Dosage plans for sotrasib / carboplatin / pemetrexed in cancer treatment

Abstract

Provided herein is a method for treating cancer involving a KRAS G12C mutation in a subject requiring treatment, the method comprising administering to the subject an effective dose of sotrasib, carboplatin, and pemetrexed to treat the cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 459,349 filed on 18 April 2023 and U.S. Provisional Patent Application No. 63 / 520,050 filed on 16 August 2023 (the latter being incorporated herein by reference in its entirety). [Background technology]

[0002] The rat sarcoma (RAS) proto-oncogene has been identified as a carcinogenic driver in tumorigenesis in cancers such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The RAS family consists of three closely related genes that express guanosine triphosphate (GTP)ases, which are responsible for regulating cell proliferation and survival. The RAS protein, Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus oncogene homolog (HRAS), and neuroblastoma RAS virus oncogene homolog (NRAS) can be mutant-activated at codons 12, 13, or 61, potentially causing human cancer. Different tumor types are associated with mutations in specific isoforms of RAS, with KRAS being the most frequently mutated isoform in most cancers. Although the role of KRAS mutations in human cancer has been known for decades, anticancer therapies specifically targeting KRAS mutations have not been successfully developed until recently. One of the main reasons for this is that proteins have been considered difficult to inhibit with small molecules.

[0003] As further detailed in this disclosure, Sotrasib is KRAS G12CIt is a small molecule that irreversibly inhibits proteins. In 2021, LUMAKRAS became the first compound in its class to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of specific KRAS G12C mutations in lung cancer, and subsequently approved by regulatory agencies worldwide. While sotracib monotherapy appears to drive substantial antitumor activity, conjunctival therapy is desired to improve treatment options for patients. [Overview of the project] [Means for solving the problem]

[0004] Provided herein is a method for treating cancer involving a KRAS G12C mutation in a subject requiring treatment, comprising administering to the subject a first regimen comprising (a)(i) a therapeutically effective dose of sotrasib, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, followed by a second regimen comprising (b)(i) a therapeutically effective dose of sotrasib and (ii) a therapeutically effective dose of pemetrexed. In various embodiments, the therapeutically effective dose of sotrasib is 240 mg. In various embodiments, the therapeutically effective dose of sotrasib is 960 mg. In some various embodiments, the subject has not received prior systemic anticancer therapy for cancer prior to treatment (first-line treatment). In various embodiments, the cancer exhibits a tumor cell (TC) score of less than 1% or a tumor percentage score (TPS) of less than 1%. [Modes for carrying out the invention]

[0005] Provided herein is a method for treating a patient in need of treatment for a cancer containing a KRAS G12C mutation, comprising administering to the patient a first regimen comprising (a)(i) a therapeutically effective dose of sotrasib, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, followed by a second regimen comprising (b)(i) a therapeutically effective dose of sotrasib and (ii) a therapeutically effective dose of pemetrexed. In various embodiments, the therapeutically effective dose of sotrasib is 240 mg. In various embodiments, the therapeutically effective dose of sotrasib is 960 mg.

[0006] In various embodiments, the first regimen is administered over a period of 1 to 10 cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cycles). In various embodiments, the first regimen is administered over a period of 4 cycles. In various embodiments, the cycle is a period of 14 to 28 days or 18 to 24 days. In some embodiments, the cycle is a period of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days. In various embodiments, the cycle is a period of 21 days.

[0007] Provided herein are methods of treatment involving the administration of two or more therapeutic agents (e.g., sotrasib, carboplatin, and pemetrexed). Unless otherwise specified herein, combination therapies of two or more therapeutic agents considered herein include both concurrent and sequential administration.

[0008] definition As used herein, the term “adult” means a person who is 18 years of age or older, or the legal age of majority in the country where the subject is located at the time of treatment by the products or methods disclosed herein (whichever is higher).

[0009] As used herein, the term "pharmaceutically acceptable" means generally accepted for use in a subject, particularly in humans.

[0010] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed by inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid), or acid addition salts formed by organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, and methanesulfonic acid). Additional examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition (2011).

[0011] As used herein, the term “prior systemic anticancer therapy” means (i) prior or ongoing anticancer hormone therapy given in an adjuvant context after complete resection of early-stage breast cancer without known active disease for more than two years, or (ii) systemic anticancer therapy within two years prior to the commencement of treatment by any of the methods disclosed herein, with the exception of prior neoadjuvant / adjuvant therapy (for radical surgery) for early-stage non-small cell lung cancer (NSCLC), with or without anti-PD-1 / L1 therapy (which was completed more than six months before the diagnosis of cancer intended to be treated by one or more of the methods disclosed herein). This includes, but is not limited to, chemotherapy, antibody therapy, molecular targeted therapy, hormone therapy, retinoid therapy, or any anticancer agent under investigation.

[0012] In some embodiments, previous systemic anticancer therapies are used in KRAS G12C This is a therapy using inhibitors. In some embodiments, KRAS G12CThe inhibitor is sotorasib, adagrasib, GDC-6036, D-1553, JDQ443, LY3484356, BI1823911, JAB-21822, RMC-6291, or APG-1842. In some embodiments, KRAS G12C The inhibitor is sotorasib. In some embodiments, KRAS G12C The inhibitor is adagrasib.

[0013] The term "subject" is used interchangeably with "patient".

[0014] Sotorasib Provided herein is a method of treating cancer in a subject who needs treatment for cancer comprising KRAS G12C mutation, the method comprising administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasib, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed, and then (b) a second regimen comprising (i) a therapeutically effective amount of sotorasib and (ii) a therapeutically effective amount of pemetrexed. In various embodiments, the therapeutically effective amount of sotorasib is 240 mg. In some embodiments, when administered on the same day, i.e., day 1 of each cycle of the first regimen, sotorasib is administered before carboplatin.

[0015] Sotorasib is G12C a small molecule that irreversibly inhibits the KRAS protein. Sotorasib is also referred to as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one and is sold as a pharmaceutical composition in tablet form under the name LUMAKRAS® (e.g., in the United States) or LUMYKRAS® (e.g., in Europe). Sotorasib has the following structure:

Chemical formula

[0016] Sotorasib binds to the P2 pocket of KRAS adjacent to the mutated cysteine at position 12 and to the nucleotide-binding pocket. The inhibitor contains a thiol-reactive moiety that covalently modifies the cysteine residue to lock KRAS in an inactive guanosine diphosphate (GDP)-bound conformation (Canon et al., 2019). This blocks the interaction of KRAS with effectors such as rapidly accelerated fibrosarcoma (RAF), thereby preventing downstream signaling, such as phosphorylation of extracellular signal-regulated kinase (ERK) (Simanshu et al., 2017; Ostrem et al., 2013). Inactivation of KRAS by small molecule inhibitors has previously been demonstrated to inhibit cell proliferation and induce apoptosis in tumor cell lines and xenografts bearing the KRAS G12C mutation (Janes et al., 2018; Ostrem and Shokat, 2016; Patricelli et al., 2016). Studies of sotorasib have demonstrated inhibition of the growth and regression of cells and tumors bearing KRAS (Canon et al., 2019). See also LUMAKRAS (registered trademark) US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revised January 2023) (incorporated herein by reference in its entirety). G12C G12C G12C

[0017] ​​​Provided herein are methods comprising administering sotrasib as a free base. In various embodiments, sotrasib is administered as a pharmaceutically acceptable salt. For clarity, the term “sotrasib” as used herein refers to the free base of sotrasib. Furthermore, any method described herein that references sotrasib may be carried out using a pharmaceutically acceptable salt of sotrasib. In some embodiments, sotrasib may be administered as a hydrochloride, phosphate, or mesylate. In some embodiments, sotrasib may be administered as a hydrochloride. In some embodiments, sotrasib may be administered as a phosphate. In some embodiments, sotrasib may be administered as a mesylate. For clarity, if a method provided herein describes, for example, the administration of 240 mg (or 960 mg) of sotrasib or a pharmaceutically acceptable salt thereof to a subject, the method requires the administration of 240 mg (or 960 mg) of sotrasib free base or an amount of a pharmaceutically acceptable salt corresponding to the administration of 240 mg (or 960 mg) of sotrasib free base.

[0018] Further provided herein are methods for the oral administration of sotrasib. In various embodiments, sotrasib is administered once daily. In some embodiments, the total daily dose of sotrasib (e.g., 240 mg) is administered twice daily in two equal doses (e.g., 2 × 120 mg). In various embodiments, sotrasib is administered in solid dosage form. In some embodiments, the solid dosage form is a tablet. In various embodiments, 240 mg of sotrasib is administered as one tablet containing 240 mg of sotrasib, or as two tablets each containing 120 mg of sotrasib. In various embodiments, 960 mg of sotrasib is administered as three tablets each containing 320 mg of sotrasib, four tablets each containing 240 mg of sotrasib, or eight tablets each containing 120 mg of sotrasib.

[0019] In various embodiments, sotrasib is taken daily at approximately the same time, with or without food. In some embodiments, sotrasib tablets are dispersed in 120 mL (4 ounces) of still, room-temperature water in a container without crushing. The liquid is stirred for about 3 minutes until the tablets are dispersed into small pieces, and then administered to the subject immediately or within 2 hours. The container is then rinsed with an additional 120 mL (4 ounces) of water before administration to the subject. This method can be used to administer sotrasib in a solid dosage form, for example, to subjects who have difficulty swallowing tablets.

[0020] Carboplatin Provided herein is a method for treating a patient in need of treatment for a cancer containing a KRAS G12C mutation, comprising administering to the patient a first regimen comprising (a)(i) a therapeutically effective dose of sotrasib, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, followed by a second regimen comprising (b)(i) a therapeutically effective dose of sotrasib and (ii) a therapeutically effective dose of pemetrexed. In various embodiments, the therapeutically effective dose of sotrasib is 240 mg. In various embodiments, the therapeutically effective dose of sotrasib is 960 mg.

[0021] Carboplatin is a platinum-coordinate compound. The chemical name of carboplatin is platinum, diammine[1,1-cyclobutane-dicarboxylato(2-)-0,0'])-, (SP-4-2) or cis-(1,1-cyclobutanedicarboxylato)-diamine-platinum(II), and it has the following structural formula: [ka]

[0022] Carboplatin acts by crosslinking deoxyribonucleic acid (DNA) strands, thereby inhibiting DNA synthesis and function. Carboplatin was introduced in 1981 as an analogue of cisplatin, which had reduced non-hematological toxicity compared to cisplatin in experimental models. Calvert et al., 1989. In certain cases, platinum-containing chemotherapy was the frontline regimen for patients with advanced or metastatic non-small cell lung cancer (NSCLC) without genomic epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tumor abnormalities, until the recent introduction of immunotherapy in combination with chemotherapy (e.g., pembrolizumab in combination with pemetrexed and platinum chemotherapy; see KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ 07033 (revised March 2023) (the whole is incorporated herein by reference)). Other chemotherapeutic agents that may be combined with platinum may include pemetrexed (for non-squamous NSCLC), gemcitabine (for squamous NSCLC), or taxanes (paclitaxel, nab-paclitaxel, or docetaxel).

[0023] Carboplatin administration Carboplatin is marketed under the names PARAPLATIN®, BLASTOCARB®, BLASTOPLATIN®, CARBOKEM®, CARBOMAX®, PARAPLATIN®, CARBOPA®, KARPLAT®, and others. Complete information regarding the preparation, distribution, dosage, and administration schedule of carboplatin can be found in the local prescribing information (for the United States, see, for example, CARBOplatin Injection, US Prescribing Information, Fresenius KABI, Lake Zurich, Illinois, 60047 (revised May 2021) (the entire document is incorporated herein by reference)).

[0024] Provided herein is a method comprising the administration of a therapeutically effective dose of carboplatin. The Calvert formula [Total dose of carboplatin (mg) = (Target area under the concentration-time curve (AUC) × (Glomerular filtration rate (GFR) + 25)] is used to calculate the therapeutically effective dose of carboplatin. In some embodiments, the therapeutically effective dose of carboplatin is equivalent to 5 mg / (mL × min) (AUC 5), multiplied by the target GFR (mL / min) increasing at 25 mL / min. The GFR used in the Calvert formula to calculate the AUC-based dose should not exceed 125 mL / min, calculated using the Cockcroft-Gault formula (Calvert et al., 1989; Cockcroft et al., 1976; and see Example 2 below). For example, based on a target carboplatin AUC of 5, the maximum dose of carboplatin is 750 mg (i.e., 5 mg / ml / min × 150 mL / min). Therefore, also provided herein are methods for a therapeutically effective dose of carboplatin of 750 mg or less.

[0025] In various embodiments, carboplatin is administered intravenously.

[0026] Carboplatin is administered during the first regimen of the method provided herein, not during the second regimen. That is, the method provided herein is one in which the subject is not administered carboplatin during the second regimen. In various embodiments, the first regimen is administered over several cycles. In some embodiments, the first regimen is administered over four cycles (each 21 days). In various embodiments, carboplatin is administered on day 1 of each cycle during the first regimen. In some embodiments, sotrasib is administered before carboplatin when administered on the same day, i.e., on day 1 of each cycle of the first regimen.

[0027] Pemetrexed and other drugs Provided herein is a method for treating a patient in need of treatment for a cancer containing a KRAS G12C mutation, comprising administering to the patient a first regimen comprising (a)(i) a therapeutically effective dose of sotrasib, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, followed by a second regimen comprising (b)(i) a therapeutically effective dose of sotrasib and (ii) a therapeutically effective dose of pemetrexed. In various embodiments, the therapeutically effective dose of sotrasib is 240 mg. In various embodiments, the therapeutically effective dose of sotrasib is 960 mg.

[0028] Furthermore, the method provided herein further comprises administering to a subject another drug. In various embodiments, the method provided herein further comprises administering to a subject a therapeutically effective amount of folic acid. In various embodiments, the method provided herein further comprises administering to a subject a therapeutically effective amount of vitamin B12. In various embodiments, the method provided herein further comprises administering to a subject a therapeutically effective amount of a corticosteroid, such as dexamethasone or an equivalent thereof.

[0029] Pemetrexed is a folate analog metabolism inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. Pemetrexed is approved by the FDA as an early-line treatment for patients with metastatic non-squamous NSCLC without EGFR or ALK tumor genome abnormalities, for example, in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin).

[0030] Pemetrexed is marketed under the names ALIMTA® and others. Complete information regarding the preparation, distribution, dosage, and administration schedule of pemetrexed can be found in the local prescribing information (for the United States, see, for example, ALIMTA® US Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revised August 2022) (the entire information is incorporated herein by reference)). The active pharmaceutical ingredient of ALIMTA (pemetrexed for injection) is pemetrexed disodium heptahydrate, chemical name L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate (C 20 H 19 It has the molecular formula N5Na2O6·7H2O and a molecular weight of 597.49. Its structural formula is as follows: [ka]

[0031] ALIMTA is a sterile, white to pale yellow or green to yellow lyophilized powder in a single-dose vial, intended for reconstitution for intravenous injection.

