AST levels are greater than about 20-fold increase compared to the upper limit of normal (ULN) (i.e., "Grade 4 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 4 abnormality is an abnormal level of ALT and / or AST greater than about a 20-fold increase compared to baseline. In some embodiments, an abnormal level of ALP is greater than about a 20-fold increase compared to the upper limit of normal (ULN) (i.e., "Grade 4 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 4 abnormality is an abnormal level of ALP greater than about a 20-fold increase compared to baseline. In some embodiments, the total daily dose is reduced when bilirubin levels are greater than about a 10-fold increase compared to the upper limit of normal (ULN) (i.e., "Grade 4 abnormality"). In some embodiments, if the patient has an abnormal baseline, a Grade 4 abnormality is an abnormal level of bilirubin that is greater than about a 10-fold increase compared to baseline.

[0055] In some embodiments, the methods described herein further include increasing the total dose of sotorasib (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg) when liver biomarkers in the patient improve to Grade 1 or less (e.g., baseline).

[0056] Nausea / vomiting In some embodiments, the adverse event is nausea or vomiting. In some embodiments, the nausea / vomiting is present despite adequate supportive therapy (e.g., antiemetic therapy). "Nausea," as used herein, refers to a disorder characterized by a nauseating sensation and / or an urge to vomit.

[0057] Adverse effect grades for nausea and vomiting are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 3. See 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 by reference herein in its entirety.

[0058] [Table 3]

[0059] In some embodiments, the methods described herein include withholding sotorasib administration in patients with >Grade 3 nausea until the patient has improved to <Grade 1 or baseline. In some embodiments, once the patient has improved to <Grade 1 or baseline, the methods include administering to the patient a reduced total daily dose of sotorasib (e.g., 240 mg to 480 mg, or 480 mg to 960 mg).

[0060] In some embodiments, the methods described herein include withholding sotorasib administration in patients with >Grade 3 emesis until the emesis has improved to <Grade 1 or baseline. In some embodiments, once the patient has improved to <Grade 1 or baseline, the methods include administering to the patient a reduced total daily dose of sotorasib (e.g., 240 mg to 480 mg, or 480 mg to 960 mg).

[0061] In some embodiments, the methods described herein further include increasing the total dose of sotorasib (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg) when nausea or vomiting in the patient has improved to Grade 1 or less (e.g., baseline).

[0062] diarrhea In some embodiments, the adverse event is diarrhea. In some embodiments, the diarrhea is present despite adequate supportive therapy (e.g., antidiarrheal therapy).

[0063] Adverse effect grades for diarrhea are defined herein by the revised Common Toxicity Criteria (CTC) provided in Table 4. See 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 by reference herein in its entirety.

[0064] [Table 4]

[0065] In some embodiments, the methods described herein include withholding sotorasib administration in patients with >Grade 3 diarrhea until the patient has improved to <Grade 1 or baseline. In some embodiments, once the patient has improved to <Grade 1 or baseline, the methods include administering to the patient a reduced total daily dose of sotorasib (e.g., 240 mg to 480 mg, or 480 mg to 960 mg).

[0066] In some embodiments, the methods described herein further include increasing the total dose of sotorasib (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg) when diarrhea in the patient improves to Grade 1 or less (e.g., baseline).

[0067] Response to sotorasib therapy The response rate or outcome for patients administered a total daily dose of 240 mg sotorasib in the methods disclosed herein can be measured in several ways after the patient has been administered 240 mg sotorasib therapy for a suitable period of time. In various embodiments, the patient is administered a total daily dose of 240 mg sotorasib for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, such as 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 a total daily dose of 240 mg sotorasib for at least 1 month. In various embodiments, the patient is administered a total daily dose of 240 mg sotorasib for at least 3 months. In various embodiments, the patient is administered a total daily dose of 240 mg sotorasib for at least 6 months.

[0068] Patients can respond to sotorasib therapy as measured by at least stable disease (SD) as determined by RECIST 1.1 protocol (Eisenhauer, et al., 2009). At least stable disease is stable disease, or has shown 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 does not shrink enough to qualify as partial response (PR) or expand enough to qualify as progressive disease (PD). In various embodiments, patients show at least partial response (i.e., "at least PR" = PR + CR, often referred to as objective response).

[0069] Response may be measured by one or more of: reduction in tumor size, inhibition or reduction in tumor growth, reduction in target or tumor lesions, delayed progression-free time, 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, the progression of a patient's disease may be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by evaluating the patient using computed tomography (CT) scans, positron emission tomography (PET) scans, magnetic resonance imaging (MRI) scans, x-rays, ultrasound, or some combination thereof.

[0070] Progression-free survival can be evaluated as described in RECIST 1.1 protocol.In various embodiments, the patient shows a PFS of at least 3 months.In some embodiments, the patient shows a PFS of at least 6 months.

[0071] Additional means for assessing response are described in detail in the Examples below and may be generally applicable to the methods disclosed herein.

[0072] KRAS G12C cancer Without wishing to be bound by any particular theory, the following is noted: sotorasib inhibits KRAS G12C Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS p.G12C (Hong et al., 2020). Hong et al. report that "[p]re-clinical studies showed that [sotorasib] inhibited nearly all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, and produced durable complete tumor regression in mice bearing KRAS p.G12C tumors" (ibid., see also Canon et al., 2019, and Lanman et al., 2020). Thus, in various embodiments, a total daily dose of 240 mg sotorasib is disclosed for use in treating cancers in which one or more cells express a KRAS G12C mutant protein.

[0073] Sotorasib was evaluated in a phase 1 dose escalation and expansion study in 129 subjects with locally advanced or metastatic cancer harboring histologically confirmed KRAS G12C mutations identified by local molecular testing on tumor tissue, including 59 subjects with non-small cell lung cancer, 42 subjects with colorectal cancer, and 28 subjects with other tumor types (Hong et al., 2020, at page 1208-1209). Hong et al. reported disease control rates (95% CI) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer, and 75.0% for other tumor types (Hong et al., 2020, at page 1213, Table 3). The cancer types showing either stable disease (SD) or partial response (PR) reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, cholangiocarcinoma, or melanoma (Hong et al., 2020, p. 1212 (Figure A), and appendix (p. 59 (Figure S5) and p. 63 (Figure S6)).

[0074] KRAS G12C mutations occur at the alteration frequencies shown in the table below (Cerami et al., 2012; Gao et al., 2013). For example, the table shows that 11.6% of subjects with non-small cell lung cancer have cancer in which one or more cells express the KRAS G12C mutant protein. Thus, KRAS G12C Sotorasib, which specifically and irreversibly binds to, is useful for treating subjects with cancer, including, but not limited to, those listed in Table 5 below.

[0075] [Table 5]

[0076] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, 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 neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In some embodiments, the cancer is small intestine cancer, appendix cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumors, ovarian cancer, gastrointestinal neuroendocrine tumors, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In various embodiments, the cancer is non-small cell lung cancer, and in some particular embodiments, metastatic or locally advanced and unresectable non-small cell lung cancer. In various embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.

[0077] Methods for detecting KRAS, STK11, KEAP1 EGFR, ALK, and / or ROS1 mutation status The presence or absence of G12C, STK11, KEAP1, EGFR, ALK and / or ROS1 mutations in cancers as described herein can be determined using methods known in the art. Determining whether a tumor or cancer contains a mutation can be done, for example, by evaluating the nucleotide sequence encoding the protein, by evaluating the amino acid sequence of the protein, or by evaluating the characteristics of a putative mutant protein, or by any other suitable method known in the art. Wild-type human KRAS (nucleotide sequence set forth in Genbank Accession No. BC010502; amino acid sequence set forth in Genbank Accession No. AGC09594), STK11 (Gene ID: 6794; available at https: / / 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: 1956 ; available at www.ncbi.nlm.nih.gov / gene / 1956; accessed March 2021), ALK (Gene ID: 238; available at https: / / www.ncbi.nlm.nih.gov / gene / 238; accessed March 2021), and ROS1 (Gene ID: 6098; available at https: / / www.ncbi.nlm.nih.gov / gene / 6098; accessed March 2021) nucleotide and protein sequences are known in the art.