[0032] Pemetrexed administration Provided herein is a therapeutically effective dose of pemetrexed of 500 mg / m². 2 This is the method. In various embodiments, pemetrexed is administered intravenously. In some embodiments, pemetrexed is administered intravenously over a period of 10 minutes.

[0033] In the methods provided herein, pemetrexed is administered throughout the entire course of treatment, i.e., until the end of pemetrexed administration, on day 1 of the first cycle of the first regimen, and then at 21-day intervals thereafter (i.e., on day 1, day 22, day 43, etc.). In various embodiments, both pemetrexed and carboplatin are administered on day 1 of each cycle during the administration of the first regimen. In some embodiments, pemetrexed is administered at 21-day intervals after the administration of carboplatin has been interrupted. In some embodiments, sotrasib is administered before pemetrexed, if administered on the same day, for example, on day 1 of each cycle of the first regimen and day 1 of the second regimen.

[0034] In various embodiments, pemetrexed is administered to subjects with a creatinine clearance (CrCl, calculated by the Cockcroft-Gault formula (Cockcroft et al., 1976; and see Example 2 below)) of 45 mL / min or more.

[0035] Therefore, provided herein is a method of initiating pemetrexed administration on day 1 of the first regimen. Furthermore, provided herein is a method of administering pemetrexed at 21-day intervals during the period in which the first and second regimens are administered to the subject.

[0036] Other drugs and their administration As discussed above, also provided herein is a method further comprising administering to a subject a therapeutically effective amount of folic acid; and administering to a subject a therapeutically effective amount of vitamin B 12 This method further includes administering [the substance]. See, for example, ALIMTA® US Presscribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revised August 2022).

[0037] Provided herein is a method in which the therapeutically effective dose of folic acid is 350 μg to 1000 μg once daily. In some embodiments, the therapeutically effective dose of folic acid is 400 μg once daily. In various embodiments, the therapeutically effective dose of folic acid is 400 μg to 1000 μg once daily. In various embodiments, the administration of folic acid is started 7 days before the administration of pemetrexed and ended 21 days after the discontinuation of pemetrexed.

[0038] Furthermore, the following are provided in this specification: Vitamin B 12 The therapeutic effective dose is 1 mg. In various embodiments, vitamin B12 is administered once within the week prior to the first pemetrexed administration, and then every 9 weeks (±2 weeks) thereafter until pemetrexed administration is discontinued. In some embodiments, vitamin B 12 It is administered once every nine weeks thereafter, one week before the first pemetrexed administration, and then until pemetrexed administration is discontinued. In various embodiments, vitamin B12 is administered intramuscularly.

[0039] As discussed above, the method provided herein also further comprises administering to a subject a therapeutically effective dose of a corticosteroid, such as dexamethasone or an equivalent thereof.

[0040] Pemetrexed-induced skin rashes are reported more frequently in subjects not previously treated with corticosteroids. Prior treatment with corticosteroids (dexamethasone or equivalent) reduces the incidence and severity of skin reactions. In clinical studies, dexamethasone 4 mg is administered orally twice daily on the day before, the day of, and the day after pemetrexed administration. See, for example, ALIMTA® US Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (approved August 19, 2004) (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2004 / 021677lbl.pdf, last accessed March 30, 2023). Therefore, the method provided herein also further comprises administering a therapeutically effective dose of corticosteroids to the subject. In some embodiments, the corticosteroid is dexamethasone or an equivalent thereof. In some embodiments, the corticosteroid is dexamethasone. In various embodiments, the therapeutically effective dose of dexamethasone is 4 mg twice daily. In some embodiments, dexamethasone is administered to the subject on the day before, on the day of, and after each pemetrexed administration.

[0041] Simultaneous therapy In various embodiments, the patient requires further treatment with antacids. Antacids include, but are not limited to, proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and topical antacids. In some embodiments, the patient requires further treatment with a PPI or H2RA. Exemplary PPIs include, but are not limited to, omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. Exemplary H2RAs include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine, roxatidine, and lafutidine. Exemplary topical antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide. In some embodiments, patients requiring further antacid treatment are not administered a proton pump inhibitor or H2 receptor antagonist in combination with sotrasib. In some embodiments, patients requiring further antacid therapy are not administered proton pump inhibitors or H2 receptor antagonists in combination with sotrasib, but are administered topical antacids in combination with sotrasib. In some embodiments, sotrasib is administered approximately 4 hours before or approximately 10 hours after topical antacids. In some embodiments, if the subject requires further treatment with an acid reducing agent, the subject is administered sotrasib with an acidic beverage (such as cola). In some embodiments, the subject has not received a PPI or H2RA within 7 days prior to the initiation of the first regimen, i.e., before day 1 of cycle 1 of the first regimen.

[0042] In various embodiments, subjects require further treatment with CYP3A4 inducers. In some embodiments, subjects are not administered CYP3A4 inducers in combination with sotrasib. Exemplary CYP3A4 inducers include, but are not limited to, barbiturates, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, ellagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritabancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, tetrotristat, and troglitazone. See, for example, 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, patients are not administered potent CYP3A4 inducers in combination with sotrasib. Exemplary potent CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. 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, potent CYP3A4 inducers include, but are not limited to, rifampin, phenytoin, mitotane, carbamazepine, abasimib, enzalutamide, rifapentin, St. John's wort extract, apalutamide, lumaphthol, and ivosidenib. In some embodiments, subjects have not received a potent CYP3A4 inducer within 14 days prior to the initiation of the first regimen, i.e., before day 1 of cycle 1 of the first regimen.

[0043] In various embodiments, subjects require further treatment with a CYP3A4 substrate. In some embodiments, subjects are not administered a CYP3A4 substrate in combination with sotracib. Exemplary CYP3A4 substrates include abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, caliprazine, ceritinib, cerivastatin, chlorpheniramine, and silos. Tasol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib, cyclosporine, dabrafenib, daclatasvir, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, dolutegravir, domperidone, doxepin, elagolix, elbasvir / grazoprevir, eliglustat, enzalutamide, eplerenone, erythromycin Icin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, gleevec, haloperidol, hydrocortisone, ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isabconazonium, ivabradine, ivacaftol, lansoprazole, lenvatinib, relcanidipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, midazolam, naldemedine, naloxegol, nategu Linid, nelfinavir, neratinib, netupitant / palonosetron, nevirapine, nifedipine, nisoldipine, nitrendipine, olaparib, omeprazole, ondansetron, osimertinib, ospemifene, palbociclib, panobinostat, pantoprazole, perampanel, pimavanserin, pimozide, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, ribociclib, rilpivirine, risperidone, ritonavir,Examples of medications that can be used include, but are not limited to, rivaroxaban, roflumilast, lorapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus, sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus (FK506), tamoxifen, tasimerteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, bilazodone, vincristine, borapaxar, voriconazole, zaleplon, and ziprasidone. For example, see Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table, Indiana University School of Medicine (2007), https: / / drug-interactions.medicine.iu.edu (last accessed May 2021).

[0044] In some embodiments, the subject is not administered a CYP3A4 substrate in combination with sotrasib, and the CYP3A4 substrate is a CYP3A4 substrate with a narrow therapeutic index. Examples of CYP3A4 substrates with a narrow therapeutic index include, but are not limited to, alfentanil, fentanyl, cyclosporine, pimozide, dihydroergotamine, quinidine, ergotamine, cyclosporine, everolimus, and tacrolimus. In some embodiments, the subject is not administered a CYP3A4 with a narrow therapeutic index within 14 days prior to the initiation of the first regimen, i.e., before day 1 of cycle 1 of the first regimen.

[0045] In various embodiments, subjects require further treatment with a P-glycoprotein (P-gp) substrate. In some embodiments, subjects are not administered a P-gp substrate in combination with sotrasib. Exemplary P-gp substrates include, but are not limited to, dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine. See, for example, www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers (last accessed May 2021). In some embodiments, subjects are not administered a P-gp substrate in combination with sotrasib, and the P-gp substrate is a P-gp substrate with a narrow therapeutic index. Examples of 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 a narrow therapeutic index are compounds in which even minimal concentration changes may cause significant toxicity. In some embodiments, subjects have not been administered a P-gp substrate with a narrow therapeutic index within 14 days prior to the initiation of the first regimen, i.e., before day 1 of cycle 1 of the first regimen.

[0046] Pembrolizumab Pembrolizumab is a non-investigational drug used as a comparator with sotrasib in the study described in Example 2 below.

[0047] Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody (mAb) that inhibits the interaction between PD-L1 and programmed cell death ligand-2 (PD-L2) due to its high binding specificity to the PD-1 receptor. Pembrolizumab is approved as a monotherapy for frontline treatment, post-disease progression, or after platinum-containing chemotherapy in patients with metastatic NSCLC expressing PD-L1 (TPS ≥ 1%) as determined by FDA-approved testing (see, for example, KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ 07033 (revised March 2023) (the entire document is incorporated herein by reference)). Patients with EGFR or ALK genomic tumor abnormalities should have experienced disease progression during FDA-approved targeted therapy for the abnormality prior to receiving pembrolizumab.

[0048] The comparator group in the study described in Example 2 (pembrolizumab combination with carboplatin and pemetrexed) is a selective therapy for subjects with non-squamous NSCLC without active oncogenic driver mutations, such as those with low or negative PD-L1 expression (NCCN Guidelines, 2022).

[0049] Pembrolizumab in combination with pemetrexed-platinum chemotherapy is approved based on the results of Cohort G of the KEYNOTE-021 and the confirmatory KEYNOTE 189 study (Gandhi, et al., 2018; Langer et al., 2016). The initial results of KEYNOTE 189 demonstrated significant improvements in OS (HR 0.49 (95% CI: 0.38, 0.64; p<0.001)) and PFS (HR 0.52 (95% CI: 0.43, 0.64; p<0.001)), and the ORR was 47.6% in the immunotherapy-chemotherapy combination compared to 18.9% in the control group (p<0.001) (Gandhi et al., 2018; Gadgeel et al., 2020). As a result of these and other data, pembrolizumab, in combination with pemetrexed and platinum chemotherapy, is approved in the United States, the European Union, and other countries as a first-line treatment for patients with metastatic non-squamous NSCLC without EGFR or ALK genomic tumor abnormalities (e.g., KEYTRUDA® US Prescribing Information, Merck & Co.). (See Co., Kenilworth, NJ 07033 (revised March 2023)). Therefore, pembrolizumab with platinum doublet chemotherapy (the current standard treatment) was selected as the study comparator.

[0050] Patient group In various embodiments, the subjects are adults. In some embodiments, the subjects are 18 years of age or older.

[0051] In various embodiments, the subject has not received prior systemic anticancer therapy for cancer prior to treatment by the method provided herein. In some cases, the patient has not received prior treatment for KRAS G12C-mutated cancers, such as metastatic colorectal cancer and pancreatic cancer. In some embodiments, the patient has not received prior treatment with an anti-angiogenic agent. In some embodiments, the patient has not been concurrently treated with an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent is an anti-VEGF antibody (e.g., bevacizumab or ramucirumab), aflibercept, or regorafenib. In some embodiments, the patient has not been concurrently treated with bevacizumab. In some embodiments, the patient has not received prior treatment for metastatic disease. The method disclosed herein is a frontline or first-line treatment.

[0052] In various embodiments, the subjects have a creatinine clearance (CrCl) of 45 mL / min or more, calculated by the Cockcroft-Gault formula. See Cockcroft et al., 1976. In various embodiments, the subjects have a creatinine clearance (CrCl) of 45 mL / min or more and 125 mL / min or less.

[0053] In various embodiments, subjects have an East Coast Cancer Clinical Trials Group (ECOG) performance status of 0 or 1. See, for example, Oken et al., 1982. Status 0 indicates fully active and able to perform all pre-disease performance without limitation. Status 1 indicates able to walk and perform light or sedentary work, but with limitations on physically strenuous activity. Status 2 indicates able to walk and fully self-care, but unable to perform any work activities; able to get up and move around for more than 50% of waking hours. Status 3 indicates able to perform only limited self-care and spends more than 50% of waking hours in bed or chair. Status 4 indicates completely immobile, unable to perform any self-care, and spends all of waking hours in bed or chair. Status 5 indicates death.

[0054] KRAS G12C mutated cancer Provided herein is a method for treating a patient in need of treatment for a cancer containing a KRAS G12C mutation, comprising administering to the patient a first regimen comprising (a)(i) a therapeutically effective dose of sotrasib, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, followed by a second regimen comprising (b)(i) a therapeutically effective dose of sotrasib and (ii) a therapeutically effective dose of pemetrexed. In various embodiments, the therapeutically effective dose of sotrasib is 240 mg. In various embodiments, the therapeutically effective dose of sotrasib is 960 mg.

[0055] Furthermore, provided herein is a method for treating non-small cell lung cancer in a subject requiring treatment for non-small cell lung cancer containing a KRAS G12C mutation, comprising administering to the subject a first regimen comprising (a) (i) 240 mg of sotrasib, (ii) an effective dose of carboplatin, and (iii) an effective dose of pemetrexed, followed by a second regimen comprising (b) (i) 240 mg of sotrasib and (ii) an effective dose of pemetrexed; (1) the effective dose of carboplatin is an amount equivalent to 5 mg / (mL × min) (AUC 5) multiplied by the subject's glomerular filtration rate (GFR) mL / min plus 25 mL / min, and (2) the effective dose of pemetrexed is 500 mg / m² 2 (3) The subjects have not received prior systemic anticancer therapy for cancer prior to treatment (first-line treatment), and (4) the cancer shows (a) a tumor cell (TC) score of less than 1% or (b) a PD-L1 tumor percentage score (TPS) of less than 1%.

[0056] Furthermore, provided herein is a method for treating non-small cell lung cancer in a subject requiring treatment for non-small cell lung cancer containing a KRAS G12C mutation, comprising administering to the subject a first regimen comprising (a)(i) 960 mg of sotrasib, (ii) an effective dose of carboplatin, and (iii) an effective dose of pemetrexed, followed by a second regimen comprising (b)(i) 960 mg of sotrasib and (ii) an effective dose of pemetrexed; (1) the effective dose of carboplatin is an amount equivalent to 5 mg / (mL × min) (AUC 5) multiplied by the subject's glomerular filtration rate (GFR) mL / min plus 25 mL / min, and (2) the effective dose of pemetrexed is 500 mg / m² 2 (3) The subjects have not received prior systemic anticancer therapy for cancer prior to treatment (first-line treatment), and (4) the cancer shows (a) a tumor cell (TC) score of less than 1% or (b) a PD-L1 tumor percentage score (TPS) of less than 1%.