[0078] Methods for detecting mutations include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct and / or next generation sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for mutations, such as KRAS G12C mutations, by real-time PCR. In real-time PCR, a fluorescent probe specific for a particular mutation, such as KRAS G12C mutation, is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, mutations are identified using a direct sequencing method of a specific region in a gene. This approach identifies all possible mutations in the sequenced region. In some embodiments, the presence or absence of an insertion mutation can be detected using gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and / or arrays. In some embodiments, methods include, but are not limited to, detection of the mutant using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0079] In some embodiments, multiplex PCR-based sequencing is used for mutation detection and may include some amplicons to provide improved sensitivity of detection of one or more genetic biomarkers. For example, multiplex PCR-based sequencing may include about 60 amplicons (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 amplicons). In some embodiments, multiplex PCR-based sequencing may include 61 amplicons. Amplicons generated using multiplex PCR-based sequencing may range from about 15 bp to about 1000 bp (e.g., about 25 bp to about 1000 bp, about 35 bp to about 1000 bp, about 50 bp to about 1000 bp, about 100 bp to about 1000 bp, about 250 bp to about 1000 bp, about 500 bp to about 1000 bp, about 750 bp to about 1000 bp, about 15 bp to about 750 bp, about 15 bp to about 500 bp, about 15 bp to about 300 bp, about 15 bp to about 200 bp, about 15 bp to about 100 bp, about 15 bp to about 80 bp, about 15 bp to about 75 bp, about 15 bp to about 50 bp, about 15 bp to about 40 bp, about 15 bp to about 30 bp, about 15 bp to about 20 bp, about 20 bp to about 100 bp, about 25 bp to about 50 bp, or about 30 bp to about 40 bp). For example, an amplicon generated using multiplex PCR-based sequencing may include a nucleic acid having a length of about 33 bp.

[0080] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using a sequencing technique (e.g., a next-generation sequencing technique). Various sequencing techniques are known in the art. For example, methods for the detection and characterization of circulating tumor DNA in cell-free DNA may be described elsewhere (see, e.g., Haber and Velculescu, 2014). Non-limiting examples of such approaches 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).

[0081] In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using droplet digital PCR (ddPCR), a method known to be highly sensitive for detecting mutations. In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using other sequencing techniques, including, but not limited to, chain termination techniques, shotgun techniques, sequencing by synthesis methods, methods using microfluidic technology, other capture techniques, or other sequencing techniques known in the art that are useful for detecting small amounts of DNA in a sample (e.g., ctDNA in a cell-free DNA sample).

[0082] In some embodiments, the presence of one or more mutations present in the sample obtained from the patient is detected using an array-based method.For example, the step of detecting genetic alterations (e.g., one or more genetic alterations) in cell-free DNA is carried out using a DNA microarray.In some embodiments, the DNA microarray can detect one or more of a plurality of cancer cell mutations.In some embodiments, the cell-free DNA is amplified before detecting genetic alterations. Non-limiting examples of array-based methods that may be used in any of the methods described herein include complementary DNA (cDNA) microarrays (see, e.g., Kumar et al. 2012; Laere et al. 2009; Mackay et al. 2003; Alizadeh et al. 1996), oligonucleotide microarrays (see, e.g., Kim et al. 2006; Lodes et al. 2009), bacterial artificial chromosome (BAC) clone chips (see, e.g., Chung et al. 2004; Thomas et al. 2005), single nucleotide polymorphism (SNP) microarrays (see, e.g., Mao et al. 2007; Jasmine et al. 2012), microarray-based comparative genomic hybridization arrays (array-CGH) (see, e.g., Beers and Nederlof, 2006; Pinkel et al. 2005; Michels et al. 2009), and other array-based methods. al. 2007), molecular inversion probe (MIP) assays (see, e.g., Wang et al. 2012; Lin et al. 2010). In some embodiments, the cDNA microarray is an Affymetrix microarray (see, e.g., Irizarry 2003; Dalma-Weiszhausz et al. 2006), a NimbleGen microarray (see, e.g., Wei et al. 2008; Albert et al. 2007), an Agilent microarray (see, e.g., Hughes et al. 2001), or a BeadArray array (see, e.g., Liu et al. 2017).In some embodiments, the oligonucleotide microarray is a DNA tiling array (see, e.g., Mockler and Ecker, 2005; Bertone et al. 2006). Other suitable array-based methods are known in the art.

[0083] The method for determining whether a tumor or cancer contains a mutation can use a variety of samples. In some embodiments, the sample is taken from a patient with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded (FFPE) sample. In some embodiments, the sample is a circulating cell-free DNA and / or circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In certain embodiments, the sample is obtained by resection, 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 mutation status.

[0084] In various embodiments, a patient is diagnosed with a mutation, e.g., KRAS, using a test approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA). G12CIt is determined whether a patient has a mutated cancer or whether a tumor or tissue sample obtained from such a patient contains cells with a mutation. In some embodiments, the test for KRAS mutation used is the therascreen® KRAS RGQ PCR kit (Qiagen). The therascreen® KRAS RGQ PCR kit is a real-time quantitative PCR assay for the detection of seven somatic mutations (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) in codons 12 and 13 of the human KRAS oncogene using a Rotor-Gene Q MDx 5plex HRM instrument. The kit is intended for use with DNA extracted from FFPE samples of NSCLC samples obtained by resection, CNB, or FNA. Mutation testing for STK11, KEAP1, EGFR, ALK, and / or ROS1 can be performed with commercially available tests such as the Resolution Bioscience Resolution ctDx Lung™ Assay, which includes 24 genes (including those therapeutic in NSCLC). Tissue samples can be tested using the Tempus xT 648 panel.

[0085] In some embodiments, the cancer is identified as having a KRAS G12C mutation. In some embodiments, the cancer is identified as having a STK11 mutation, e.g., a loss-of-function mutation. In some embodiments, the cancer is identified as having a KEAP1 mutation, e.g., a loss-of-function mutation. In some embodiments, the cancer is identified as having wild-type STK11. In some embodiments, the cancer is identified as having wild-type KEAP1.

[0086] In various embodiments, the cancer is identified as having a loss-of-function mutation in STK11 and a wild-type KEAP1. In some embodiments, the cancer is identified as having a loss-of-function mutation in STK11 and a loss-of-function mutation in KEAP1. In some embodiments, the cancer is identified as having a wild-type STK11 and a wild-type KEAP1. In some embodiments, the cancer is identified as having a wild-type STK11 and a loss-of-function mutation in KEAP1.

[0087] The term "loss-of-function mutation" as used herein refers to a mutation (e.g., substitution, deletion, truncation, or frameshift mutation) that results in the expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological or enzymatic activity), or that results in the expression of only a fragment of a protein that no longer exhibits wild-type activity, or that does not result in the expression of a wild-type protein. For example, a loss-of-function mutation affecting the STK11 gene in a cell can result in the expression of a reduced STK11 protein, the expression of only a fragment of the STK11 protein, or the expression of an STK11 protein that exhibits reduced or no enzymatic activity in a cancerous cell (e.g., no serine / threonine kinase enzymatic activity). Similarly, a loss-of-function mutation affecting the KEAP1 gene in a cell can result in the expression of a reduced KEAP1 protein, the expression of only a fragment of the KEAP1 protein, or the expression of a KEAP1 protein that exhibits reduced or no activity in a cell (e.g., unable to interact with or activate erythroid transcription factor 2-related transcription factor 2 (NRF2)).

[0088] Methods for detecting PDL1 protein expression PDL1 expression can be determined by methods known in the art. For example, PDL1 expression can be detected using PDL1 IHC 22C3 pharmDx, an FDA approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Meyers Squibb as a companion test for pembrolizumab treatment. This is a quantitative assay that uses monoclonal mouse anti-PD-L1, clone 22C3 PDL1, and EnVision FLEX visualization system on an automated stainer Lin 48 to detect PDL1 in FFPE samples such as human non-small cell lung cancer tissue. Expression levels can be measured using tumor proportion score (TPS), which measures the percentage of viable tumor cells that show partial or complete membrane staining at any intensity. Staining can indicate PDL1 expression from 0% to 100%.

[0089] PDL1 expression can also be detected using PDL1 IHC 28-8 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with nivolumab. This quantitative assay uses monoclonal rabbit anti-PDL1, clone 28-8, and the EnVision FLEX visualization system on the automated stainer Lin 48 to detect PDL1 in formalin-fixed paraffin-embedded (FFPE) human cancer tissues.

[0090] Other commercially available tests for PDL1 detection include the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca), which utilizes a monoclonal rabbit anti-PD-L1, clone SP263, and the Ventana SP142 assay (developed by Ventana in collaboration with Genentech / Roche), which uses rabbit monoclonal anti-PDL1 clone SP142.

[0091] In some embodiments, a test approved by a regulatory agency, such as the US Food and Drug Administration (FDA), is used to determine the PDL1 TPS of a cancer as disclosed herein. In various embodiments, the PDL1 TPS is determined using an immunohistochemistry (IHC) test. In some embodiments, the IHC test is a PDL1 IHC 22C3 pharmDx test. In various embodiments, the IHC test is performed using a sample obtained, for example, by resection, CNB, or FNA.

[0092] In various embodiments, the patient has a PDL1 TPS of less than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In various embodiments, the patient has a PDL1 TPS of less than 50% or less than 1%. In various embodiments, the patient has a PDL1 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 more. In various embodiments, the patient has a PDL1 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 PDL1 TPS of 50% or less, or 1% or less. In various embodiments, the patient has a PDL1 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 more than 1%. In various embodiments, the patient has a PDL1 TPS score in a range bounded by any of the values ​​recited in the preceding embodiments. For example, the patient has a PDL1 TPS score in a range of less than 50% and 1% or more, less than 50% and more than 1%, less than 50% and more than 1%, less than 50% and more than 1%, or less than 50% and more than 1%.

[0093] In various embodiments, the patient has a PDL1 TPS score ranging from less than 50% and equal to or greater than 1%. In some embodiments, the patient has a PDL1 TPS score ranging from greater than or equal to 0% and less than 1%. In some embodiments, the patient has a PDL1 TPS score ranging from greater than 50% and equal to or less than 100%. In some embodiments, the patient has a PDL1 TPS score less than 1%. In some embodiments, the patient has a PDL1 TPS score between 1 and 49%. In some embodiments, the patient has a PDL1 TPS score of greater than 50% (i.e., between 50% and 100%).

[0094] Embodiment 1. A method of treating cancer in a patient, comprising administering to the patient a total daily dose of 240 mg of sotorasib, wherein the cancer is a KRAS p G12C mutant cancer. 2. A method of treating cancer in a patient, comprising administering to the patient an initial total daily dose of 960 mg of sotorasib, and if the patient experiences an adverse event to the initial total daily dose, administering a reduced total daily dose of 480 mg of sotorasib, wherein the cancer is a KRAS p G12C mutant cancer. 3. The method of embodiment 2, further comprising administering a second reduced total daily dose of 240 mg of sotorasib if the patient experiences an adverse event to the reduced total daily dose. 4. The method of embodiment 2 or 3, wherein the adverse event is an elevation of one or more liver enzymes in the patient, and the liver enzyme is alanine aminotransferase (ALT) or aspartate aminotransferase (AST). 5. The method of embodiment 4, wherein the elevated levels of ALT and / or AST are >3×ULN. 6. The method of any one of embodiments 2-5, further comprising withholding sotorasib treatment from the patient until ALT and / or AST levels in the patient improve to Grade 1 or baseline prior to administering the reduced total daily dose of sotorasib or a second reduced total daily dose of sotorasib. 7. The method of any one of embodiments 2-6, comprising discontinuing sotorasib treatment when AST or ALT levels are >3×ULN with total bilirubin >2×ULN in the absence of another cause. 8. The method of any one of embodiments 2-7, wherein the adverse event is diarrhea. 9. The method of embodiment 8, further comprising withholding sotorasib treatment from the patient until diarrhea in the patient improves to Grade 1 or baseline prior to administering the reduced total daily dose of sotorasib or a second reduced total daily dose of sotorasib. 10. The method of any one of embodiments 2-9, wherein the adverse event is nausea / vomiting. 11. The method of embodiment 10, further comprising withholding sotorasib treatment from the patient until nausea / vomiting in the patient improves to Grade 1 or baseline before administering the reduced total daily dose of sotorasib or a second reduced total daily dose of sotorasib. 12. The method of any one of embodiments 1-11, wherein sotorasib is administered once a day. 13. The method of any one of embodiments 1-12, wherein sotorasib is administered orally. 14. The method of any one of embodiments 1-13, wherein the cancer is a solid tumor. 15. The method of any one of embodiments 1-14, wherein the cancer is non-small cell lung cancer. 16. The method of embodiment 15, wherein the cancer is metastatic non-small cell lung cancer. 17. The method of embodiment 16, wherein the cancer is locally advanced and unresectable. 18. The method of any one of embodiments 1-13, wherein the cancer is colorectal cancer. 19. The method of any one of embodiments 1-13, wherein the cancer is pancreatic cancer. 20. The method of any one of embodiments 1-13, wherein the cancer is small intestine cancer, appendix cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumors, ovarian cancer, gastrointestinal neuroendocrine tumors, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. 21. The method of any one of embodiments 1-20, wherein the patient has received at least one other systemic cancer therapy prior to initiation of sotorasib therapy. 22. The method of embodiment 21, wherein the patient has received at least two other systemic cancer therapies. 23. The method of embodiment 21 or 22, wherein the at least one systemic cancer therapy is selected from anti-PD1 immunotherapy, anti-PDL1 immunotherapy, and platinum-based chemotherapy. 24. The method of embodiment 23, wherein the patient has previously received (i) anti-PD1 or anti-PDL1 therapy, unless contraindicated, or (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK, or ROS1. 25. The method of embodiment 23, wherein the patient has previously received (i) anti-PD1 or anti-PDL1 therapy, unless contraindicated, and (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK, or ROS1. 26. The method of any one of embodiments 1-25, wherein the patient does not have brain metastases within 4 weeks of initiating sotorasib therapy. 27. The method of any one of embodiments 1-26, wherein the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 28. The method of any one of embodiments 1-27, wherein the patient is administered sotorasib for at least 1 month. 29. The method of any one of embodiments 1-27, wherein the patient is administered sotorasib for at least 3 months. 30. The method of any one of embodiments 1-27, wherein the patient has been administered sotorasib for at least 6 months. 31. The method of any one of embodiments 28-30, wherein the patient exhibits stable disease (SD) as measured by RECIST 1.1 protocol at least after 1, 3, or 6 months of sotorasib therapy. 32. The method of embodiment 31, wherein the stable disease has not shrunk sufficiently to qualify as a partial response (PR) or expanded sufficiently to qualify as progressive disease (PD). 33. The method of any one of embodiments 28-31, wherein the patient exhibits at least a partial response (PR) as measured by RECIST 1.1 protocol after 1, 3, or 6 months of sotorasib therapy. 34. The method of embodiment 33, wherein the partial response is at least a 30% reduction in the sum of the diameters of the target lesions. 35. The method of any one of embodiments 1-34, wherein the patient exhibits a progression-free survival (PFS) of at least 3 months. 36. The method of embodiment 35, wherein the patient exhibits a PFS of at least 6 months. 37. The method of any one of embodiments 1-36, wherein the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of 1-49%. 38. The method of any one of embodiments 1-36, wherein the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of less than 1%. 39. The method of any one of embodiments 1-36, wherein the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of 50-100%. 40. The method of any one of embodiments 1-39, wherein the cancer further comprises an STK11 mutation. 41. The method of any one of embodiments 1-40, wherein the cancer further comprises a KEAP1 mutation. 42. The method of any one of embodiments 1-39 and 41, wherein the cancer further comprises STK11 wild type. 43. The method of any one of embodiments 1-40 and 42, wherein the cancer further comprises KEAP1 wild type. 44. The method of any one of embodiments 1-43, wherein the patient exhibits hepatotoxicity and the method further comprises administering a steroid to the patient. 45. The method of embodiment 44, wherein the steroid is prednisone at a dose of 0.25 to 1.0 mg / kg / day. 46. ​​The method of any one of embodiments 1-45, wherein the patient further requires treatment with an antacid. 47. The method of embodiment 46, wherein the antacid is a proton pump inhibitor (PPI), an H2 receptor antagonist (H2RA), or a locally acting antacid. 48. The method of embodiment 46 or embodiment 47, wherein sotorasib is administered about 4 hours before or about 10 hours after the locally acting antacid, provided the patient further requires treatment with an antacid. 49. The method of any one of embodiments 46-48, wherein the locally acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide. 50. The method of any one of embodiments 1-45, wherein the patient further requires treatment with a proton pump inhibitor (PPI) or an H2 receptor antagonist (H2RA). 51. The method of embodiment 47, wherein the patient is not administered a PPI or H2RA in combination with sotorasib. 52. The method of any one of embodiments 47 or 50-51, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. 53. The method of any one of embodiments 47 or 50-51, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine. 54. The method of any one of embodiments 1-53, wherein the patient further requires treatment with a CYP3A4 inducer. 55. The method of embodiment 54, wherein the patient is not administered a CYP3A4 inducer in combination with sotorasib. 56. The method of embodiment 54 or 55, wherein the CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, and troglitazone. 57. The method of embodiment 54, wherein the patient is not administered a strong CYP3A4 inducer in combination with sotorasib. 58. The method of embodiment 57, wherein the strong CYP3A4 inducer is phenytoin or rifampin. 59. The method of any one of embodiments 1-58, wherein the patient further requires treatment with a CYP3A4 substrate. 60. The method of embodiment 59, wherein the patient is not administered a CYP3A4 substrate in combination with sotorasib. 61. CYP3A4 substrates include: Abemaciclib, Abiraterone, Acalabrutinib, Alectinib, Alfentanil, Alprazolam, Amitriptyline, Amlodipine, Apixaban, Aprepitant, Aripiprazole, Astemizole, Atorvastatin, Avanafil, Axitinib, Boceprevir, Bosutinib, Brexpiprazole, Brigatinib, Buspirone, Calfergot, Caffeine, Carbamazepine, Cariprazine, Ceritinib, Cerivastatin, Chlorpheniramine, Cilostazol, Cisapride, Citalopram, Clarithrombin, isin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib, cyclosporine, dabrafenib, daclatasvir, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, dolutegravir, domperidone, doxepin, elagolix, elbasvir / grazoprevir, eliglustat, enzalutamide, eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, fentanyl, Finasteride, Flibanserin, Gleevec, Haloperidol, Hydrocortisone, Ibrutinib, Idelalisib, Indacaterol, Indinavir, Irinotecan, Isavuconazonium, Ivabradine, Ivacaftor, Lansoprazole, Lenvatinib, Lercanidipine, Lidocaine, Linagliptin, Lovastatin, Macitentan, Methadone, Midazolam, Naldemedine, Naloxegol, Nateglinide, Nelfinavir, Neratinib, Netupitant / Palonosetron, Nevirapine, Nifedipine, Nisoldipine, Nitrendipine, Olaparib, Omeprazole, Ondansetron, Osimertinib, Ospemifene, Palbociclib, Panobinostat, Pantoprazole, Perampanel, Pimavanserin, Pimozide, Pomalidomide, Ponatinib, Progesterone, Propranolol, Quetiapine, Quinidine, Quinine, Regorafenib, Ribociclib, Rilpivirine, Risperidone, Ritonavir, Rivaroxaban, Roflumilast, Rolapitant, Romidepsin, Ruxolitinib, Salmeterol, Saquinavir, Selexipag, Sildenafil, Simeprevir, Simvastatin, Sirolimus,The method of embodiment 59 or 60, wherein the agonist is selected from the group consisting of sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus (fk506), tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, vilazodone, vincristine, vorapaxar, voriconazole, zaleplon, and ziprasidone. 62. The method of any one of embodiments 1-61, wherein the patient further requires treatment with a P-glycoprotein (P-gp) substrate. 63. The method of embodiment 62, wherein the patient is not administered a P-gp substrate in combination with sotorasib. 64. The method of embodiment 57 or embodiment 58, wherein the P-gp substrates are etexilate, digoxin, and fexofenadine. EXAMPLES