[0057] While we do not wish to be bound by any particular theory or previous considerations, please note the following: Sotrasib is KRAS G12C It is a small molecule that specifically and irreversibly inhibits (Hong et al., 2020). Hong et al. reported that "[p]Reclinical studies have shown that [sotrasib] inhibits almost all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, resulting in permanent complete tumor regression in mice with KRAS p.G12C tumors" (ibid., see also Canon et al., 2019 and Lanman et al., 2020).

[0058] Sotrasib was evaluated in a Phase 1 dose-escalation and expansion trial involving 129 patients with locally advanced or metastatic cancer with histologically confirmed KRAS G12C mutations identified by local molecular examination of tumor tissue, including 59 patients with non-small cell lung cancer, 42 patients with colorectal cancer, and 28 patients with other tumor types (Hong et al., 2020, pp. 1208-1209). Hong et al. reported disease control rates (95% CI) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer, and 75.0% for other tumor types (Hong et al., 2020, p. 1213, Table 3). The cancer types that showed stable disease (SD) or partial response (PR) as reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary origin, ampulla cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma (Hong et al., 2020, pp. 1212 (Figure A), and appendix (pp. 59 (Figure S5) and pp. 63 (Figure S6)).

[0059] KRAS G12C mutations occur at the abnormal 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 containing the KRAS G12C mutation. Therefore, KRAS G12C Sotracib, which binds specifically and irreversibly to the following cancers, is useful in treating patients with cancers including, but not limited to, the following:

[0060] [Table 1]

[0061] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, pancreatic cancer, hepatobiliary tract cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, paranasal sinus cancer, or bile duct cancer. In some embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, paranasal sinus cancer, or bile duct cancer. In various embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.

[0062] non-small cell lung cancer Lung cancer is the leading cause of cancer death, with over 80% of all lung cancer cases classified as NSCLC. Globally, lung cancer (small cell and non-small cell) is the second most common cancer overall, with an estimated 2.21 million cases in 2020 (World Health Organization Statistics, 2020). In 2020, more than 253,537, 477,543, and 1,315,136 new cases of lung cancer were reported in North America, Europe, and Asia, respectively. The estimated number of deaths attributable to lung cancer in 2020 was 159,641 in North America, 384,176 in Europe, and 1,112,517 in Asia (Globocan-Lung Cancer, 2020). Advanced NSCLC (stages IIIB / C and IV) is a serious and life-threatening disease with a 5-year survival rate of only 9.3% (Surveillance, Epidemiology, and End Results [SEER], 2022).

[0063] The choice of systemic therapy for patients with advanced NSCLC is based on the molecular characteristics of the cancer, specifically the presence of active driver genetic abnormalities and the level of PD-L1 expression in tumor cells (NCCN Guidelines, 2022; Besse et al., 2014).

[0064] The level of PD-L1 expression on cell tumors, or the tumor cell (TC) score, as measured by TPS, is positively correlated with the response rate and duration of response to programmed cell death protein 1 / ligand-1 (PD-1 / L1) checkpoint inhibitors alone or in combination with platinum doublet chemotherapy in patients with NSCLC who do not have active mutations in the EGFR or ALK genes (Reck et al., 2019; Gandhi et al., 2018; Paz-Ares et al., 2018). The combination of an immune checkpoint inhibitor such as pembrolizumab with platinum doublet chemotherapy is the optimal treatment for advanced NSCLC that is negative for PD-L1 expression and does not have active mutations in the EGFR or ALK genes.

[0065] In contrast, the presence of activating driver mutations in the EGFR or ALK genes indicates low efficacy of PD-1 / L1 checkpoint inhibitors, regardless of the level of PD-L1 expression in the tumor. Therefore, oral tyrosine kinase inhibitors (TKIs) of the EGFR or ALK proteins are NCCN Category 1 frontline treatment options in such patients. The role of immune checkpoint inhibitors in these groups of patients is limited and is typically combined with chemotherapy commonly used beyond second-line treatment (NCCN Guidelines, 2022).

[0066] Patients with advanced non-squamous NSCLC without EGFR or ALK driver mutations are treated with pembrolizumab monotherapy, cemiplimab-rwlc monotherapy, or immunotherapy in combination with platinum chemotherapy (pembrolizumab, atezolizumab, or cemiplimab) (Reck et al., 2019; Gandhi et al., 2018; Sezer et al., 2021; Gogishvili et al., 2022).

[0067] The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy was investigated in a randomized, multicenter, double-blind study (KEYNOTE-189) in patients with metastatic non-squamous NSCLC, stratified by PD-L1 tumor expression levels, who had not previously received systemic therapy for metastatic disease and did not have EGFR or ALK genomic tumor abnormalities. Despite a substantial improvement in 2-year overall survival (OS) in the treatment intention population (45.5%; hazard ratio [HR] 0.56) in KEYNOTE-189, the response rate in the pembrolizumab-chemotherapy group was only 48% (95% CI 43.1–53.0) (Gadgeel et al, 2020). Response rates, PFS, and OS were strongly associated with higher levels of PD-L1 expression in the tumors, as demonstrated in an updated analysis (Rodriguez-Abreu et al., 2021). Specifically, the objective response rate (ORR), PFS, and OS in the PD-L1 <1% group were 33.1% (95% CI: 25.0, 42.0) and 6.2 months (HR 0.59, 95% CI: 0.40, 0.86) compared to the PD-L1 1%~49% group (50% (95% CI: 41.0, 59.0), 9.4 months (HR 0.53, 95% CI: 0.38, 0.74), and 21.8 months (HR 0.66, 95% CI: 0.46, 0.96), respectively, compared to the PD-L1 >50% group (62% (95% CI: 53.3, 70.4), 11.1 months (HR 0.35, 95% CI: 0.25, 0.49), and 27.7 months (HR 0.59, 95% CI: 0.40, 0.86), respectively. The HRs were 0.67 (95% CI: 0.49, 0.93) and 17.2 months (HR 0.51, 95% CI: 0.36, 0.71). Similar observations have been made with cemiplimab in combination with carboplatin-pemetrexed (Gogishvili et al., 2022), suggesting that PD-L1-negative NSCLC patients may benefit from alternative therapies, and / or additional biomarkers may help further select patients in this group who will benefit from novel treatment options.

[0068] Over the past 20 years, numerous driver mutations in specific genes have been identified (i.e., EGFR, ERBB2, BRAF, ROS1, ALK, METex14 skipping, NTRK, and RET). Among subjects with driver mutations, improved outcomes were observed in those treated with targeted therapy compared to those who did not receive targeted therapy (Kris et al., 2017). In most subjects with driver mutations, the efficacy of immunotherapy, particularly in frontline settings, was lower than in subjects with NSCLC without driver mutations, and in some groups, specifically in ALK and EGFR-driven cancers, the response rate to immune checkpoint inhibitors was low (Addeo et al., 2021).

[0069] The combination of targeted small molecule therapies (e.g., EGFR inhibitors, BRAF inhibitors, or vascular endothelial growth factor inhibitors) and immunotherapies (e.g., anti-PD-[L]1, anticytotoxic T lymphocyte-associated protein 4 [CTLA-4]) contributed to an unexpected increase in the frequency and / or severity of adverse events. Some examples include elevated liver enzymes (ipilimumab and vemurafenib, durvalumab and gefitinib, pembrolizumab and axitinib, durvalumab and osimertinib, pembrolizumab and gefitinib) (Yang et al., 2019; Rini et al., 2019; Ahn et al., 2016; Gibbons et al., 2016; Ribas et al., 2013) and interstitial lung disease (osimertinib and durvalumab) (Ahn et al., 2016), regardless of the presence or absence of simultaneous bilirubin elevation. Even when oral targeted agents are administered after immunotherapy, an increased frequency and severity of immune-mediated toxicity, likely due to the prolonged presence and effects of anti-PD-1 / L1 therapeutic antibodies, has been noted.

[0070] Therefore, the NCCN and ESMO recommend the use of targeted therapy as frontline treatment for patients with advanced or metastatic NSCLC with target-directed mutations (NCCN Guidelines, 2022; Hendriks et al, 2023a; Hendriks et al, 2023b). If used for driver-mutation-positive NSCLC, immune checkpoint inhibitors are recommended only as salvage therapy, in combination with chemotherapy, and after failure of available targeted agents.

[0071] Subjects with KRAS mutations, generally associated with a history of heavy smoking, demonstrate similar responses to immune checkpoint inhibitor chemotherapy combinations as subjects without KRAS mutations (Jeanson et al, 2019). Currently, NSCLC subjects with KRAS G12C mutations receive anti-PD-1 inhibitors, with or without chemotherapy in frontline treatment, similar to other subjects without molecularly defined targets. Therefore, subjects with previously untreated locally advanced or metastatic KRAS G12C mutations who have been treated with frontline targeted therapy, particularly those with tumors where PD-L1-expressing tumor cells <1% (Herbst et al., 2019; Gadgeel et al., 2019), represent a population in need of new therapeutic approaches, such as those disclosed herein.

[0072] Accordingly, provided herein are methods for treating cancer in a subject requiring treatment of cancer containing the KRAS G12C mutation, wherein the cancer is non-small cell lung cancer. In various embodiments, the cancer is metastatic or locally advanced non-small cell lung cancer. In some embodiments, the cancer is non-squamous non-small cell lung cancer. In some embodiments, the cancer is stage IV or advanced stage IIIB / C non-squamous non-small cell lung cancer. For example, AJCC Cancer Staging Manual 8 th See ed., 2017.

[0073] Determination of KRAS G12C mutation status Methods and tests for determining whether a subject has cancer containing the KRAS G12C mutation are known in this technology. The determination of KRAS G12C mutation status can be performed using Guardant360® NGS (plasma) and Qiagen therascreen® KRAS RGQ PCR (tissue; derived from formalin-fixed paraffin-embedded (FFPE) tissue or cell block). The KRAS G12C mutation status of cancer can be determined by any test approved by regulatory authorities, such as the U.S. Food and Drug Administration (FDA).

[0074] Determination of PD-L1 expression status As background, PD-L1 is a transmembrane protein that downregulates the immune response through its binding to two receptors, programmed death-1 (PD-1) and B7-1 (Keir et al., 2008). PD-1 is an inhibitory receptor expressed on T cells after T cell activation, and it persists under prolonged stimulation, for example, in chronic infections or cancer (Blank et al., 2007). PD-L1 binding to PD-1 inhibits T cell proliferation, cytokine production, and cytolytic activity, leading to functional inactivation or exhaustion of T cells (Blank et al., 2007). B7.1 is a molecule expressed on antigen-presenting cells and activated T cells. PD-L1 binding to B7.1 on T cells and antigen-presenting cells can mediate downregulation of the immune response, including inhibition of T cell activation and cytokine production (Butte et al., 2007). PD-L1 expression has been observed in immune cells and malignant cells (Dong et al., 1999; Massard et al., 2016), and abnormal expression of PD-L1 on malignant cells has been reported to interfere with antitumor immunity and result in immune evasion (Blank et al., 2007; Massard et al., 2016). Therefore, disruption of the PD-L1 / PD-1 pathway represents an attractive strategy for further activating tumor-specific T cell immunity, which is suppressed by PD-L1 expression in the tumor microenvironment. The relationship between PD-L1 expression in TCs or tumor-infiltrating immune cells (ICs) and the clinical benefits of PD-L1 / PD-1 pathway inhibitors has been reported across multiple cancers. See also, for example, VENTANA PD-L1(SP263) Assay, Instructions 2021-10-10, 1020514US Rev 1, Ventana Medical Systems, Inc. 1910 E. Innovation Park Drive Tucson, Arizona 85755 USA (available at https: / / www.accessdata.fda.gov / cdrh_docs / pdf16 / P160046S010C.pdf (last accessed March 31, 2023)).

[0075] PD-L1 expression can be determined by methods known in the art. For example, PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for pembrolizumab treatment. See PD-L1 IHC 22C3 pharmDx, Dako North America, Inc. 6392 Via Real, Carpinteria, California 93013, USA (available at https: / / www.accessdata.fda.gov / cdrh_docs / pdf15 / p150013c.pdf, Edition 09 / 15 (last accessed March 31, 2023)) (the entire document is incorporated herein by reference). PD-L1 IHC 22C3 pharmDx is a qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3, intended for use in the detection of PD-L1 protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue using the EnVision FLEX visualization system with respect to Autostainer Link 48. PD-L1 protein expression is determined by using the Tumor Percentage Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining.

[0076] For example, PD-L1 expression can also be detected using the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca). This assay is a qualitative immunohistochemical assay using rabbit monoclonal anti-PD-L1 clone SP263, intended for use in evaluating programmed death ligand-1 (PD-L1) protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens by light microscopy. The assay is performed using the OptiView DAB IHC Detection Kit for staining with a BenchMark ULTRA instrument. PD-L1 protein expression in NSCLC is determined by the percentage of tumor cells (TC%) where any membrane staining exceeds the background. The assay is shown as an aid in identifying individuals eligible for treatment with, for example, atezolizumab (TECENTRIQ®) for non-small cell lung cancer with a TC score of ≥1%. VENTANA PD-L1 (SP263) Assay, Instructions 2021-10-10, 1020514US Rev 1, Ventana Medical Systems, Inc. 1910 E. Innovation Park Drive Tucson, Arizona 85755 USA (Available at https: / / www.accessdata.fda.gov / cdrh_docs / pdf16 / P160046S010C.pdf (Last accessed March 31, 2023)) (The entire document is incorporated herein by reference).

[0077] In some embodiments, PD-L1 negativity is determined using PD-L1 TPS or TC scores for cancers enumerated in the methods disclosed herein, using tests approved by regulatory authorities such as the U.S. Food and Drug Administration (FDA). In various embodiments, PD-L1 TPS or TC scores are determined using immunohistochemistry (IHC) testing. In various embodiments, IHC testing is performed on samples obtained, for example, by excision, needle biopsy (CNB), or fine-needle aspiration (FNA). In some embodiments, the IHC test is the PD-L1 IHC 22C3 pharmDx test for determining TPS. In some embodiments, the IHC test is the Ventana PD-L1(SP263) IHC assay for determining the TC score.

[0078] In various embodiments, cancer exhibits a PD-L1 TPS of 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or less than 1%. In various embodiments, cancer exhibits a PD-L1 TPS of less than 1%. In some embodiments, cancer exhibits a PD-L1 TPS score in the range of 0% or more and less than 1%. In some embodiments, cancer exhibits a PD-L1 TPS score of 1 to 49%. In some embodiments, cancer exhibits a PD-L1 TPS score of 50% or more (i.e., 50% to 100%). In some embodiments, the PD-L1 TPS score is the PD-L1 IHC 22C3 pharmDx test.