[0095] Example 1 - Pharmacokinetic Analysis of Sotorasib at 960 mg, 360 mg, 180 mg, and 240 mg Preliminary pharmacokinetic (PK) data were available for patients with advanced solid tumors harboring a specific KRAS p.G12C mutation with doses ranging from 180 to 960 mg PO QD. A dose-related increase in exposure was observed from 180 to 960 mg PO QD on day 1. The increase in exposure was less than the dose ratio on day 1. There was no accumulation with multiple PO QD doses for 8 days. The change in exposure from 180 to 960 mg PO QD was less than the dose ratio on day 8. Rapid absorption was observed with tmax 1 to 2 hours after PO administration. Figure 1 shows the mean plasma concentration time profiles following oral administration of 180, 360, 720, or 960 mg sotorasib on day 1. Figure 2 shows concentrations following once daily dosing for 8 days (day 8). The table below provides the pharmacokinetic parameters and the AUC 0~24h is the area under the concentration-time curve from time zero to 24 hours after administration; C maxis the maximum drug concentration during the dosing interval; t 1 / 2,z is the terminal elimination half-life; t max is C max Data are reported as median (range) and arithmetic mean (SD), respectively. max and t 1 / 2 Values ​​are reported to 0 and 2 significant digits, respectively, for CV% and t max are reported to three significant digits, except

[0096] [Table 6]

[0097] Example 2 - Efficacy of 180mg, 360mg, and 720mg QD in Non-Small Cell Lung Cancer Patients diagnosed with non-small cell lung cancer or other solid tumors and have KRAS G12C Patients determined to have the mutation were administered sotorasib orally at 180 mg, 360 mg, 720 mg, and 960 mg QD. Responses were seen across all dose levels tested (Hong et al., 2020). Box plots of best tumor shrinkage for NSCLC patients given 180 mg QD, 360 mg QD, 720 mg QD, and 960 mg QD are shown in Figure 3.

[0098] Among 24 NSCLC patients who were evaluable and treated with doses of 180 mg, 360 mg, or 720 mg, responses were observed in 8 subjects (ORR of 33.3%). Among 34 NSCLC patients treated with 960 mg, responses were observed in 12 subjects (ORR of 35.5%). In a Phase 2 study of sotorasib 960 mg QD, the ORR in NSCLC (N=124) was 37.1%.

[0099] The objective responses of patients with NSCLC are shown in Table 7 below.

[0100] [Table 7]

[0101] Example 3 - Dose Comparison Study of 960 mg QD and 240 mg QD Sotorasib at 960 mg QD was shown to be safe and effective under the test conditions under Study 20170543 (CodeBreak100). However, sotorasib exhibits a non-linear pharmacokinetic profile in humans, with observed responses at all dose levels ranging from 180 mg to 960 mg. Based on the observed pharmacokinetic profile discussed in Example 1, the 240 mg QD dose is expected to approximate exposure at lower doses of 180 mg or 360 mg QD. Drug exposure at the 240 mg QD dose is expected to be similar to the 960 mg QD dose, and the 240 mg QD dose is expected to exceed the concentration associated with 90% inhibition in vitro in a 2-hour cellular pERK assay (e.g., Hong et al. 2020, Appendix, Figure S3).

[0102] The multicenter, randomized, open-label study is designed to evaluate the safety and efficacy of sotorasib as monotherapy in subjects with previously treated locally advanced and unresectable or metastatic KRAS G12C mutant progressive NSCLC. Approximately 200 subjects will be enrolled and randomized 1:1 to receive sotorasib at 960mg QD or 240mg QD. Tumor response will be assessed utilizing RECIST 1.1 based on contrast-enhanced CT / MRI with assessment performed by an independent radiology central laboratory. Subjects will continue treatment until disease progression, intolerance to treatment leading to treatment discontinuation, initiation of another anticancer therapy, or withdrawal of consent. Subjects will be scanned for independent central confirmation of progression (COP) at the time of first progressive disease (PD). After central confirmation of progression, subjects in both arms will have the option to continue sotorasib therapy at their existing dose if no tolerable and reasonable alternative treatment options are available in the investigator's judgment. Subjects receiving treatment after progression will continue to undergo scanning after confirmation of the first PD.

[0103] Inclusion criteria included the following: Subjects provided informed consent prior to the initiation of any study-specific actions / procedures.

[0104] Male or female, at least 18 years of age.

[0105] Pathologically documented locally advanced or metastatic malignancies with KRAS G12C mutations identified via molecular testing.

[0106] For NSCLC: Subjects must have progressed following anti-PD1 or anti-PDL1 immunotherapy (unless contraindicated) and / or platinum-based combination chemotherapy and targeted therapy (if amenable oncogenic driver mutations (i.e., EGFR, ALK, and ROS1) have been identified).

[0107] For all NSCLC subjects, the following guidance should be used: (1) Adjuvant therapy counts as a line of therapy if the subject progressed at or within 6 months of receiving adjuvant therapy. (2) In locally advanced and unresectable NSCLC, disease progression at or within 6 months of the end of prior curative-intent multimodality therapy counts as a line of therapy. If planned systemic therapy is administered after chemoradiation with no documented progression between chemoradiation and systemic therapy, the entire treatment period counts as one line of therapy. (3) Maintenance therapy after platinum doublet chemotherapy is not considered as another line of therapy.

[0108] For CRC: Subjects must have progressed after receiving fluoropyrimidine and oxaliplatin and irinotecan. For those CRC subjects with tumors that are MSI-H, at least one of the prior systemic regimens must have included anti-PD1 therapy if the subject is clinically able to take an inhibitor and one of these agents is approved for that indication in the region or country.

[0109] For advanced solid tumor types other than NSCLC or CRC, subjects must have received at least one prior systemic therapy or be intolerant or ineligible for available therapies known to provide clinical benefit. Subjects with advanced solid tumor types other than NSCLC or CRC may be enrolled and treated in Phase 1 or Phase 2 without central laboratory confirmation of the KRAS p.G12C mutation.

[0110] Subjects willing to provide archived tumor tissue samples (formalin-fixed, paraffin-embedded [FFPE] samples taken within the last 5 years) or willing to undergo a pre-treatment tumor biopsy. Subjects with tumor types other than NSCLC or CRC with a previously molecularly confirmed KRAS p.G12C mutation who do not have archived tissue available may be allowed to enroll without tumor biopsy upon consent by the investigator and medical monitor if a tumor biopsy is not feasible.

[0111] Subjects with lesions that can be adequately biopsied will be required to undergo optional biopsy upon tumor progression.

[0112] Measurable disease per RECIST 1.1 criteria.

[0113] Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

[0114] Adequate renal laboratory tests as follows: Estimated glomerular filtration rate ≥ 45 ml / min / 1.73 m based on MDRD (Modification of Diet in Renal Disease) calculations 2 .

[0115] Exclusion criteria included the following: Active brain metastases from non-brain tumors. Subjects whose brain metastases have been resected or who have completed radiation therapy at least 4 weeks prior to Study Day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms of grade ≦2; b) receiving a stable dose of dexamethasone, if applicable; and c) a follow-up MRI performed within 30 days shows no appearance of new lesions.

[0116] History or presence of hematological malignancy, unless no evidence of disease for 2 years or more and cured by treatment.

[0117] Myocardial infarction, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina, or cardiac arrhythmia requiring medical therapy within 6 months prior to Day 1 of the study.

[0118] Gastrointestinal (GI) tract disease making oral medications impossible, malabsorption syndromes, need for intravenous nutritional support, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).

[0119] Active infection requiring IV antibiotics within 1 week of study enrollment (Day 1).

[0120] Exclusion of hepatitis infection based on the following results and / or criteria: positive Hepatitis B surface antigen (HepBsAg) (indicating chronic hepatitis B or recent acute hepatitis B); negative HepBsAg that is positive for Hepatitis B core antibody (Hepatitis B core antibody test is not required for screening, but if it is done and positive, Hepatitis B surface antibody [anti-HBs] test is required). Undetectable anti-HBs in this situation suggests possible uncertain infection and needs to be excluded); positive Hepatitis C virus antibody: Hepatitis C virus RNA by PCR is required. Detectable Hepatitis C virus RNA suggests chronic hepatitis C.

[0121] Known positive test for HIV.

[0122] Unresolved toxicities attributable to previous antineoplastic therapy defined as Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1 or not resolved to the level indicated in the eligibility criteria, except for alopecia (grade 2 or 3 toxicities attributable to previous antineoplastic therapy that are deemed irreversible [defined as present for >6 months and stable], such as ifosfamide-associated proteinuria, may be allowed if they are not listed in the exclusion criteria and agreed to by both the investigator and sponsor).

[0123] Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormone therapy [excluding subjects with breast cancer], or investigational drug) within 28 days of Study Day 1; concomitant use of hormone-refractory prostate cancer or hormone deprivation therapy for breast cancer is permitted.

[0124] Curative or palliative radiation therapy within 2 weeks of Study Day 1. Subjects must have recovered from all radiation therapy-related toxicities.

[0125] Currently enrolled in another investigational device or investigational drug trial, or is less than 28 days from the end of another investigational device or investigational drug trial, or is receiving another investigational drug.Exception: Subjects enrolled in the long-term follow-up portion of another investigational device or investigational drug trial but not using the respective investigational drug or investigational device.

[0126] Other investigational treatments are excluded.

[0127] Major surgery within 28 days of study day 1.

[0128] Monotherapy with AMG 510: Men and women of childbearing potential (WOCBP) who are not willing to practice an acceptable method of birth control during treatment and for at least 7 days (women) or 7 days (men) after receiving the last dose of AMG 510. Acceptable methods of highly effective birth control for women include abstinence (abstaining from heterosexual intercourse); vasectomy with tests showing no sperm in the semen (women with one male sexual partner); tubal ligation or occlusion; or intrauterine device. Acceptable methods of birth control for men include abstinence (abstaining from heterosexual intercourse); vasectomy with tests showing no sperm in the semen; bilateral tubal ligation or occlusion in the partner; or condoms (female partners should also consider a form of birth control). Note: Women are considered to be of childbearing potential (WOCBP), i.e., of fertility, after menarche and until postmenopause unless permanently infertile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menstruation for 12 months without another medical cause. High follicle-stimulating hormone levels in the postmenopausal range can be used to confirm the postmenopausal status of women who are not using hormonal contraception or hormone replacement therapy. However, if amenorrhea has not occurred for 12 months, a single measurement of follicle-stimulating hormone is insufficient.

[0129] Women who are lactating / breastfeeding or plan to breastfeed during the study until 7 days after receiving the last dose of study drug.

[0130] Women with a positive pregnancy test.

[0131] Women who plan to become pregnant during the study up to 7 days after receiving the last dose of study drug.

[0132] The subject has a known sensitivity to any of the products that will be administered during administration.

[0133] To the best of the subject's and the investigator's knowledge, the subject will not be available for any study visits or procedures required by the protocol.

[0134] The subject has any disability that, in the judgment of the Investigator, may impair the subject's ability to give written informed consent and / or to comply with all necessary study procedures.

[0135] History or evidence of any other clinically significant disorder, condition, or disease (other than those outlined above) that the Investigator or Company physician determines may pose a risk to the subject's safety or interfere with the evaluations, procedures, or completion of the study.

[0136] Use of known P-gp sensitive substrates (narrow therapeutic window) within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that have not been reviewed and approved by the investigator.

[0137] Use of a proton pump inhibitor (PPI) or H2 receptor antagonist within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that has not been reviewed and approved by the investigator.

[0138] Use of known cytochrome P450 (CYP) 3A4 sensitive substrates (narrow therapeutic window) within 14 days prior to study day 1 or within 5 half-lives of the drug or its major active metabolite, whichever is longer, that have not been reviewed and approved by the investigator and company medical monitor.

[0139] Use of strong inducers of CYP3A4 (including herbal supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to Study Day 1 without review and approval by the investigator and company medical monitor.

[0140] History of other malignancies within the past 2 years with the following exceptions: malignancies treated with curative intent, without active disease for at least 2 years prior to enrollment, and considered by the treating physician to be at low risk of recurrence; adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease; adequately treated cervical cancer in situ with no evidence of disease; adequately treated ductal carcinoma in situ with no evidence of disease; prostatic intraepithelial neoplasia with no evidence of prostate cancer; adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ.

[0141] Direct KRAS G12C Previous treatment with an inhibitor.

[0142] Randomization of subjects Subjects will be randomized in an open-label fashion in a 1:1 allocation ratio to either sotorasib 960 mg QD or 240 mg QD after meeting all enrollment requirements. Randomization will be stratified by number of prior lines of therapy for metastatic disease (1-2 or >2), history of CNS metastases (yes or no), performance status (<2 or 2), and race (Asian vs. non-Asian).

[0143] Dosage and Administration Sotorasib is administered orally once daily. No drug holidays are permitted. Subjects should take their sotorasib dose (all tablets at the same time) at approximately the same time each day, with or without food. The dose should be taken within a two-hour window of the scheduled time. A dose of sotorasib may be replaced upon vomiting if vomiting occurs within 15 minutes of administration and all tablets administered are accounted for (e.g., if four tablets are administered, four tablets should be retrieved) and are intact by visual inspection (not disintegrated, partially dissolved, chewed, or crushed). Subjects should omit the sotorasib dose if six hours have passed since the scheduled time of administration.

[0144] Drug suspension Subjects randomized to the 960 mg QD arm will be allowed up to two dose interruptions, as outlined in Table 8 below, followed by dose reductions to either 480 mg QD (one dose reduction) or 240 mg QD (two dose reductions). Subjects requiring a dose reduction below 240 mg should permanently discontinue treatment, as the 240 mg QD dose most readily approximates the exposure profile at lower doses with observed clinical responses. Subjects randomized to the 240 mg QD arm will be allowed up to two dose interruptions, but sotorasib will not be reduced upon resumption of sotorasib if deemed medically safe and appropriate according to the investigator's judgment. Subjects in the 960 mg QD arm who require 3 or more dose reductions due to sotorasib-related toxicity management and subjects in the 240 mg QD arm who require 3 or more dose interruptions due to sotorasib-related toxicity management should permanently discontinue treatment.