[0079] In various embodiments, cancer exhibits a TC score of 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or less than 1%. In various embodiments, cancer exhibits a TC score of less than 1%. In some embodiments, cancer exhibits a TC score in the range of 0% or more and less than 1%. In some embodiments, cancer exhibits a TC score of 1 to 49%. In some embodiments, cancer exhibits a TC score of 50% or more (i.e., 50% to 100%). In some embodiments, the TC score is determined using the Ventana PD-L1 (SP263) IHC assay.

[0080] Determination of abnormal status for EGFR, ALK, and ROS1. Patients with advanced non-small cell lung cancer (NSCLC) with active mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and a few other genes demonstrate superior outcomes with small molecule targeted therapy compared to platinum doublet chemotherapy, immune checkpoint inhibitors alone, or combinations with chemotherapy (European Society for Medical Oncology [ESMO] Clinical Practice Guidelines, 2020; National Cancer Network [NCCN] Guidelines, 2022).

[0081] Therefore, provided herein are methods for treating cancer in which the cancer does not include an EGFR abnormality. In some embodiments, the cancer does not include an ALK abnormality. In some embodiments, the cancer does not include a ROS 1 abnormality. In some embodiments, the cancer does not include an EGFR or ALK abnormality.

[0082] Methods for determining abnormal status of EGFR, ALK, and ROS1 are known in this technology (see, for example, Oncomine Dx Target Test by ThermoFisher Scientific or https: / / testdirectory.questdiagnostics.com / test / test-guides / CF_NSCLC / non-small-cell-lung-cancer-nsclc-laboratory-support-of-diagnosis-and-management (last accessed March 30, 2023)).

[0083] Embodiment 1. A method for treating cancer involving a KRAS G12C mutation in a subject requiring treatment, comprising: administering to the subject a first regimen comprising (a) (i) a therapeutically effective dose of sotrasib, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, and then (b) a second regimen comprising (i) a therapeutically effective dose of sotrasib and (ii) a therapeutically effective dose of pemetrexed. 2. The first regimen is the method of Embodiment 1, which is performed over a period of 4 cycles. 3. The method of Embodiment 2, wherein each cycle has a period of 21 days. 4. Any one of Embodiments 1 to 3, wherein the therapeutically effective dose of sotrasib is 240 mg. 5. Any one of Embodiments 1 to 3, wherein the therapeutic effective dose of sotrasib is 960 mg. 6. Sotrasib is administered orally, according to any one of Embodiments 1 to 5. 7. Sotrasib is administered once daily, according to any one of embodiments 1 to 6. 8. Sotracib is administered as a solid dose in any one of Embodiments 1 to 7. 9. The method of Embodiment 8, wherein the solid dosage form is a tablet. 10. The method of Embodiment 9, in which sotrasib is administered as one tablet containing 240 mg of sotrasib, two tablets each containing 120 mg of sotrasib, three tablets each containing 320 mg of sotrasib, four tablets each containing 240 mg of sotrasib, or eight tablets each containing 120 mg of sotrasib. 11. The therapeutically effective dose of carboplatin is an amount equivalent to the value obtained by multiplying 5 mg / (mL × min) (AUC 5) by the value obtained by adding 25 mL / min to the target glomerular filtration rate (GFR) mL / min, according to any one of the methods in Embodiments 1 to 10. 12. The method of Embodiment 11, wherein the therapeutically effective dose of carboplatin is 750 mg or less. 13. Carboplatin is administered intravenously, according to any one of Embodiments 1 to 12. 14. Carboplatin is administered on day 1 of each cycle, according to any one of embodiments 2 to 13. 15. The subject is any one of Embodiments 1 to 14, in which carboplatin is not administered during the second regimen. 16. The effective therapeutic dose of pemetrexed is 500 mg / m². 2 The method is one of the embodiments 1 to 15. 17. Pemetrexed is administered intravenously in any one of the embodiments 1 to 16. 18. Administration of pemetrexed is initiated on day 1 of the first regimen, according to any one of Embodiments 1 to 17. 19. Any one of Embodiments 1 to 18, wherein pemetrexed is administered at 21-day intervals in the first and second regimens. 20. Any one of Embodiments 1 to 19, further comprising administering a therapeutically effective amount of folic acid to the subject. 21. The therapeutically effective dose of folic acid is 350 μg to 1000 μg once daily, according to the method of Embodiment 20. 22. The therapeutically effective dose of folic acid is 400 μg once daily, according to the method of Embodiment 20. 23. The therapeutically effective dose of folic acid is 400 μg to 1000 μg once daily, according to the method of Embodiment 20. 24. The method of Embodiment 20 or 23, wherein folic acid administration is started 7 days before pemetrexed administration and ends 21 days after discontinuation of pemetrexed administration. 25. Any one of Embodiments 1 to 24, further comprising administering a therapeutically effective amount of vitamin B12 to the subject. 26. The method of Embodiment 25, wherein the therapeutically effective dose of vitamin B12 is 1 mg. 27. The method of Embodiment 25 or 26, wherein vitamin B12 is administered once every 9 weeks (±2 weeks) thereafter, within the week prior to the first pemetrexed administration, and until the discontinuation of pemetrexed administration. 28. The method of Embodiment 25 or 26, wherein vitamin B12 is administered once every nine weeks thereafter, one week before the first pemetrexed administration and then until the discontinuation of pemetrexed administration. 29. Vitamin B12 is administered intramuscularly, according to any one of embodiments 25-28. 30. Any one of claims 1 to 29, further comprising administering a therapeutically effective dose of dexamethasone to a subject. 31. The therapeutically effective dose of dexamethasone is 4 mg twice daily, according to the method of embodiment 30. 32. The method of Embodiment 30 or 31, wherein dexamethasone is administered to the subject on the day before, the day of, and the day after each pemetrexed administration. 33. One of the embodiments 1 to 32, wherein the subject is an adult. 34. The subjects are those who have not received prior systemic anticancer therapy for cancer (first-line treatment) prior to treatment, and one of the methods described in Embodiments 1 to 33. 35. The subject is any one of the methods from Embodiments 1 to 34, wherein the creatinine clearance (CrCl) is 45 mL / min or more, as calculated by the Cockcroft-Gault formula. 36. The subject is any one of the methods of Embodiments 1 to 35, wherein the ECOG performance status is 0 or 1. 37. Cancer exhibiting a TC score of less than 1%, according to any one of Embodiments 1 to 36. 38. The method of Embodiment 37, wherein the therapeutic effective dose of sotrasib is 960 mg. 39. The TC score was determined using the Ventana PD-L1 (SP263) IHC assay, according to the method of Embodiment 37. 40. Cancer exhibiting a PD-L1 tumor percentage score (TPS) of less than 1%, according to any one of Embodiments 1 to 36. 41. The method of Embodiment 40, wherein the therapeutic effective dose of sotrasib is 960 mg. 42. TPS was determined using the PD-L1 IHC 22C3 pharmDx assay, according to the method of Embodiment 40. 43. Cancer is a method according to any one of Embodiments 1 to 42, which does not involve abnormalities in EGFR or ALK. 44. The cancer is lung cancer, according to any one of Embodiments 1 to 43. 45. The cancer is non-small cell lung cancer, according to any one of Embodiments 1 to 43. 46. ​​The cancer is non-squamous non-small cell lung cancer, according to any one of Embodiments 1 to 43. 47. The method of Embodiment 46, wherein the non-squamous non-small cell lung cancer is stage IV or advanced stage IIIB / C. 48. The patient is not administered antibodies in any one of the embodiments 1 to 47. 49. The method of Embodiment 48, wherein the antibody is an anti-VEGF antibody. 50. The method of Embodiment 49, wherein the anti-VEGF antibody is bevacizumab. 51. Sotrasib used to treat KRAS G12C mutated cancer, wherein the treatment comprises administering to a subject a first regimen comprising (a)(i) a therapeutically effective dose of sotrasib, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, and then administering to the subject a second regimen comprising (b)(i) a therapeutically effective dose of sotrasib and (ii) a therapeutically effective dose of pemetrexed. 52. Sotrasib used to treat KRAS G12C mutated cancer, wherein the treatment comprises administering to the subject a first regimen comprising (a)(i) sotrasib, (ii) carboplatin, and (iii) pemetrexed, and then administering to the subject a second regimen comprising (b)(i) sotrasib and (ii) pemetrexed. [Examples]

[0084] Example 1 - Phase 1b / 2 protocol to evaluate the safety, tolerability, pharmacokinetics, and efficacy of sotracib monotherapy and combination therapy with other anticancer therapies in patients with advanced solid tumors containing the KRAS p.G12C mutation (CodeBreak 101). research design Subprotocol F is part of the Study 20190135 master protocol (Study 20190135), which evaluates various ongoing combinations of sotracib with other agents in advanced solid tumors with KRAS p.G12C mutations (CodeBreaK 101, ClinicalTrials.gov identifier: NCT04185883, https: / / clinicaltrials.gov / ct2 / show / NCT04185883, last accessed March 27, 2023). Cohort A of Subprotocol F of CodeBreaK 101 evaluates the safety, tolerability, and efficacy of sotracib plus pemetrexed maintenance therapy following sotracib in combination with four cycles of carboplatin and pemetrexed.

[0085] This study, including a dose-exploratory phase (Part 1) and an expansion phase (Part 2), is being conducted at approximately 65 research centers in the United States. Part 1 of the study consists of two cohorts. Cohort A evaluates the safety of maintenance therapy with sotrasib and pemetrexed, following sotrasib and pemetrexed in combination with carboplatin and pemetrexed (4 cycles, each 21 days). Currently, subjects have been treated, in particular, in Cohort A Part 1, Cohort A1 Part 2, and Cohort A2 Part 2, which are listed below: Cohort A Part 1 = Sotrasib 960mg QD + Carboplatin AUC5 Q3W + Pemetrexed 500mg / m² 2 Q3W (n=7) Cohort A1 Part 2 = Sotrasib 960mg QD + Carboplatin AUC5 Q3W + Pemetrexed 500mg / m² 2 Q3W: No prior treatment experience (n=11) Cohort A2 Part 2 = Sotrasib 960mg QD + Carboplatin AUC5 Q3W + Pemetrexed 500mg / m² 2 Q3W: History of treatment (n=8) Vitamin B12 and dexamethasone were administered to study subjects according to the label instructions for pemetrexed (see, for example, ALIMTA® US Pressuris Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revised August 2022) (the entire document is incorporated herein by reference)). Primary safety endpoints were dose-limiting toxicity, treatment-induced adverse events, and the occurrence of changes in vital signs, electrocardiogram, and clinical laboratory tests. Secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to response (TTR), overall survival (OS), progression-free survival (PFS), stability period, and pharmacokinetic (PK) parameters.

[0086] The planned enrollment for sotrasib in combination with carboplatin and pemetrexed has reached 47 participants.

[0087] Target dynamics and demographics As of the data snapshot date of December 1, 2022, a total of 26 subjects were enrolled in Cohort A subprotocol F of Study 20190135 and received at least one dose of any investigational drug. Of these 26 subjects, 17 were male and 9 were female. The subjects were either white (n=23) or black / african American (n=3), and the mean (SD) age was 65.3 (8.8) years. PD-L1 expression levels were reported as ≥50% tumor cell expression in 7 of the 26 subjects (26.9%), 1%–49% in 4 of the 26 subjects (15.4%), and <1% tumor cell expression in 7 of the 26 subjects (26.9%) (unknown in 8 of the 26 subjects [30.8%]).

[0088] In Cohort A Part 1, five of the seven subjects (71.4%) had no prior history of chemotherapy for metastasis, and three subjects (42.9%) had no prior anti-PD-1 / PD-L1 therapy. All subjects in Cohort A1 Part 2 were treatment-naïve, and all subjects in Cohort A2 Part 2 had a prior history of chemotherapy, including five of the eight subjects (62.5%) who had previously received anti-PD-1 / PD-L1 therapy.

[0089] exposure In Cohort A Part 1, the subjects had a median (minimum to maximum) exposure to sotrasib of 148.0 (93–589) days. The median sotrasib exposure in Cohort A1 Part 2 was 85.0 (9–191) days, and in Cohort A2 Part 2 it was 46.5 (7–233) days. Exposure to carboplatin ranged from a median (minimum to maximum) of 60.5 (15–85) to 84.0 (63–91) days across the entire cohort, while exposure to pemetrexed ranged from a median (SD) of 70.5 (15–253) to 105.0 (16–197) days across the entire cohort.

[0090] Effectiveness data As of December 1, 2022, the 23 subjects in Part A were evaluable for efficacy based on having received at least one dose of the investigational drug, had at least one measurable lesion at baseline as assessed using RECIST 1.1 (Eisenhauer et al., 2009), and had the opportunity to be followed for at least 7 weeks. A summary of investigator-assessed objective responses is shown by cohort in Table 1. For the best overall response (BOR) analysis, of these 23 subjects, 6 (26.1%) had a confirmed partial response (PR), 14 (60.9%) had stable disease (SD) (including 12 unconfirmed PR pending confirmation scans), 1 (4.3%) had progressive disease (PD), and 2 subjects did not have a post-baseline assessment. The confirmed ORRs were 42.9% (95% CI: 9.90–81.59) in Cohort A Part 1, 11.1% (95% CI: 0.28–48.25) in Cohort A1 Part 2, and 28.6% (95% CI: 3.67–70.96) in Cohort A2 Part 2.

[0091] [Table 2]

[0092] [Table 3]

[0093] Safety data As of December 1, 2022, 26 subjects had received at least one investigational drug and were eligible for safety evaluation. Table 2 summarizes the adverse events associated with the treatment. 24 subjects (92.3%) experienced at least one adverse event. The most common adverse events occurring in ≥50% of subjects per cohort were as follows: Cohort A Part 1 (n=7): In Cohort A Part 1, diarrhea (71.4%), nausea (71.4%), fatigue (71.4%), and anemia (57.1%) were observed. Cohort A1 Part 2 (n=11): Nothing observed in Cohort A1 Part 2. Cohort A2 Part 2 (n=8): In Cohort A2 Part 2, decreased appetite (50.0%)

[0094] Overall, 12 out of 26 subjects (46.2%) experienced one or more treatment-induced adverse events classified as Grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE) v5, including anemia (n=5), diarrhea (n=2), abdominal pain, increased alanine aminotransferase, increased aspartate aminotransferase, increased serum alkaline phosphatase (ALP), coronavirus disease 2019 (COVID-19), decreased appetite, caries, febrile neutropenia, abnormal liver function, hepatotoxicity, hypertransaminasemia, nausea, neutropenia, decreased neutrophil count, decreased platelet count, rectal pain, and pulmonary embolism (n=1 each). Three subjects experienced Grade 4 treatment-induced adverse events: neutropenia (n=2), decreased neutrophil count, and thrombocytopenia (n=1 each). There were no treatment-induced fatal adverse events.