[0145] [Table 8]

[0146] Hepatotoxicity Guidelines for Sotorasib: Guidelines for management and monitoring of patients with elevated AST, ALT, or alkaline phosphatase (ALP) are provided below in Table 9.

[0147] [Table 9]

[0148] Hepatotoxic Reactions: Subjects with abnormal liver laboratory values ​​(i.e., alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBL)) and / or international normalized ratio (INR) and / or signs / symptoms of hepatitis (as described below) may meet the criteria for withholding or permanently discontinuing sotorasib.

[0149] The following discontinuation and / or withholding rules apply to subjects in whom another cause for their changes in liver biomarkers (TBL, INR, and transaminases) is identified. Important additional causes of elevated AST / ALT and / or TBL values ​​include, but are not limited to, hepatobiliary disease; viral hepatitis (e.g., Hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, chickenpox, toxoplasmosis, and parvovirus); any cause of hypoxia to the liver causing right heart failure, hypotension, or ischemia; exposure to hepatotoxic agents / drugs or hepatotoxins, including herbal and dietary supplements, plants, and mushrooms; genetic disorders causing impaired glucuronidation (e.g., Gilbert syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); alpha-1-antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson's disease and hemochromatosis; nonalcoholic fatty liver disease, including steatohepatitis; and / or extrahepatic causes (e.g., rhabdomyolysis, hemolysis).

[0150] As described in Table 10 below, rechallenge may be considered if another cause for elevated liver tests (ALT, AST, ALP) and / or TBL is discovered and / or laboratory abnormalities return to normal or baseline.

[0151] [Table 10]

[0152] Radiological image evaluation The extent of disease will be assessed by contrast-enhanced MRI / CT according to RECIST 1.1 as follows: Low-dose CT should be utilized whenever possible to reduce radiation exposure to the subject.

[0153] A screening scan must be performed within 28 days prior to enrollment and will be used as a baseline. All subsequent scans will be performed in the same manner as at screening, preferably on the same scanner, using the same contrast agent. Radiological evaluation should include MRI / CT of the chest, abdomen, and pelvis, as well as evaluation of all other known sites of disease. Magnetic resonance imaging (MRI) of the brain should be performed if signs or symptoms suggestive of central nervous system metastases are present.

[0154] The same imaging modality, MRI field strength, and intravenous and oral contrast agents that should be used at screening should be used for all subsequent evaluations. Liver-specific MRI contrast agents should not be used. To mitigate potential safety concerns, macrocyclic gadolinium contrast agents are recommended to follow National Health Institute guidelines or, if more stringent, local standards.

[0155] During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, and all other known sites of disease will be performed every 6 ± 1 weeks regardless of treatment cycle until the first 8 response assessments, with the first scan after baseline occurring 6 ± 1 weeks after C1D1. After the 8 6-weekly response assessments, radiological imaging and tumor assessments will be performed every 12 ± 1 weeks. Radiological imaging and tumor assessments will be performed until disease progression or end of study drug, whichever occurs later. Imaging may also be performed more frequently if clinically indicated at the discretion of the managing physician. Radiological response (complete response, partial response) requires confirmation by a repeat scan at least 4 weeks after initial documentation of response and may be delayed until the next scheduled scan to avoid unnecessary procedures. The minimum time interval for determination of stable disease is ≥ 5 weeks.

[0156] All subjects with brain metastases must have a brain MRI performed within 28 days prior to the first dose of AMG 510. Thereafter, brain scans may be performed at any time if clinically indicated in the judgment of the managing physician. All brain scans on the protocol must be MRI unless MRI is contraindicated, followed by CT with contrast is permitted.

[0157] Radiologic imaging evaluation during the EOT visit should only be performed for patients who discontinue treatment for reasons other than disease progression according to RECIST 1.1 guidelines.

[0158] Determination of disease response for the clinical management of subjects will be assessed at the clinical center according to RECIST 1.1.

[0159] Independent central laboratory progress check (COP) When the investigator identifies radiological progression according to RECIST v1.1, the current imaging and all previous images must be sent immediately to the central imaging provider. After any critical doubts have been resolved, the central imaging provider will perform an independent COP to provide a second independent opinion to the study site and sponsor as to whether the participant has reached progressive disease according to RECIST v1.1. This will be performed by a single radiologist who is separate from the central group of radiologists who read the images for efficacy. The results of the independent COP will not be discussed with the central efficacy reviewer and therefore will not affect the response or progression determination by the central efficacy reviewer. The independent COP will only be utilized to provide the site PI with a second opinion on the presence or absence of progressive disease according to RECIST v1.1 at the current time, and the clinical subject data will not be discussed.

[0160] If the central imaging provider's assessment of radiological disease progression does not confirm disease progression at this time, the central imaging provider may convene a conference between one radiologist and the facility's radiologist to review the participant's images to determine confirmation of radiological disease progression. The facility PI will make final treatment and subject management decisions.

[0161] Radiographic disease progression should be verified centrally before discontinuation of investigational drug, local intervention, initiation of new anticancer therapy, or post-progression treatment. If no safety concerns exist and the study participant is clinically stable, the participant will continue to receive investigational drug while central laboratory confirmation of progression is ongoing and until confirmation of radiographic disease progression is completed.

[0162] KRAS G12C, PD1, and various mutation studies The therascreen® KRAS RGQ PCR kit from QIAGEN is a real-time quantitative PCR assay performed on a Rotor-Gene Q MDx instrument for the detection of seven somatic mutations in the human KRAS oncogene using DNA extracted from FFPE tissue. The mutations detected are G12A, G12D, G12R, G12C, G12S, G12V, G13D. The therascreen® KRAS RGQ PCR kit is an available in-vitro diagnostic device for investigation that will be used to test subjects with NSCLC and CRC for the KRAS p.G12C mutation. The Qiagen therascreen® KRAS RGQ PCR kit may be approved in certain regions.

[0163] PDL1 testing will be performed at a central laboratory using the Dako PharmDx 22C3 immunohistochemistry FDA approved kit following the instructions for use.

[0164] Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) definition Measurable lesions Measurable tumor lesion - a non-lymph node lesion with clearly defined borders that can be accurately measured in at least one dimension and a longest diameter ≥10 mm on a CT / MRI scan with a slice thickness of 5 mm or less. When the slice thickness is greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness.

[0165] Nodal involvement - lymph nodes are to be considered pathologically enlarged and measurable, lymph nodes must be ≥15mm in the short axis when assessed by CT / MRI (recommended scan slice thickness ≤5mm). At baseline and follow-up, only the short axis is measured and tracked. Node size is usually reported as two dimensions in the axial plane. The smaller of these measurements is the short axis (perpendicular to the long axis).

[0166] Irradiated Lesions - Tumor lesions located in areas previously irradiated or subjected to other locoregional therapy are not measurable unless disease progression has been documented prior to enrollment.

[0167] Non-measurable Lesions: All other lesions, including small lesions (longest diameter <10 mm or pathologic lymph nodes with a short axis ≥10 mm but <15 mm and a CT scan slice thickness of 5 mm or less), are considered non-measurable and are characterized as non-target lesions.

[0168] Other examples of non-measurable lesions include lesions with previous local therapy: tumor lesions located in areas previously irradiated or subjected to other locoregional therapy should not be considered measurable unless progression of the disease has been documented; biopsied lesions; and, categorically, small lesions, bone lesions, inflammatory breast disease, and clusters of leptomeningeal disease are non-targetable.

[0169] How to measure Lesion Measurements - The longest diameter of the selected lesion should be measured in the plane in which the image was acquired (axial plane). All measurements should be taken and recorded in metric units. All baseline evaluations should be performed as close to the start of treatment as possible and no later than 4 weeks prior to Study Day 1.

[0170] Methods of Assessment - The same methods of assessment and the same techniques should be used to characterize each identified and reported lesion throughout the study.

[0171] CT / MRI- All lesions should be evaluated using contrast-enhanced CT or MRI. Optimal visualization and measurement of metastases in solid tumors requires consistent IV contrast administration (dose and rate) and timing of scans. CT and MRI should be performed with contiguous slices ≦5 mm thick.

[0172] Baseline documentation of "target" and "non-target" lesions Target Lesions - All measurable lesions, representing all involved organs, up to a maximum of two lesions per organ and up to five lesions in total, should be identified, recorded, and measured as target lesions at baseline.

[0173] Target lesions should be selected based on their size (lesions with the longest diameter) and amenability to accurate repeated measurements.

[0174] Pathologic lymph nodes (with a short axis of ≥15 mm) may be identified as target lesions. All other pathologic lymph nodes (those with a short axis of ≥10 mm but <15 mm) should be considered non-target lesions.

[0175] For all target lesions, the sum of diameters (longest diameter for non-nodal lesions and short axis for nodal lesions) will be calculated and reported as baseline sum of diameters. The baseline sum of diameters will be used as the criterion for characterizing objective tumor response.

[0176] Non-target Lesions - All other lesions (or sites of disease), including pathological lymph nodes, should be identified as non-target lesions and should also be recorded at baseline. Measurement of these lesions is not required, and these lesions should be tracked as "present," "absent," or "overt progression" throughout the study. In addition, multiple non-target lesions involving the same organ may be recorded as one item on the case report form (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases").

[0177] Response criteria

[0178] [Table 11]

[0179] [Table 12]

[0180] Overall response assessment Best overall response is the best response recorded from the start of study treatment until the end of treatment or disease progression / relapse (taking the minimum measurement recorded since treatment began as the criterion for PD).

[0181] In general, the assignment of a subject's best response will depend on the findings of both target and non-target disease, and will also take into account the emergence of new lesions.

[0182] [Table 13]

[0183] [Table 14]

[0184] [Table 15]

[0185] Special notes for response evaluation Lymph node lesions - Lymph nodes identified as target lesions should always have the actual short axis measurement recorded, even if the node regresses to less than 10 mm on study. To qualify for CR, each lymph node must achieve a short axis of <10 mm rather than complete loss. The short axis measurement of the lymph node target lesion is added with the longest diameter measurement of the target lesion to create a total target lesion diameter for a particular assessment (time point).

[0186] "Too Small to Measurable" Target Lesions - During the study, all lesions (lymph node and non-lymph node) recorded at baseline should have their measurements recorded at each subsequent evaluation. When lesions become smaller than 5 mm, the accuracy of the measurements decreases. Therefore, lesions smaller than 5 mm are considered "too small to measurable" and are not measured. With this designation, they are assigned a default measurement of 5 mm. Lesion measurements smaller than 5 mm do not need to be recorded unless the lesion has completely resolved and a "0" can be recorded for the measurement.

[0187] New Lesions - The term "new lesions" always refers to the presence of new findings that are clearly neoplastic. New findings that could only be neoplastic but may also be benign (infection, inflammation, etc.) are not selected as new lesions until such time as review confirms that they are neoplastic.

[0188] For example, if a new lesion is uncertain due to small size, continued therapy and follow-up evaluations will reveal whether it actually represents new disease. If repeat scans establish that a new lesion is clearly present, progression should be declared using the date of the first scan.

[0189] Lesions identified on follow-up examination in an anatomical location not scanned at baseline will be considered new lesions and will represent disease progression notwithstanding any responses that may be observed in target or non-target lesions present from baseline.

[0190] Subjects with a global deterioration in health status necessitating discontinuation of treatment without objective evidence of disease progression at that time should be classified as having "symptomatic worsening." Even after cessation of treatment, every attempt should be made to document objective progression by additional imaging evaluations.

[0191] In some circumstances, residual disease may be difficult to distinguish from scar or normal tissue. When assessment of complete response (CR) relies on this determination, it is recommended that residual disease be further investigated by fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET / computed tomography (PET / CT), or possibly fine-needle aspiration / biopsy, to confirm CR status.

[0192] Confirmatory measurement / duration of response Confirmed Response - In nonrandomized trials where response is the primary endpoint, confirmation of PRs and CRs is required to ensure that the identified responses are not the result of measurement error.

[0193] Duration of Overall Response - Duration of overall response is measured from the first fulfillment of the metrics for CR / PR (whichever is first documented) to the first date of objectively documented recurrence or progressive disease or death, whichever occurs first.

[0194] Duration of stable disease-SD is measured from the start of treatment until criteria for disease progression are met and taken as the lowest measurement recorded since treatment was initiated or death, whichever occurs first.

[0195] Preliminary data (February 21, 2022): A table summarizing the pharmacokinetic (PK) data following administration of sotorasib (240 mg or 960 mg) on ​​days 1 and 8 is provided below.

[0196] [Table 16]

[0197] In short, the numerically higher average exposure (C max and AUC 0-24h ) were observed on days 1 and 8 after 960 mg compared to 240 mg. PK at 960 mg was consistent with the expected exposure range and elimination half-life. Exposure on day 8 was 30-40% lower than day 1 for both the 240 mg and 960 mg doses, which is consistent with the expected steady-state profile.

[0198] Additionally, preliminary data from two patients with NSCLC adenocarcinoma (stage IV) treated with sotorasib 240 mg once daily were reviewed. One patient after nine cycles of treatment with sotorasib 240 mg showed stable disease (SD) after cycles 3 and 5, and partial response (PR) after cycles 7 and 9. One patient after nine cycles of treatment showed partial response (PR) after cycles 3, 5, and 7, and progressive disease (PD) with new lesions after cycle 9.

[0199] Example 4 - Sotorasib Dose Reduction Protocol The most common adverse events to sotorasib treatment during Phase 2 trials included laboratory abnormalities (≥10%), decreased lymphocytes, decreased hemoglobin, diarrhea, musculoskeletal pain, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urinary protein, decreased sodium, nausea, fatigue, decreased albumin, increased activated partial thromboplastin time, cough / vomiting, constipation, dyspnea, and abdominal pain.

[0200] [Table 17]

[0201] Dose reductions (from 960 mg total daily dose to 480 mg, or from 480 mg to 240 mg) were permitted when certain adverse events (e.g., hepatotoxicity, nausea / vomiting, diarrhea, other adverse reactions) were observed. Dose reduction levels are summarized in Table 17 below.

[0202] [Table 18]

[0203] [Table 19]

[0204] Among 427 subjects who received sotorasib monotherapy in any tumor type and at any dose, 56 subjects (13.1%) had dose reductions, the most common reason being due to adverse events (AEs) (46 subjects, 10.8%). See Table 19 below.

[0205] [Table 20]

[0206] Of the 56 subjects who had a dose reduction, 39 subjects (69.6%) discontinued treatment with sotorasib (Table 20), and the remaining 17 subjects were continuing treatment as of the data cutoff date.

[0207] [Table 21]

[0208] Among the 39 subjects who discontinued sotorasib treatment, only 12 subjects (21.4%) discontinued due to AEs, confirming that the majority of subjects who received a modified dose of sotorasib did not require complete discontinuation of sotorasib treatment due to AEs. The majority of the 39 subjects who discontinued sotorasib after dose reduction did so due to disease progression (25 subjects, 44.6%). The data suggest that, unexpectedly, given the nonlinear pharmacokinetic properties of sotorasib as presented here, dose reduction may have improved the individual safety profile and the rate of sotorasib discontinuation due to AEs may have remained low.

[0209] Example 5 - Contraindications for simultaneous administration of antacids and sotorasib under fasting conditions This phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Subjects received 960 mg sotorasib on day 1, 40 mg omeprazole once daily on days 4-8, and 40 mg omeprazole on day 9 followed by 960 mg sotorasib. All doses were administered under fasting conditions. Blood samples for sotorasib PK were collected predose and up to 48 hours after sotorasib administration. Plasma PK parameters of sotorasib were estimated using noncompartmental methods.

[0210] Coadministration of sotrasib and omeprazole increased the maximum plasma concentration (t max ) was delayed by 0.75 hours. 1 / 2 ) were similar after coadministration of sotrasib and omeprazole compared with administration of sotrasib alone. Geometric mean sotrasib AUC after coadministration of sotrasib and omeprazole inf (area under the curve from zero to infinity) and C max The maximum plasma concentrations (17000 h*ng / mL and 3100 ng / mL, respectively) were lower compared with sotorasib administered alone (29300 h*ng / mL and 7200 ng / mL, respectively). Sotorasib was safe and well tolerated when coadministered with 40 mg omeprazole or administered alone in healthy subjects.

[0211] Results showed that coadministration of sotrasilib and omeprazole in the fasting state significantly increased the AUC inf 42% and C max The study showed that it reduced the

[0212] Example 6 - Contraindications for simultaneous administration of sotorasib with postprandial antacids This was a phase 1, open-label, fixed-sequence, crossover, single-center study to explore mitigation strategies to limit the effect of antacids on sotorasib exposure. The study evaluated the PK of sotorasib administered alone and in combination with famotidine or omeprazole after a meal in healthy men and women (14 subjects in total). Subjects received a single dose of sotorasib on day 1, an evening dose of famotidine (10 hours prior to sotorasib administration) on day 3, a single dose of sotorasib on day 4 followed by a repeat dose of famotidine 2 hours later, daily doses of omeprazole on days 6 through 10, and a single dose of both omeprazole and sotorasib on day 11. All sotorasib doses were administered after consumption of a standard calorie, moderate-fat meal. Blood was collected at predefined time points to characterize sotorasib plasma concentrations. Safety and tolerability monitoring was performed throughout the study.