[0095] Twenty-four subjects (92.3%) experienced at least one treatment-related adverse event. Six of the 26 subjects (23.1%) experienced one or more serious adverse events, and three of the 26 subjects (11.5%) discontinued sotrasib due to adverse events. In general, the reported adverse events were consistent with the individual safety profiles of the investigational drug, and no new safety concerns were identified.

[0096] [Table 4]

[0097] [Table 5]

[0098] The updated data cut date is February 3, 2023.

[0099] As of February 3, 2023, 30 subjects (median age 67 years; 60% male; ECOG 0 / 1: 47% / 53%) were treated with sotrasib in combination with carboplatin and pemetrexed. Nineteen subjects were treatment-naïve (Cohort A1 Part 2, first-line treatment (1L)), and 11 had received previous treatment for metastatic / locally advanced disease (Cohort A2 Part 2, second-line or better treatment (2L+)). Treatment-related adverse events (TRAEs) occurred in 29 subjects (97%), and were grade 3-4 in 19 subjects (63%) (Table 3). The most common grade 3-4 TRAEs were neutropenia (9 subjects [30%]), anemia, and thrombocytopenia (5 subjects [17%] for both). No fatal adverse events occurred. In the first-line treatment setting (1L) for previously untreated patients treated with sotrasib in combination with carboplatin and pemetrexed, the ORR (objective response rate, confirmed + unconfirmed) was 73% (95% CI: 45 patients, 92 patients), and the DCR (disease control rate, Table 3) was 100%. Among the PD-L1 tumor percentage score (TPS) <1% treated in 1L, a response occurred in 8 out of 11 patients (ORR 73%). In the second-line setting (2L+), the ORR was 55%. The median DOR (duration of response) could not yet be evaluated for all confirmed responders. PFS and OS data were immature.

[0100] The combination of sotrasib with carboplatin and pemetrexed was safe and tolerable, and the incidence of grade 3–4 TRAEs was largely consistent with other platinum doublet-based approaches. Promising efficacy was most evident in treatment-naive patients with high unmet needs and low PD-L1 expression.

[0101] [Table 6]

[0102] [Table 7]

[0103] The updated data cut date is May 7, 2023.

[0104] As of May 7, 2023, 38 patients had been treated with sotrasib in combination with carboplatin and pemetrexed.

[0105] Baseline characteristics The patient enrollment cohorts were Cohort A Part 1 (prior anti-PD-1 / L1 immunotherapy and / or platinum-based combination chemotherapy, or rejection of standard treatment), Part 2 Cohort A1 (no prior anti-PD-1 / L1 immunotherapy or platinum-based combination chemotherapy), and Cohort A2 Part 2 (prior anti-PD-1 monotherapy, platinum-based chemotherapy, or neoadjuvant / adjuvant chemotherapy) (Cohort A Part 1: n=2 (29%) first-line patients, n=5 (71%) second-line patients; Part 2 Cohort A1: n=22 (100%) first-line patients; Part 2 Cohort A2: n=1 (11%) first-line patients, n=8 (89%) second-line patients). Data were pooled and analyzed by exposure to prior treatment in terms of locally advanced / metastatic status (n=25 first-line patients; n=13 second-line patients).

[0106] Of the 25 subjects, there were no prior treatments (first-line treatment (1L)), and 13 had received previous treatment for metastatic / locally advanced disease (second-line treatment or better (2L+)). The median age of the treatment-naive subjects was 64 years (48% male), while the median age of the previously treated subjects was 67 years (62% male). The baseline characteristics of the patient population are as follows:

[0107] [Table 8]

[0108] safety Treatment-related adverse events (TRAEs) occurred in 36 patients (95%), with grade 3–4 events occurring in 22 patients (58%). The most common grade 3–4 TRAEs, occurring in ≥5% of all patients, were neutropenia / decreased neutrophil count (32%), anemia (21%), thrombocytopenia / decreased platelet count (16%), elevated ALT (5%, Grade 304 elevated ALT was observed only in second-line settings), diarrhea (5%), febrile neutropenia (5%), and nausea (5%). No fatal adverse events occurred. TRAEs were consistent with sotrasib and platinum doublet-based regimens.

[0109] [Table 9]

[0110] Effectiveness In the first-line treatment (1L) of treatment-naive patients treated with sotrasib in combination with carboplatin and pemetrexed, the ORR (objective response rate) was 65%, the DCR (disease control rate) was 100%, and the 95% confidence interval (CI) was 83.2–100%. In the second-line treatment (2L+), the ORR was 54%, the DCR was 85%, and the 95% CI was 54.6–98.1%.

[0111] [Table 10]

[0112] The ORRs for both 1L (n=20) and 2L+ (n=13) subjects were similar across all PD-L1 expression levels. (A) For 1L+ subjects with PD-L1 expression levels <1%, the ORR was 62% (n=8 / 13); (B) For PD-L1 expression levels between 1% and 49%, the ORR was 75% (n=3 / 4); (C) For PD-L1 expression levels ≥50%, the ORR was 67% (n=2 / 3). (A) For 2L+ subjects with PD-L1 expression levels <1%, the ORR was 50% (n=2 / 4); (B) For PD-L1 expression levels between 1% and 49%, the ORR was 67% (n=2 / 3); (C) For PD-L1 expression levels ≥50%, the ORR was 50% (n=3 / 6).

[0113] Rapid and durable preliminary responses were observed during a median follow-up period of 3.0 months. PFS and OS data were immature. All patients in first-line and second-line situations were included who received ≥1 dose of the study drug, had ≥1 measurable lesion per RECIST v 1.1 at baseline, and could be followed for ≥7 weeks starting from day 1.

[0114] The updated data cut date is December 1, 2023.

[0115] As of December 1, 2023, 58 patients (median age 65.5 years; 45% male; ECOG status 0 / 1, 38% / 62%) had been treated with sotrasib plus carboplatin and pemetrexed; 37 patients (64%) were in first-line treatment (1L) and 21 patients (36%) were in second-line plus treatment (2L+). In the 2L+ group, 18 / 21 patients (86%) had received prior anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 54 patients (93%); 30 patients (52%) had grade 3-4 TRAEs, and one patient (2%) was fatal (see table immediately below). In the 1L group, the ORR was 65% (95% CI, 46.5–80.3), the DCR was 100%, the median DOR was 9.1 months (95% CI, 4.4–12.5), and the median PFS was 10.8 months (95% CI, 5.4–NE; median follow-up period [f / u], 9.2 months). The median PFS was 11.9 months (95% CI, 5.3–NE) in the PD-L1 < 1% subgroup (n=19). For the 2L+ group, the ORR was 42% (95% CI, 20.3–66.5), the DCR was 84%, the median DOR was NE, and the median PFS was 8.3 months (95% CI, 4.1–NE; median f / u, 4.4 months). OS data remained immature.

[0116] [Table 11]

[0117] Sotrasib plus platinum doublet chemotherapy demonstrated a robust and durable response with a manageable safety profile in CodeBreaK 101. This supports the evaluation of this regimen in the ongoing Phase 3 CodeBreaK 202 trial in a treatment-naive, PD-L1-negative, KRAS G12C-mutated advanced NSCLC (NCT05920356).

[0118] Example 2 - Phase 3 study of sotrasib as a frontline platinum doublet therapy against pembrolizumab in PD-L1-negative, KRAS p.G12C-positive advanced / metastatic non-small cell lung cancer (NSCLC) (CodeBreaK 202) This is a Phase 3 international multicenter randomized open-label study (CodeBreaK 202) evaluating the efficacy and safety of sotrasib in combination with carboplatin and pemetrexed compared to sotrasib in combination with carboplatin and pemetrexed in frontline treatment in subjects with stage IV or advanced stage IIIB / C non-squamous PD-L1-negative and KRAS p.G12C mutation-positive non-small cell lung cancer (NSCLC). (CodeBreaK 202, https: / / clinicaltrials.gov / study / NCT05920356, last accessed February 29, 2024.)

[0119] This study consists of a pre-treatment phase (pre-screening period (optional for subjects for whom molecular data are available) and screening period), a treatment phase (four platinum-containing cycles followed by maintenance therapy), and a post-treatment phase (safety follow-up period [SFU] and long-term follow-up period [LTFU]).

[0120] The study target population consists of subjects with non-squamous NSCLC that are PD-L1 immunohistochemistry (IHC) negative (tumor cells (TC) or tumor percentage score (TPS) < 1%) and KRAS p.G12C-mutation positive, as determined by the central laboratory, or in select cases, by a local laboratory. The central laboratory uses the VENTANA SP263 assay to determine PD-L1 negativity (TC < 1%), and Guardant360® next-generation sequencing (NGS) from plasma and therascreen® KRAS RGQ PCR (polymerase chain reaction) from formalin-fixed paraffin-embedded (FFPE) tissue to determine KRAS p.G12C. Positive KRAS p.G12C from either test is sufficient for enrollment. Enrollment and randomization using local results for PD-L1 IHC and KRAS mutation analysis are permitted for subjects requiring accelerated initiation of anticancer therapy due to progressive cancer-related signs (provided that results are obtained in a qualified laboratory using a qualified assay), and subjects complete and meet all other inclusion / exclusion criteria and submit the samples required for retrospective molecular pathology establishment by a central laboratory.

[0121] Approximately 750 participants will be enrolled in the study. The study will be conducted at approximately 350 sites in total. Participants will be randomized in a 1:1 ratio to receive either sotrasib in combination with carboplatin and pemetrexed, or pembrolizumab in combination with carboplatin and pemetrexed.

[0122] The target group is those with the disease stage (stage IV or advanced stage IIIB / C, AJCC Cancer Staging Manual 8) th (See ed., 2017), stratified by brain metastases (present or absent) and region (North America, Europe, or other parts of the world). Subjects are considered to have brain metastases, regardless of prior treatment for brain lesions.

[0123] In the sotrasib (under investigation) treatment group, subjects received intravenous (IV) 5 mg / mL / min (AUC5) and pemetrexed 500 mg / m² every 21 days for 4 cycles.2 Sotrasib 240 mg (or 960 mg) once daily (QD) oral (PO) doses, combined with the carboplatin area under the concentration-time curve, followed by sotrasib 240 mg (or 960 mg) PO doses and pemetrexed 500 mg / m² every 21 days. 2 Patients receive IV maintenance therapy (from cycle 5 onwards). Within the pembrolizumab (control) treatment group, patients receive carboplatin AUC5 and pemetrexed 500 mg / m² every 21 days for 4 cycles. 2 This is followed by pembrolizumab 200 mg in combination with IV, then pembrolizumab 200 mg IV every 21 days (up to 35 cycles) and pemetrexed 500 mg / m². 2 Receive maintenance treatment with IV (from cycle 5 onwards).

[0124] Treatment with sotrasib continues until a blinded, independent central review (BICR) confirms progressive disease, unacceptable toxicity, withdrawal of consent, termination of the study, or death (whichever occurs first), according to the criteria for evaluating the effectiveness of treatment for solid tumors version 1.1 (RECIST v1.1). Pembrolizumab may be administered for up to two years. Patients who discontinue study treatment for reasons other than disease progression confirmed by BICR will continue to be evaluated for tumors (if clinically feasible) until disease progression is confirmed by BICR.

[0125] As detailed below, the study allows for treatment beyond progression only under specific circumstances.

[0126] Tumor response is evaluated by radiographic imaging (computed tomography [CT] scans and / or magnetic resonance imaging [MRI]) using the RECIST v1.1 criteria.

[0127] [Table 12]

[0128] [Table 13]

[0129] [Table 14]

[0130] [Table 15]

[0131] Estimates regarding the main objective Hazard ratio (HR) for progression-free survival (PFS) between subjects receiving sotrasib in platinum doublet chemotherapy versus pembrolizumab in platinum doublet chemotherapy in subjects with stage IV or advanced stage IIIB / C non-squamous non-squamous NSCLC that is PD-L1 negative and KRAS p.G12C positive and requires frontline treatment; the intermediate event is the initiation of a new anticancer therapy prior to the PFS event, and the primary analysis censors PFS at the date of the last evaluable assessment before or at the initiation of the new anticancer therapy. A sensitivity analysis is performed for PFS including all evaluable assessments after the initiation of the new anticancer therapy.

[0132] Estimates regarding important secondary objectives: The difference in objective response rates between patients receiving sotrasib in platinum doublet chemotherapy and those receiving pembrolizumab in platinum doublet chemotherapy in patients with stage IV or advanced stage IIIB / C non-squamous non-squamous NSCLC who are PD-L1 negative and KRAS p.G12C positive and require frontline treatment. Patients who initiate a new anticancer therapy before achieving an objective response are considered non-responders.

[0133] In patients with stage IV or stage IIIB / C non-squamous NSCLC requiring frontline treatment, who are PD-L1 negative and KRAS p.G12C positive, the hazard ratio for overall survival (OS) was assessed between patients receiving sotrasib in addition to platinum doublet chemotherapy and those receiving pembrolizumab in addition to platinum doublet chemotherapy; the intermediate event was the initiation of a new anticancer therapy, and the primary analysis estimated the HR for OS regardless of subsequent anticancer therapy.

[0134] In patients with stage IV or stage IIIB / C non-squamous non-squamous non-cancerous cell carcinoma (NSCLC) requiring frontline treatment, who are PD-L1 negative and KRAS p.G12C positive, the change in patient-reported outcome (PRO) endpoints from baseline to week 12 between patients receiving sotrab in addition to platinum doublet chemotherapy and patients receiving pembrolizumab in addition to platinum doublet chemotherapy. Treatment efficacy is estimated using PRO measurements taken before or at the start of the new anticancer therapy.

[0135] Summary of eligibility criteria Subjects aged 18 or older (or the legal age of majority in their country, whichever is higher) who have provided informed consent before commencing any research-specific activity / procedure are eligible if they meet the following important inclusion criteria: - Histologically or cytologically confirmed diagnosis of non-squamous histological NSCLC (adenosquamous histology is permitted if non-squamous histological structure constitutes >50% of the tumor); the presence of small cell or large cell neuroendocrine components is an exclusion criterion. - Stage IV or advanced stage IIIB / C NSCLC (not a candidate for targeted multimodality therapy due to the severity of the disease) - No history of systemic anticancer therapy in metastatic / incurable cases. - You must provide a tumor tissue sample for central molecular analysis (or be willing to undergo a biopsy). - Test using the SP263 IHC assay and the tumor tissue must be negative for PD-L1 expression (TC < 1%). - Must be positive for the KRAS p.G12C mutation in circulating tumor DNA (ctDNA) and / or tumor tissue. - Must have a measurable disease as defined by the RECIST v1.1 criteria. - US East Coast Cancer Clinical Trials Group (ECOG) Performance Status is 0 or 1

[0136] The following are important exclusion criteria: - Mixed histology NSCLC with small cell or large cell neuroendocrine system components (any percentage) or dominant squamous epithelial cell tissue structure (over 50% of available tumors) - Tumors known to possess abnormalities in molecules other than KRAS p.G12C for which targeted therapy is approved locally (including, but not limited to, EGFR or ALK abnormalities). - Active brain metastases, defined as symptomatic (treated or untreated) brain metastases; subjects with asymptomatic untreated metastases or asymptomatic treated brain metastases are eligible if they meet all pre-specified criteria. - Active autoimmune disease - Evidence of active hepatitis B or C (hepatitis panel testing performed during screening) - Known uncontrolled human immunodeficiency virus (HIV) infection, defined by a detectable level of HIV in the blood and / or a CD4 level of less than 400; known controlled HIV is permitted.

[0137] The complete list of eligibility criteria is shown below: Complete inclusion criteria: Participants are eligible to take part in the study only if they meet all of the following criteria:

[0138] Participants were provided with informed consent before the commencement of any research-specific activity / procedure.

[0139] The target age is 18 years or older (or the legal age of majority in Japan, whichever is higher).

[0140] The subjects are those whose diagnosis of non-squamous NSCLC has been confirmed histologically or cytologically. - If the tumor has mixed histology including squamous epithelial components, the case is suitable for registration if the squamous epithelial components constitute only a small portion of the tumor in the sample (<50% of the tumor).

[0141] The target is AJCC Cancer Staging Manual 8. th The patient has stage IV (metastatic) or advanced stage IIIB or IIIC NSCLC (not a candidate for targeted multimodality therapy due to the severity of the disease), according to ed. 2017.

[0142] The target population is those with metastatic / incurable disease and no history of systemic anticancer therapy. Previous targeted (curative) therapies for early-stage NSCLC are permitted if: Regardless of whether or not anti-PD-1 / L1 therapy was administered, neoadjuvant / adjuvant systemic anticancer therapy (for radical surgery) was completed more than 6 months prior to the diagnosis of the current metastatic disease. - Regardless of whether or not anti-PD-1 / L1 therapy was administered, targeted concurrent chemotherapy with radiotherapy was completed more than six months prior to the diagnosis of the current metastatic disease.

[0143] The subjects provided blood samples for central analysis of KRAS p.G12C status.

[0144] The subjects provided a sufficient amount of tumor tissue sample for central analysis of the KRAS p.G12C status.

[0145] The subjects provided a sufficient amount of tumor tissue sample for central analysis of PD-L1 status.

[0146] Tumors are negative for PD-L1 expression (Clinical Laboratory Improvement Amendments [CLIA]-certified or equivalent according to local standards) as assessed by a central or local laboratory using an assay that meets research technical specifications (TC or TPS < 1%).

[0147] The subjects must be plasma circulating tumor DNA (ctDNA) or tumor tissue positive for the KRAS p.G12C mutation as tested by a central laboratory. In select cases, local laboratory results can be used for study registration and randomization, while central laboratory results are inconclusive.

[0148] Participants must have a measurable disease as defined by the RECIST v1.1 criteria.

[0149] The target group is those with an East Coast Cancer Clinical Trials Group (ECOG) performance status of 0 or 1.

[0150] The lifespan of the subjects, according to the researchers, is >3 months.

[0151] Participants must be able to take oral medication and be willing to record their daily adherence to the investigational drug.

[0152] The subjects are those for whom hematology laboratory evaluation is sufficient: - Neutrophil absolute number (ANC) ≥ 1.5 × 10⁻⁶ 9 / L. - Hemoglobin ≥ 9.0 g / dL or > 5.6 mmol / L (no blood transfusion in the previous week). - Platelet count ≥ 100 × 10 9 / L.

[0153] The subjects were those with sufficient renal laboratory evaluation and an estimated creatinine clearance (CrCl) of ≥45 mL / min (using the Cockcroft-Gault formula, see Cockcroft et al., 1976 and further below). - If the estimated CrCl is less than 45 mL / min, direct measurement of CrCl can be performed, and subjects may be enrolled in the study if their actual creatinine clearance (CrCl) is ≥ 45 mL / min.

[0154] The subjects are those for whom liver laboratory evaluation has been sufficiently performed, as follows: -AST and ALT < 2.5 × upper limit of normal [ULN] or ≤ 5 × ULN for subjects with liver lesions. -Total bilirubin ≤ 1.5 × ULN. - Patients with total bilirubin >1.5 × ULN and clinically confirmed Gilbert's syndrome are eligible if their direct bilirubin is within the normal range.

[0155] The target group is those whose coagulation laboratory evaluation is sufficient: - International normalized ratio (INR) ≤ 1.5 × ULN, or within the target range if receiving prophylactic anticoagulation therapy.

[0156] The subjects have adequate or adequately compensated thyroid function, as recorded below: - Thyroid-stimulating hormone (TSH) levels are within the normal range (if TSH levels are not within the normal range, eligibility is met if total triiodothyronine [T3] [or free T3] and free thyroxine [T4] levels are within the normal range).

[0157] Subjects with asymptomatic hypothyroidism or hyperthyroidism are eligible for study approval.

[0158] Complete exclusion criteria Participants will be excluded from the study if they meet any of the following criteria:

[0159] Related diseases - The target tumors are those with mixed histological NSCLC having small cell or large cell neuroendocrine cell components (any percentage) or a dominant squamous epithelial cell structure (more than 50% of available tumors). - The subjects are tumors known to have abnormalities in molecules other than KRAS p.G12C for which targeted therapy is approved locally (including, but not limited to, EGFR or ALK abnormalities). - Subjects have active brain metastases, defined as symptomatic (treated or untreated) brain metastases. Subjects with untreated brain metastases are permitted to study if they are asymptomatic without systemic steroids and if radiotherapy is not required according to the determination of a qualified radiation oncologist. Subjects with treated brain metastases are eligible if they have completed targeted therapy (stereotactic radiotherapy following surgery, or stereotactic radiotherapy or whole-brain radiotherapy) and meet all of the following criteria: - There was a washout period of at least 7 days between the completion of targeted therapy and day 1 of cycle 1. - The subject has returned to neurological baseline (apart from any remaining signs or indications related to CNS treatment). In addition, the subject must have discontinued corticosteroids or reduced their dose to ≤10 mg of daily prednisone (or equivalent) before day 1 of cycle 1. - Patients with symptomatic spinal cord compression caused by cancer metastasis. - Patients with carcinomatous meningitis (a disease of the leptomeninges).

[0160] Other medical symptoms The control group consists of individuals with a history of other malignancies within the past three years, with the exception of the following: - Malignant tumors that are being treated with the intention of curing, have not had any known active disease in the ≥2 years prior to registration, and that the treating physician considers to have a low risk of recurrence. - Well-treated non-melanoma skin cancer or lentigo malignant, cervical carcinoma in situ, or mammary ductal carcinoma in situ, without evidence of disease. - Prostatic carcinoma in situ without evidence of prostate cancer - Well-treated urothelial papillary non-invasive carcinoma or carcinoma in situ. - Other malignancies that have demonstrated stability over the past five years or more and do not require systemic treatment may be considered concurrently with approval by medical monitors.

[0161] Participants are either severely unhealthy or have serious surgical conditions that may require surgery within the first cycle of treatment (as assessed by the researcher).

[0162] Participants were those who had undergone major surgery (e.g., intrathoracic, abdominal, or vascular surgery requiring up to four weeks for healing, according to surgical assessment) within four weeks prior to the first dose of the study treatment, or whose surgical wounds had not healed.

[0163] The target group consists of individuals with severely active infections requiring antibiotic therapy.

[0164] The subjects are individuals with active autoimmune diseases who have required systemic treatment with immunosuppressants / immunomodulators (i.e., corticosteroids, tumor necrosis factor alpha inhibitors, or others) in the past two years. The following types of treatments are not considered forms of systemic immunosuppression and will not be excluded from the study: - Replacement therapy for adrenal insufficiency (e.g., corticosteroids at physiological doses). - Inhaled steroids.

[0165] The target population includes individuals with interstitial lung disease or a history of pneumonia requiring oral or IV glucocorticoids for management support.

[0166] The subjects have a history of solid organ transplantation.

[0167] The subjects have a history of allogeneic bone marrow transplantation.

[0168] The target group includes those with severe gastrointestinal disorders that result in significant malabsorption requiring intravenous nutrition or prevent the administration of oral medications.

[0169] Eligibility is limited to individuals with a significant cardiovascular condition, such as New York Heart Association heart disease (class III or higher), myocardial infarction within six months prior to randomization, unstable arrhythmia, or unstable angina.

[0170] The subjects are those with active hepatitis B or C defined by positive hepatitis B surface antigen (HepBsAg) (hepatitis panel testing was performed during screening); or those with evidence of positive hepatitis C antibody and detectable hepatitis C virus RNA: - Subjects whose HBV infection (defined as the presence of hepatitis B core antibodies [anti-HBc] and the absence of HBsAg) is in the past or has been resolved are eligible.

[0171] Subjects with known uncontrolled human immunodeficiency virus infection (HIV), defined by detectable levels of HIV in the blood and / or CD4 levels below 400. - Patients with known controlled HIV (undetectable by PCR) and who adhere to highly active antiretroviral therapy (HAART) are eligible. These patients must continue HAART throughout the entire research treatment, in accordance with local standards.

[0172] Previous treatments / concurrent therapies The subjects received >30 Gy of radiation therapy to the lungs within six months of the first dose of the study treatment.

[0173] The subjects completed palliative radiotherapy within 7 days of the first dose of the research treatment (for brain radiation).

[0174] The target is sotracib or other KRAS G12C The patient had previously been treated with an inhibitor.

[0175] The subjects were those who had received anti-cancer therapy (chemotherapy, antibody therapy (e.g., anti-VEGF antibody bevacizumab), molecular targeted therapy, hormone therapy, retinoid therapy, or drugs under investigation) within the past two years, except for the following: - The subjects are those who have received or are continuing to receive anti-cancer hormone therapy in an adjuvant setting for more than two years after complete removal of early-stage breast cancer without known active disease, or - Patients with previous neoadjuvant / adjuvant therapy for NSCLC.

[0176] The subjects were those who used known cytochrome P450 (CYP) 3A4-sensitive substrates or P-glycoprotein (P-gp) substrates (both with narrow therapeutic windows) within 14 days prior to day 1 of cycle 1. Exemplary CYP3A substrates with narrow therapeutic indices include, but are not limited to, alfentanil, fentanil, cyclosporine, pimozide, dihydroergotamine, quinidine, ergotamine, cyclosporine, everolimus, and tacrolimus. Exemplary P-gp substrates with narrow therapeutic indices include, but are not limited to, cyclosporine, sirolimus, digoxin, tacrolimus, everolimus, and vincristine.

[0177] The subjects received potent CYP3A4 inducers (including herbaceous adjuvants such as St. John's wort) within 14 days prior to day 1 of cycle 1. Examples of potent CYP3A inducers include, but are not limited to, rifampin, mitotane, abasimib, rifapentin, apalutamide, ivosidenib, phenytoin, carbamazepine, enzalutamide, St. John's wort extract, and lumaphthol.

[0178] The subjects were those who had used a proton-pump inhibitor (PPI) or histamine 2 receptor antagonist (H2RA) within 7 days prior to day 1 of cycle 1.

[0179] Participants must have received live attenuated virus vaccination within four weeks of the first dose of the study treatment; vaccines not containing live virus are acceptable.

[0180] Previous / contemporary clinical research experience Participants must currently be receiving treatment in another ongoing device or drug study, or have completed treatment in another ongoing device or drug study less than four weeks prior. Procedures in other studies conducted while participating in this study will be excluded.

[0181] Other exclusions The subjects are known to be susceptible to any of the products or components that will be administered during the course of treatment.

[0182] Subjects who, to the best of the knowledge of the subjects and researchers, are unlikely to be able to attend or complete all protocol-required study visits or procedures, and / or to be unlikely to be able to comply with all required study procedures (e.g., clinical outcome assessments [COAs]).

[0183] Subjects who, in the opinion of the investigator, or the medical monitor if requested, have a history or evidence of any other clinically significant impairment, condition, or disease (excluding those outlined above) that would pose a risk to the safety of the subject or interfere with the evaluation, procedure, or completion of the study.

[0184] This program is for women who are capable of becoming pregnant and whose pregnancy test is positive, as assessed by a highly sensitive urine or serum pregnancy test, at the time of screening and / or on day 1 of cycle 1.

[0185] This applies to women of childbearing potential who do not intend to use the protocol-designated method of contraception during treatment with sotrasib, carboplatin, pemetrexed, and pembrolizumab, and who also include the following: - 7 days after the last dose of sotrasib; -Four months after the last dose of pembrolizumab; and - Six months after the last dose of carboplatin and pemetrexed.

[0186] This study included women who were being studied while undergoing treatment with sotracib, carboplatin, pemetrexed, and pembrolizumab, and who were planning to become pregnant or donate eggs, and who also met the following criteria: - 7 days after the last dose of sotrasib; -Four months after the last dose of pembrolizumab; and - Six months after the last dose of carboplatin and pemetrexed.

[0187] The study included women who were breastfeeding or planning to breastfeed, and was conducted over 7 days after the last dose of sotrasib, carboplatin, and pemetrexed, and over 4 months after the last dose of pembrolizumab.

[0188] This study is for men who are being treated with sotrasib, carboplatin, pemetrexed, and pembrolizumab, have a fertile female partner who practices sexual abstinence (refraining from heterosexual intercourse) or does not intend to use contraception, and who also meet the following criteria: - 7 days after the last dose of sotrasib and pembrolizumab; -Three months after the last dose of pemetrexed; and - Six months after the last dose of carboplatin.

[0189] This applies to men who, during treatment with sotracib, carboplatin, pemetrexed, and pembrolizumab, have a pregnant partner, do not intend to practice abstinence or use condoms, and also have the following conditions: - 7 days after the last dose of sotrasib and pembrolizumab; -Three months after the last dose of pemetrexed; and - Six months after the last dose of carboplatin.

[0190] This applies to men who are unwilling to refrain from sperm donation during treatment with sotracib, carboplatin, pemetrexed, and pembrolizumab, and who also meet the following criteria: - 7 days after the last dose of sotrasib and pembrolizumab; -Three months after the last dose of pemetrexed; and - Six months after the last dose of carboplatin.

[0191] Research interference The details of each treatment administration are described below. The investigational drugs used during this study are sotrasib and pembrolizumab.