[0213] A total of 15 healthy subjects (1 female and 13 males) were enrolled in the study. Thirteen of the 14 subjects received all treatments and completed the study.

[0214] AUC of sotorasib inf and C max The geometric least squares mean ratios of AUC1, AUC2, and AUC3, AUC4, and AUC5, were 0.622 and 0.654, respectively, when comparing sotorasib coadministered with famotidine after a meal with sotorasib alone. inf and C maxThe geometric least squares mean ratios of sotorasib coadministered with omeprazole and sotorasib alone were 0.430 and 0.349, respectively. The 960 mg dose of sotorasib was shown to be safe and well tolerated when coadministered with a single 40 mg dose of famotidine after meals and after multiple daily doses of 40 mg omeprazole in healthy subjects.

[0215] In summary, the concomitant administration of a single dose of famotidine (an H2 receptor antagonist) given 10 hours before and 2 hours after a single dose of sotoraxine after a meal significantly increased the C max In addition, coadministration of a single dose of sotrasilamide with multiple doses of omeprazole (PPI) reduced the C and AUC of sotrasilamide after a meal by 35% and 38%, respectively. max reduced the RR-100 by 65% ​​and the AUC by 57%.

[0216] Example 7 - Contraindications for coadministration of strong CYP34A4 inducers with sotorasib This phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 960 mg sotorasib on days 1, 3, and 18, and 600 mg rifampin on days 3 and 5-19. Blood samples for sotorasib PK were collected predose and up to 48 hours after sotorasib administration. Plasma PK parameters of sotorasib were estimated using noncompartmental methods.

[0217] result Geometric Mean Sotorasib AUC Following Coadministration of Single Doses of Sotorasib and Rifampin inf (area under the curve from zero to infinity) and C max The maximum plasma concentrations (19600 h*ng / mL and 5340 ng / mL, respectively) were similar to those of sotorasib alone (25600 h*ng / mL and 6350 ng / mL, respectively). Geometric mean sotorasib AUC after multiple doses of sotorasib and rifampin were coadministered. inf and C max(12400 h*ng / mL and 4110 ng / mL, respectively) were lower compared with sotorasib alone (25600 h*ng / mL and 6350 ng / mL, respectively).

[0218] Sotorasib was safe and well tolerated when coadministered with 600 mg rifampin or administered alone in healthy subjects. Single doses of rifampin had no clinically meaningful effect on the PK of sotorasib, indicating that sotorasib is not a substrate of OATP1B1. Multiple doses of rifampin increased the AUC inf 51%, C max by 35%, indicating that sotorasib is a CYP3A4 substrate, consistent with in vitro data.

[0219] Example 8 - Contraindications for coadministration of CYP34A substrates with sotorasib This phase 1, open-label, fixed-sequence study enrolled five subjects with previously untreated NSCLC and administered a single oral dose of 2 mg midazolam alone on day 1, 960 mg oral sotorasib on days 1 through 14, and a single oral dose of 2 mg midazolam at approximately the same time as the 960 mg oral sotorasib on day 15. Blood samples for sotorasib PK were collected predose and up to 48 hours after sotorasib administration. Plasma PK parameters of sotorasib were estimated using noncompartmental methods.

[0220] Plasma PK data for single-dose midazolam were obtained after 14 days of multiple daily dosing with sotorasib from five subjects receiving midazolam alone and midazolam coadministered with sotorasib. Results showed that exposure to midazolam was decreased when coadministered with sotorasib after multiple daily dosing with sotorasib. Coadministration of midazolam (a sensitive CYP3A4 substrate) with sotorasib increased the C max by 48% and AUVs by 53%.

[0221] Example 9 - Contraindications for co-administration of sotorasib and P-gp substrates This phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 0.5 mg digoxin on day 1 and 960 mg sotorasib on day 7 followed by 0.5 mg digoxin. Blood samples for digoxin PK were collected pre-dose and up to 144 hours after digoxin administration. Samples were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. PK parameters were estimated using noncompartmental methods. Safety and tolerability were monitored throughout the study.

[0222] Time to maximum plasma concentration of digoxin (t max ) and mean terminal half-life (t 1 / 2 ) were similar after coadministration of sotrazib and digoxin compared with digoxin alone. Geometric mean digoxin AUC after coadministration of sotrazib and digoxin inf The area under the curve from zero to infinity (40.3 h*ng / mL) was similar to that of digoxin alone (33.2 h*ng / mL). max The maximum plasma concentration (3.64 ng / mL) was higher compared to digoxin alone (1.90 ng / mL). A single dose of 0.5 mg digoxin was safe and well tolerated when administered alone or coadministered with 960 mg sotorasib.

[0223] Results showed that coadministration of a single dose of sotorasib with digoxin significantly increased the AUC inf and C max were shown to increase the IL-10 expression level by approximately 21% and 91%, respectively.

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Claims

1. 1. A pharmaceutical composition comprising a compound for use in a method of treating a KRAS G12C mutant cancer in a patient, said patient having been administered an initial total daily dose of 960 mg of said compound, said compound being sotorasib, and said patient experiencing an adverse event, said adverse event comprising: (i) Grade 3 or Grade 4 adverse event; or (ii) symptomatic Grade 2 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or both; The method further comprising: (a) withholding the initial total daily dose of sotorasib from the patient until the adverse event improves to Grade ≦1 or to a baseline grade, and then administering to the patient a first reduced total daily dose of 480 mg of sotorasib; and (b) if the patient experiences an adverse event to the first reduced total daily dose, withholding the first reduced total daily dose of sotorasib from the patient until the adverse event improves to Grade 1 or less or to baseline grade, and then administering to the patient a second reduced total daily dose of 240 mg of sotorasib.

13. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the adverse event is an elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or both, in the patient.

3. The pharmaceutical composition of claim 1 , wherein the adverse event is diarrhea.

4. The pharmaceutical composition of claim 1 , wherein the adverse event is nausea or vomiting.

5. 2. The pharmaceutical composition of claim 1, wherein the sotorasib is administered once daily.

6. The pharmaceutical composition of claim 5, wherein the sotorasib is administered orally.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the cancer is a solid tumor.

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the cancer is non-small cell lung cancer.

9. The pharmaceutical composition of claim 8, wherein the cancer is metastatic non-small cell lung cancer.

10. The pharmaceutical composition of claim 9, wherein the cancer is locally advanced and unresectable.

11. The pharmaceutical composition according to any one of claims 1 to 6, wherein the cancer is colorectal cancer.

12. The pharmaceutical composition according to any one of claims 1 to 6, wherein the cancer is pancreatic cancer.

13. The pharmaceutical composition according to any one of claims 1 to 6, wherein the cancer is small intestine cancer, appendix cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

14. The pharmaceutical composition of claim 1, wherein the patient has received at least one other systemic cancer therapy prior to initiation of sotorasib therapy.

15. The pharmaceutical composition of claim 14, wherein the patient has received at least two other systemic cancer therapies.

16. 15. The pharmaceutical composition of claim 14, wherein the at least one systemic cancer therapy is selected from anti-PD1 immunotherapy, anti-PDL1 immunotherapy, and platinum-based chemotherapy.

17. 17. The pharmaceutical composition of claim 16, wherein the patient has previously received (i) anti-PD1 or anti-PDL1 therapy, unless contraindicated, or (ii) platinum-based chemotherapy, and (iii) EGFR, ALK or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK or ROS1.

18. 17. The pharmaceutical composition of claim 16, wherein the patient has previously received (i) anti-PD1 or anti-PDL1 therapy, unless contraindicated, and (ii) platinum-based chemotherapy, and (iii) EGFR, ALK or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK or ROS1.

19. The pharmaceutical composition of claim 1, wherein the patient does not have brain metastases within 4 weeks of initiating sotorasib therapy.

20. 2. The pharmaceutical composition of claim 1, wherein the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

21. 2. The pharmaceutical composition of claim 1, wherein the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of 1-49%.

22. 2. The pharmaceutical composition of claim 1, wherein the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of greater than or equal to 0% and less than 1%.

23. 2. The pharmaceutical composition of claim 1, wherein the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of 50-100%.

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