[0192] [Table 16]

[0193] [Table 17]

[0194] The non-investigational drugs (basic therapies) used during this study were carboplatin and pemetrexed, as described below.

[0195] [Table 18]

[0196] [Table 19]

[0197] Other protocol-required treatments Other protocol-required therapies may include antiemetic treatment prior to carboplatin administration to prevent nausea / vomiting (NCCN Guidelines, 2022; Multinational Association of Supportive Care in Cancer [MASCC] / ESMO Guidelines, Roila et al., 2016), and folic acid, vitamin B12, and steroids (dexamethasone or equivalent) along with pemetrexed administration (see above, referring to the pemetrexed approval local label).

[0198] Therapeutic phase and its definition The treatment phase begins on day 1 of cycle 1. Day 1 of cycle 1 is defined as the first day on which the subject receives all treatments required by the study. Day 1 of subsequent cycles is the day following the last day of the previous cycle. The expected cycle length is approximately 21 days. The minimum cycle duration is 18 days.

[0199] The research drug formulation, frequency of administration, route of administration, responsibility, premedication regimen (if any), dosage preparation, and dosage instructions are explained above.

[0200] Dosage adjustment Reduction of up to two doses related to toxicity is allowed for sotrasib, carboplatin, or pemetrexed. Subjects who require a third dose reduction of sotrasib, carboplatin, or pemetrexed have the agent interrupted. Pembrolizumab dose reduction is not tolerated. Toxicity needs to grade ≤1 or resolve to baseline before resuming in subsequent cycles. The rationale for dose modification and the relationship of toxicity to the study agent must be documented in the source document. Once the dose is reduced, it cannot be re-escalated.

[0201] If the study agent is not linked to toxicity, the investigator may continue the agent at the current dose (assuming that the safety parameters for this drug meet the protocol-specified limits (e.g., the subject may continue sotrasib or pembrolizumab alone while interrupting chemotherapy; similarly, the subject may interrupt sotrasib or pembrolizumab and continue chemotherapy alone) or hold the study agent until the safety parameters for this drug recover to an acceptable limit (at which time the non-causative agent may be resumed at the current dose)).

[0202] Chemotherapy and / or sotrasib may be interrupted for up to 9 weeks; pembrolizumab may be interrupted for up to 12 weeks (per case). If the interruption exceeds the specified period, the drug must be permanently interrupted.

[0203]

Table 20

[0204] Dose reduction of sotrasib is not permitted. Sotrasib should be discontinued if, in the investigator's opinion, toxicity occurs that is attributable to sotrasib and meets the severity criteria for justifying interference. Table 5 below lists the guidelines for withholding and permanently discontinuing sotrasib. The reasons for withholding and permanently discontinuing sotrasib should be recorded in each patient's case report form (CRF).

[0205] [Table 21]

[0206] [Table 22]

[0207] Carboplatin and pemetrexed Complete blood counts (including platelet counts) should be performed on all subjects receiving carboplatin with pemetrexed, or either of these compounds alone.

[0208] Dose adjustments at the start of subsequent cycles should be based on the lowest hematological count (nadir hematologic count) or maximum non-hematological toxicity derived from the previous treatment cycle.

[0209] Delay the start of the next cycle of chemotherapy until the following conditions are met: - Non-hematological toxicity recovers to grade 0-2. -ANC is ≥ 1.5 × 10 9 / L, and - Platelet count ≥ 100 × 10 9 It becomes / L.

[0210] Table 6 below outlines the recommended dose modifications due to significant chemotherapy toxicity.

[0211] [Table 23]

[0212]

Table 24

[0213] Recurrent grade 3 or 4 hematologic or non-hematologic toxicities after two dose reductions should lead to discontinuation of the chemotherapy agent in question.

[0214] Evaluate CrCl before each cycle using the original weight-based Cockcroft and Gault formula. If CrCl is less than 45 mL / min, chemotherapy (carboplatin and / or pemetrexed) should not be administered. Pemetrexed and / or platinum may be delayed to allow the subject to recover from toxicity (duration of treatment interruption specified above).

[0215] Pemetrexed should be permanently discontinued if it causes interstitial pneumonia or severe or life-threatening skin toxicity. See pemetrexed information determined by the region (e.g., pemetrexed USPI, SmPC; for the United States, e.g., ALIMTA® U.S. Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revised August 2022) (which is incorporated herein by reference in its entirety)).

[0216] Pembrolizumab Dose reduction of pembrolizumab is not tolerated.

[0217] If necessary, pembrolizumab may be temporarily withheld. In general, pembrolizumab should be withheld for severe (grade 3) immune-mediated adverse reactions. Pembrolizumab should be permanently discontinued for fatal (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions requiring systemic immunosuppressive therapy, or because the corticosteroid dose cannot be reduced to prednisone ≤10 mg / day (or equivalent) within 12 weeks of initiating steroids. For guidelines on the specific management of immune-mediated adverse reactions and infusion-related reactions, refer to localized information from KEYTRUDA® (e.g., KEYTRUDA® USPI, SmPC; for the United States, see KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ 07033 (revised March 2023)).

[0218] Hepatotoxicity Termination and Rechallenge Rules This section details the rules regarding drug-induced liver injury. All research agents in this protocol (sotrasib, carboplatin, pemetrexed, and pembrolizumab) are known to cause elevated liver enzymes. Investigators should carefully identify the causative agent to ensure appropriate intervention. Guidelines for the management of patients with elevated AST, ALT, or alkaline phosphatase (ALP) associated with sotrasib, carboplatin, and / or pemetrexed, or pembrolizumab are provided previously.

[0219] Subjects with abnormal liver laboratory values ​​(i.e., alkaline phosphatase [ALP], aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]), and / or international normalized ratios (INR), and / or signs / symptoms of hepatitis (described below) may meet the criteria for withholding or permanently discontinuing the investigational drug or other protocol-required treatment, as defined in the Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 (US FDA, 2009).

[0220] Criteria for withholding and / or permanently discontinuing investigational drugs and other protocol-required treatments due to potential hepatotoxicity: The following suspension and / or suspension rules apply to subjects for whom another cause of changes in liver biomarkers (TBL, INR, and transaminase) has not been identified as a significant other cause of elevated AST / ALT and / or TBL levels: -Hepatobiliary duct disease - Viral hepatitis (e.g., hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus) - Any cause of hypoxia to the liver that leads to right-sided heart failure, hypotension, or ischemia - Exposure to hepatotoxic agents / drugs or hepatotoxins (including herbs and dietary supplements, plants, and fungi) - Hereditary disorders that cause impaired glucuronidation (e.g., Gilbert's 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 hemoglobin - Non-alcoholic fatty liver disease (NAFLD) includes fatty liver disease (steatohepatitis). - Non-hepatic causes (e.g., rhabdomyolysis, hemolysis)

[0221] If the investigational drug is withdrawn, the subjects will continue to be monitored for possible drug-induced liver injury (DILI) in accordance with the recommendations in the last section of this appendix.

[0222] If liver function tests reveal abnormalities (ALT, AST, ALP) and / or other causes for elevated TBL, and the laboratory abnormalities recover to normal or baseline levels, a rechallenge may be considered.

[0223] [Table 25]

[0224] Criteria for rechallenging investigational drugs and other protocol-required treatments after potential hepatotoxicity: The decision to rechallenge a subject is to be discussed and agreed upon unanimously by the subject, investigator, and medical monitor. If signs or symptoms recur after rechallenge, the investigational drug and other protocol-required treatments will be permanently discontinued, if necessary. Subjects who clearly meet the criteria for permanent discontinuation (listed in Table 8) should never be rechallenged.

[0225] Criteria for evaluating the effectiveness of treatment for solid tumors, version 1.1 (RECIST v1.1) (Eisenhauer et al., 2009; Schwartz et al., 2016; Therasse et al., 2000). Definition: Measurable diseases The presence of at least one measurable lesion. If the measurable disease is limited to a solitary lesion, its neoplastic nature should be confirmed by cytology / histology.

[0226] Measurable lesions Measurable non-mallotic tumor lesions A well-defined, non-narrow lesion with a maximum diameter of ≥10 mm in computed tomography (CT) / magnetic resonance imaging (MRI) scans with a slice thickness of 5 mm or less, which can be accurately measured in at least one direction. If the slice thickness is greater than 5 mm, the minimum size of the measurable lesion should be twice the slice thickness.

[0227] Nodular lesions Lymph nodes, when evaluated by CT / MRI (scan slice thickness of 5 mm or less is recommended), must have a short axis of ≥15 mm. Only the short axis should be measured and tracked at baseline and during follow-up (Schwartz et al., 2009).

[0228] Cystic lesions Cystic lesions that appear to represent cystic metastases can be considered measurable lesions if they meet the above definition of measurability for non-narrow lesions.

[0229] Bone lesions in which soft tissue components can be considered identical Bone lesions in which soft tissue components can be identified and evaluated by cross-sectional imaging techniques such as CT or MRI can be considered measurable lesions if the soft tissue components satisfy the above definition of measurability for non-nodular lesions.

[0230] Clinically measurable lesions Visible or palpable lesions can be considered measurable if the longest diameter for non-narrow lesions is ≥10 mm, or if the shortest diameter for lymph nodes is ≥15 mm. Lesions should be measured radiologically if more accurate, otherwise by caliper.

[0231] Irradiated lesions Tumor lesions located within previously irradiated areas or areas subjected to other local therapies are not measurable unless measurable progression of the lesion has been demonstrated prior to registration.

[0232] Unmeasurable lesions All other lesions, including small lesions (pathological lymph nodes with a CT scan slice thickness of 5 mm or less and a longest diameter of <10 mm or a short axis of ≥10 mm to <15 mm), are considered unmeasurable (if the slice thickness is greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness).

[0233] Other examples of lesions that are typically considered unmeasurable include: Lesions previously treated locally: Tumor lesions located within areas previously irradiated or subjected to other local therapies should not be considered measurable unless progression within the lesion has been demonstrated.

[0234] Categorically, clusters of small lesions, bone lesions without soft tissue components, inflammatory breast disease, ascites, pleural / pericardial effusion, lymphangitis / dermatopneumonia, and leptomeningeal diseases are unmeasurable.

[0235] Measurement method All measurements should be obtained using a ruler or calypso and recorded in metric units. Each identified and reported lesion should be characterized using the same evaluation methods and techniques at baseline and throughout the trial. If a lesion being followed cannot be imaged but is not evaluable by the clinical trial, an imaging-based evaluation is preferred over clinical trial evaluation. Clinical lesions should be evaluated using a calypso (e.g., skin nodules). For skin lesions, color imaging recording, including a ruler to estimate lesion size, is recommended.

[0236] CT / MRI All lesions should be evaluated using contrast-enhanced CT or MRI. Optimal visualization and measurement of metastases in solid tumors require consistent intravenous (IV) contrast administration (dosage and rate) and scanning timing. CT and MRI should be performed on adjacent slices ≤5 mm thick. The longest diameter of the selected lesion should be measured on the plane from which the image was acquired. Ideally, the same scanner or at least the same type of scanner should be used, and the image acquisition protocol should follow the previous scan as closely as possible.

[0237] PET-CT Currently, the low-dose or attenuation-corrected CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use in RECIST measurements. However, if the site can record that the CT performed as part of the PET-CT is of the same diagnostic quality as the diagnostic CT (with IV and oral contrast agents), the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT for accurate measurement of cancerous lesions over time. However, it should be noted that the PET portion of the CT introduces additional data that may bias the investigator if not performed routinely or sequentially.

[0238] Ultrasound Ultrasound is not useful for evaluating lesion size and should not be used as a measurement method. Ultrasound examinations cannot be reproduced as a whole for subsequent independent reviews and are operator-dependent; therefore, it is not possible to guarantee that the same technique and measurements will be used from one evaluation to the next. If new lesions are identified by ultrasound during a study, confirmation by CT or MRI may be recommended. If there are concerns about radiation exposure during CT, MRI may be used instead of CT in selected cases.

[0239] Endoscopy, laparoscopy The use of these techniques for objective tumor evaluation is not recommended. However, such techniques may be useful in confirming complete pathological response when a biopsy is available, or in determining recurrence in clinical trials where complete response (CR) or recurrence after surgical resection is the endpoint.

[0240] Tumor markers Tumor markers alone cannot be used to evaluate response. If a marker initially exceeds the upper limit of normal, the marker must be normalized in the subject by radiological complete response (CR) to determine if the subject has achieved CR.

[0241] Cytology, histology These techniques can be used to distinguish between partial response (PR) and complete response (CR) in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where known benign residual tumors may remain) if required by the protocol.

[0242] If exudate is known to be a potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenic inhibitors), then if a measurable tumor has met the criteria for response or stability to distinguish between response (or stability) and progressive disease, then cytological establishment of any neoplastic exudative origin that appears or worsens during treatment may be considered.

[0243] FDG-PET While evaluating the effectiveness of fluorodeoxyglucose-positron emission tomography (FDG-PET) requires further research, incorporating the use of FDG-PET scans to complement CT scans in evaluating disease progression (particularly potential "new" diseases) is occasionally justifiable. New lesions based on FDG-PET imaging can be identified according to the following algorithm:

[0244] A positive FDG-PET at follow-up, compared to a negative FDG-PET at baseline, is an indication of progressive disease based on new lesions.

[0245] If there is no FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is progressive disease. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, an additional follow-up CT scan is necessary to determine if there is indeed progression occurring at that site (if so, the date of progressive disease is the date of the first abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to an existing site of disease on CT that has not progressed based on anatomical imaging, this is not progressive disease.

[0246] If residual radiographic abnormalities are thought to represent fibrosis or scarring, FDG-PET may be used to upgrade the response to complete remission in a manner similar to biopsy.

[0247] Note: A “positive” FDG-PET scan lesion means a lesion where FDG is craving more than twice the attenuation of the surrounding tissue on the attenuated image.

[0248] Lesion evaluation Baseline recording of "targeted" and "non-targeted" lesions. Target lesion All measurable lesions (a maximum of two lesions per organ, and a total of five lesions) that represent all affected organs should be identified, recorded, and measured as target lesions at baseline.

[0249] Target lesions should be selected based on their size (the lesion with the longest diameter) and suitability for accurate, repeated measurements. All other measurable lesions should be tracked as non-target lesions.

[0250] Since lymph nodes are considered as a single organ, up to two measurable lymph nodes can be identified as target lesions.

[0251] For all target lesions, the sum of the diameters (longest diameter for non-narrow lesions, short axis for nodular lesions) is calculated and reported as the baseline sum of diameters. This baseline sum of diameters is used as a criterion to characterize objective tumor response.

[0252] Non-target lesions All other lesions (or sites of disease) that include pathological lymph nodes should be identified as non-target lesions and documented at baseline. These lesions should be tracked throughout the study as “present,” “absent,” “clearly progressing,” or “unassessable” (NE). In addition, multiple non-target lesions affecting the same organ can be documented as a single item on the case report form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).

[0253] [Table 26]

[0254] [Table 27]

[0255] Best overall response rating The best response allocation for a patient depends on findings in both the target and non-target diseases, and also takes into account the appearance of new lesions. The BOR is based on all post-baseline disease assessments that appear before the initiation of subsequent anticancer treatment. To allocate a BOR for SD, patients must meet the minimum criteria for SD duration by having no radiological disease progression for at least 5 weeks from day 1 of cycle 1. In general, patients who cannot be classified under the RECIST v1.1 response categories due to insufficient data or early death are classified as NE for BOR, but are counted in the denominator of all response rate calculations.

[0256] [Table 28]

[0257] [Table 29]

[0258] Special notes on efficacy evaluation Target lesions deemed "too small to measure"—during the study, all lesions (nodular and non-narrow) recorded at baseline should have their measurements recorded at each subsequent evaluation, even if they are very small (e.g., 2 mm). However, occasionally, lesions or lymph nodes recorded as target lesions at baseline may become unclear on CT scans, making it difficult for radiologists to assign an accurate measure, and they may report them as "too small to measure." In this case, it is important that the value is recorded in the case report form. If the radiologist believes that a non-lymph node lesion has likely disappeared, the measurement should be recorded as 0 mm. If a lesion is thought to be present and faintly visible but too small to measure, a default value of 5 mm should be assigned. (Note: This rule is unlikely to be applied to lymph nodes because, in normal cases, the size of lymph nodes is usually definable and is frequently surrounded by fat, for example, in the retroperitoneal space; however, if a lymph node is thought to be present and is faintly visible but too small to measure, a default value of 5 mm should be assigned in this situation as well.) This default value is derived from a 5 mm CT slice thickness (and should not be changed with various CT slice thicknesses). Since measurements of these lesions are potentially irreproducible, providing this default value prevents false responses or progression based on measurement errors. However, again, even if it is less than 5 mm, radiologists can achieve accurate measurements that should be recorded.

[0259] New lesions – The term "new lesions" always refers to the presence of new findings that are clearly tumorous. If new lesions are identified via modalities other than CT or MRI, CT or MRI confirmation is recommended unless the new lesion is clearly considered tumorous. New findings that are not clearly tumorous but may be benign (e.g., infection, inflammation) should not be selected as new lesions until review confirms that they represent tumors.

[0260] If a new lesion is uncertain (for example, due to its small size), continued therapy and follow-up evaluations will determine whether it actually represents a new disease. If additional imaging clearly confirms the presence of a new lesion, progression should be declared using the date of the initial scan.

[0261] Lesions identified in follow-up studies at anatomical locations not scanned at baseline are considered new lesions and represent disease progression, regardless of whether the response is present in the target lesion or non-target lesion that was present at baseline.

[0262] Any topical treatment not permitted according to the protocol Any subject receiving topical therapy not permitted in the protocol but being studied, which directly affects one or more of the target lesions selected at baseline, is considered unassessable at all disease assessments occurring on or after the day of topical therapy, except for disease progression. However, if the pathologically benign lesion was completely excised, the subject was still evaluable for response and reported a dimension of 0.

[0263] If local therapy is performed on a non-target lesion, that lesion should always be considered present unless its pathology is benign.

[0264] Lesions that split or merge during treatment—when a non-narrow lesion "fragmentes," the longest diameters of the fragmented parts should be summed to identify them as fragments of the original lesion in order to calculate the total of the target lesion. Similarly, as lesions merge, a plane between the lesions may be maintained, which helps in obtaining the maximum diameter measurement for each individual lesion. If the lesions had truly merged to the point where they could no longer be separated, then in this example the longest diameter vector should be the maximum longest diameter for the "merged lesion."

[0265] "Symptomatic exacerbation" alone is not sufficient to qualify as objective progression. If objective progression has not been previously recorded, every effort should be made to record objective progression, even after treatment has been discontinued.

[0266] Under certain circumstances, it may be difficult to distinguish residual disease from scar or normal tissue. If the assessment of complete response (CR) depends on this determination, it is recommended to further investigate the residual lesion by fine-needle aspiration / biopsy or FDG-PET to confirm the status of CR.

[0267] If a lesion disappears and then recurs at a later point in time, it should continue to be measured. However, the subject's response at the time of lesion recurrence depends on the status of their other lesions. For example, if the subject's tumor reaches CR status and then the lesion recurs, the subject is considered PD at the time of recurrence. Conversely, if the tumor status is PR or SD, and one lesion that had disappeared recurs, its largest diameter should be added to the sum of the remaining lesions for the calculated response: in other words, the recurrence of a single lesion that was clearly "disappeared" among many remaining lesions is not sufficient on its own to qualify for PD: this requires the sum of all lesions to meet the PD criteria.

[0268] Confirmation measurement / Duration of response Confirmation of CR and PR is required, and confirmation must also be present 4 weeks after the first record of CR or PR. If confirmation of CR is inconclusive, and one or more NE and / or PR evaluations are specified at a subsequent evaluation, such as when the target lesion response is CR and the non-target lesion response is NE, then CR may be subsequently confirmed to return to CR. Similarly, if confirmation of PR is inconclusive, and one or more NE and / or SD evaluations are specified at a subsequent evaluation, then PR may be subsequently confirmed. Subsequent target lesion responses after CR are limited to CR, PD, or NE; PD for target lymph nodes is met only if any lymph node target lesion reaches a short-axis measurement of ≥15 mm.

[0269] Criteria for evaluating response in neuro-oncological brain metastases (RANO-BM) This study includes an exploratory analysis of intracranial PFS according to the BICR-based response evaluation criteria for neuro-oncological brain metastases (RANO-BM) (Lin et al., 2015). RANO-BM is an extension of the RECIST 1.1 criteria for evaluating the effectiveness of treatment for solid tumors (Eisenhauer et al., 2009) and the RANO criteria for evaluating response in neuro-oncology (Wen et al., 2010) (a response evaluation criterion for high-grade gliomas).

[0270] definition Measurable central nervous system (CNS) diseases are defined as contrast-enhanced CNS lesions that can be accurately measured in at least one direction, have a minimum size of 10 mm, and are visible in two or more axial slices with a skip of 0 mm and an interval of 5 mm or less (ideally with a skip of 0 mm and an interval of ≤1.5 mm). - For a CNS lesion to be considered measurable, the diameter perpendicular to the longest diameter of the measurement surface should be at least 5 mm. - If multiple measurable CNS lesions are present at baseline, all CNS lesions (up to 5) should be recorded and measured at baseline. If CNS lesions with a maximum diameter of ≥5mm but <10mm are considered measurable, then CNS lesions should be measured by magnetic resonance imaging (MRI) with a slice thickness of 1.5mm or less. Any CNS lesion with a maximum diameter of <10mm should be considered unchanged from baseline unless the measured maximum diameter has changed by at least 3mm.

[0271] Unmeasurable CNS lesions include all other CNS lesions, such as lesions with a maximum length of <10 mm, lesions with boundaries that cannot be reliably measured, dural metastases, skull metastases, and lesions consisting solely of cysts.

[0272] Measurement method Lesion measurement: The longest diameter of the selected lesion should be measured at the location where the image was acquired. Evaluation Method: Each identified and reported lesion should be characterized using the same evaluation methods and techniques at baseline and throughout the trial. MRI: All CNS lesions should be evaluated using gadolinium-enhanced MRI. If MRI is contraindicated or inaccessible, computed tomography (CT) can be performed with or without contrast.

[0273] Evaluation of response to CNS target lesions

[0274] [Table 30]

[0275] In the case of fused lesions, a plane may be maintained between them, which helps in obtaining the maximum longest diameter of each individual lesion. If the lesions are fused and no longer separable, the vector of the longest diameter in this case should be the maximum longest diameter for the fused lesion.

[0276] New CNS lesions that were not present in previous scans must be clear and not attributable to technical variability or slice variability.

[0277] Non-target lesions should be evaluated at least qualitatively through various radiographic assessments.

[0278] Evaluation of response to non-target lesions

[0279] [Table 31]

[0280] CNS sections and non-CNS sections are evaluated separately as follows:

[0281] [Table 32]

[0282] For the evaluation of overall progression-free survival, progression in either or both compartments will satisfy the criteria for progression-free survival. Subjects who develop CNS progression in isolation may be eligible to continue the study after local therapy (e.g., whole-brain radiotherapy, stereotactic radiosurgery, or surgery).

[0283] [Table 33]

[0284] Calculate creatinine clearance For this protocol, creatinine clearance is calculated as follows: The original weight-based Cockcroft and Gault formulas (see Cockcroft et al., 1976) About men

number

number

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Claims

1. A method for treating cancer involving a KRAS G12C mutation in a subject requiring treatment, comprising: (a) a first regimen comprising (i) a therapeutically effective dose of sotrasib, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, and then (b) a second regimen comprising (i) the therapeutically effective dose of sotrasib and (ii) the therapeutically effective dose of pemetrexed.

2. The method according to claim 1, wherein the first regimen is administered over a period of four cycles.

3. The method according to claim 2, wherein each cycle is a period of 21 days.

4. The method according to any one of claims 1 to 3, wherein the therapeutically effective dose of sotrasib is 240 mg.

5. The method according to any one of claims 1 to 3, wherein the therapeutically effective dose of sotrasib is 960 mg.

6. The method according to any one of claims 1 to 5, wherein sotrasib is administered orally.

7. The method according to any one of claims 1 to 6, wherein the sotrasib is administered once daily.

8. The method according to any one of claims 1 to 7, wherein the sotracib is administered in a solid dosage form.

9. The method according to claim 8, wherein the solid dosage form is a tablet.

10. The method according to claim 9, wherein the sotrasib is administered as one tablet containing 240 mg of sotrasib, two tablets each containing 120 mg of sotrasib, three tablets each containing 320 mg of sotrasib, four tablets each containing 240 mg of sotrasib, or eight tablets each containing 120 mg of sotrasib.

11. The method according to any one of claims 1 to 10, wherein the therapeutically effective dose of carboplatin corresponds to a value obtained by multiplying 5 mg / (mL × min) (AUC 5) by the value obtained by adding 25 mL / min to the target glomerular filtration rate (GFR) mL / min.

12. The method according to claim 11, wherein the therapeutically effective dose of carboplatin is 750 mg or less.

13. The method according to any one of claims 1 to 12, wherein the carboplatin is administered intravenously.

14. The method according to any one of claims 2 to 13, wherein the carboplatin is administered on day 1 of each cycle.

15. The method according to any one of claims 1 to 14, wherein the subject is not administered carboplatin during the second regimen.

16. The effective therapeutic dose of pemetrexed is 500 mg / m². ２ The method according to any one of claims 1 to 15.

17. The method according to any one of claims 1 to 16, wherein pemetrexed is administered intravenously.

18. The method according to any one of claims 1 to 17, wherein the administration of pemetrexed is initiated on day 1 of the first regimen.

19. The method according to any one of claims 1 to 18, wherein the pemetrexed is administered at intervals of 21 days in the first regimen and the second regimen.

20. The method according to any one of claims 1 to 19, further comprising administering a therapeutically effective amount of folic acid to the subject.

21. The method according to claim 20, wherein the therapeutically effective dose of folic acid is 350 μg to 1000 μg once daily.

22. The method according to claim 20, wherein the therapeutically effective dose of folic acid is 400 μg once daily.

23. The method according to claim 20, wherein the therapeutically effective dose of folic acid is 400 μg to 1000 μg once daily.

24. The method according to claim 20 or 23, wherein the administration of folic acid is started 7 days before the administration of pemetrexed and ends 21 days after the discontinuation of pemetrexed.

25. The method according to any one of claims 1 to 24, further comprising administering a therapeutically effective amount of vitamin B12 to the subject.

26. The method according to claim 25, wherein the therapeutically effective dose of vitamin B12 is 1 mg.

27. The method according to claim 25 or 26, wherein the vitamin B12 is administered once within the week prior to the first administration of pemetrexed, and thereafter every 9 weeks (±2 weeks) until the discontinuation of pemetrexed administration.

28. The method according to claim 25 or 26, wherein the vitamin B12 is administered once one week before the first administration of pemetrexed, and then once every nine weeks thereafter until the discontinuation of pemetrexed administration.

29. The method according to any one of claims 25 to 28, wherein the vitamin B12 is administered intramuscularly.

30. The method according to any one of claims 1 to 29, further comprising administering a therapeutically effective amount of dexamethasone to the subject.

31. The method according to claim 30, wherein the therapeutically effective dose of dexamethasone is 4 mg twice daily.

32. The method according to claim 30 or 31, wherein the dexamethasone is administered to the subject on the day before each pemetrexed administration, on the day of the administration, and on the day after the administration.

33. The method according to any one of claims 1 to 32, wherein the subject is an adult.

34. The method according to any one of claims 1 to 33, wherein the subject has not received prior systemic anticancer therapy for the cancer prior to treatment (first-line treatment).

35. The method according to any one of claims 1 to 34, wherein the subject is a creatinine clearance (CrCl) of 45 mL / min or more, calculated by the Cockcroft-Gault formula.

36. The method according to any one of claims 1 to 35, wherein the subject is an ECOG performance status of 0 or 1.

37. The method according to any one of claims 1 to 36, wherein the cancer exhibits a TC score of less than 1%.

38. The method according to claim 37, wherein the therapeutically effective dose of sotrasib is 960 mg.

39. The method according to claim 37, wherein the TC score is determined using the Ventana PD-L1 (SP263) IHC assay.

40. The method according to any one of claims 1 to 36, wherein the cancer exhibits a PD-L1 tumor percentage score (TPS) of less than 1%.

41. The method according to claim 40, wherein the therapeutically effective dose of sotrasib is 960 mg.

42. The method according to claim 40, wherein the TPS is determined using the PD-L1 IHC 22C3 pharmDx assay.

43. The method according to any one of claims 1 to 42, wherein the cancer does not include an abnormality in EGFR or ALK.

44. The method according to any one of claims 1 to 43, wherein the cancer is lung cancer.

45. The method according to any one of claims 1 to 43, wherein the cancer is non-small cell lung cancer.

46. The method according to any one of claims 1 to 43, wherein the cancer is non-squamous non-small cell lung cancer.

47. The method according to claim 46, wherein the non-squamous non-small cell lung cancer is stage IV or advanced stage IIIIB / C.

48. The method according to any one of claims 1 to 47, wherein the patient is not administered antibodies concomitantly.

49. The method according to claim 48, wherein the antibody is an anti-VEGF antibody.

50. The method according to claim 49, wherein the anti-VEGF antibody is bevacizumab.

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