Dosage regimen for sotoprasib / carboplatin / pemetrexed in treatment of cancer

Abstract

Provided herein are methods of treating a cancer comprising a KRAS G12C mutation in a subject in need thereof, the methods comprising administering to the subject an amount of sotoprasib, carboplatin, and pemetrexed effective to treat the cancer.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 459,349, filed April 18, 2023, and U.S. Provisional Patent Application No. 63 / 520,050, filed August 16, 2023, the entire contents of which are hereby incorporated by reference. Background Technology

[0002] Rat sarcoma (RAS) proto-oncogenes have been identified as oncogenic drivers 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) enzymes responsible for regulating cell proliferation and survival. RAS proteins, Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus oncogene homolog (HRAS), and neuroblastoma RAS virus oncogene homolog (NRAS) can be activated by mutations at codons 12, 13, or 61, leading to human cancers. Different tumor types are associated with mutations in certain RAS isotypes, with KRAS being the most common mutant isotype in most cancers. Although the role of KRAS mutations in human cancers has been known for decades, until recently, no anticancer therapies specifically targeting KRAS mutations have been successfully developed, primarily because the protein was considered difficult to inhibit with small molecules.

[0003] As described in further detail in this disclosure, sotorasib is an irreversible inhibitor of KRAS. G12C Small molecules of protein. In 2021, LUMAKRAS was approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain KRAS G12C-mutant lung cancers, making it the world's first compound in its class to be approved by a regulatory agency. While sotorasibi monotherapy appears to drive substantial antitumor activity, combination therapies are expected to improve treatment options for patients. Summary of the Invention

[0004] This article describes methods for treating cancers containing KRAS G12C mutations in subjects in need, comprising administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasirb, (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 sotorasirb and (ii) a therapeutically effective amount of pemetrexed. In various embodiments, the therapeutically effective amount of sotorasirb is 240 mg. In various embodiments, the therapeutically effective amount of sotorasirb is 960 mg. In some different embodiments, the subject has not received prior systemic anticancer therapy (first-line treatment) for the cancer prior to treatment. In various embodiments, the cancer exhibits a tumor cell (TC) score of less than 1% or a tumor proportion score (TPS) of less than 1%. Detailed Implementation

[0005] This article provides methods for treating cancer containing a KRAS G12C mutation in a subject of need, comprising administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasirb, (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 sotorasirb and (ii) a therapeutically effective amount of pemetrexed. In various embodiments, the therapeutically effective amount of sotorasirb is 240 mg. In various embodiments, the therapeutically effective amount of sotorasirb is 960 mg.

[0006] In various embodiments, the application of the first solution lasts for 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 application of the first solution lasts for 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] This article provides information on treatment methods involving the administration of two or more therapeutic agents (e.g., sotorasidub, carboplatin, and pemetrexed). Unless otherwise described herein, combination therapy of two or more therapeutic agents discussed herein includes both concomitant and sequential administration.

[0008] definition

[0009] As used herein, the term “adult” means a subject who is 18 years of age or older or who is of legal adult age in the country in which the subject resides, whichever is older, when treated with one or more of the methods or procedures disclosed herein.

[0010] As used in this article, the term "pharmaceutically acceptable" means that it is generally accepted for use in subjects (especially humans).

[0011] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or acid addition salts formed with organic acids (such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.). Additional examples of such salts can be found in Berge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences] 66(1):1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2nd revision (2011).

[0012] As used herein, the term “prior systemic anticancer therapy” means, except for the following, prior or ongoing systemic anticancer therapy (including, but not limited to, chemotherapy, antibody therapy, molecularly targeted therapy, hormone therapy, retinoid therapy, or any investigational anticancer agent) given in adjuvant circumstances after complete resection of early breast cancer (with no known active disease for more than 2 years), or (ii) prior neoadjuvant / adjuvant systemic anticancer therapy (with or without antiPD-1 / L1 therapy) for early non-small cell lung cancer (NSCLC) (curative surgery) completed more than 6 months prior to diagnosis of cancer for which treatment with one or more of the methods disclosed herein is expected.

[0013] In some embodiments, prior systemic anticancer therapy is the use of KRAS. G12C Inhibitor therapy. In some embodiments, KRAS G12CInhibitors are sotoraraciab, adagrasib, GDC-6036, D-1553, JDQ443, LY3484356, BI1823911, JAB-21822, RMC-6291, or APG-1842. In some embodiments, KRAS G12C The inhibitor is sotorasirb. In some embodiments, KRAS G12C The inhibitor is adagaratesib.

[0014] The terms “subject” and “patient” are used interchangeably.

[0015] Sotora Sibu

[0016] This article provides methods for treating cancers containing KRAS G12C mutations in subjects of need, comprising administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasirb, (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 sotorasirb and (ii) a therapeutically effective amount of pemetrexed. In various embodiments, the therapeutically effective amount of sotorasirb is 240 mg. In some embodiments, when administered on the same day (i.e., day 1 of each cycle of the first regimen), sotorasirb is administered before carboplatin.

[0017] Sotorasibu is an irreversible inhibitor of KRAS. G12C A small molecule protein. Sotorasibil is also known as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propyl-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(propyl-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 names LUMAKRAS® (e.g., in the United States) or LUMYKRAS® (e.g., in Europe). Sotorasibil has the following structure:

[0018] .

[0019] Sotorasibol binds to the P2 pocket and nucleotide-binding pocket of KRAS adjacent to the mutant cysteine ​​residue at position 12. This inhibitor contains a thiol reaction moiety that covalently modifies the cysteine ​​residue and binds to KRAS. G12CKRAS is locked in an inactive guanosine diphosphate (GDP)-binding conformation (Canon et al., 2019). This blocks the interaction of KRAS with effectors such as rapidly accelerating fibrosarcoma (RAF), thereby preventing downstream signaling, including phosphorylation of extracellular signal-regulated kinases (ERKs) (Simanshu et al., 2017; Ostrem et al., 2013). KRAS has previously been shown to be locked in an inactive guanosine diphosphate (GDP)-binding conformation via small molecule inhibitors. G12C Inactivation of KRAS in tumor cell lines and xenografts with the G12C mutation inhibits cell growth and induces apoptosis (Janes et al., 2018; Ostrem and Shokat, 2016; Patricelli et al., 2016). Sotorasib's research has demonstrated its effectiveness against KRAS-carrying tumors. G12C The inhibition of cell and tumor growth and the regression of these cells and tumors (Canon et al., 2019). See also LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revised January 2023), which is incorporated herein by reference in its entirety.

[0020] This document provides methods comprising administering sotorasibel as a free base. In various embodiments, sotorasibel is administered in the form of a pharmaceutically acceptable salt. For clarity, as used herein, the term "storasibel" refers to the free base of sotorasibel. Any method described herein that mentions sotorasibel can also be carried out using a pharmaceutically acceptable salt of sotorasibel. In some embodiments, sotorasibel can be administered in the form of hydrochloride, phosphate, or mesylate. In some embodiments, sotorasibel can be administered in the form of hydrochloride. In some embodiments, sotorasibel can be administered in the form of phosphate. In some embodiments, sotorasibel can be administered in the form of mesylate. For clarity, if the method described herein refers to, for example, administering 240 mg (or 960 mg) of sotorasibol or a pharmaceutically acceptable salt thereof to a subject, then the method requires the administration of 240 mg (or 960 mg) of the free base of sotorasibol or a pharmaceutically acceptable salt corresponding to the amount of the free base administered.

[0021] This document further provides a method in which sotorasibel is administered orally. In various embodiments, sotorasibel is administered once daily. In some embodiments, the total daily dose of sotorasibel (e.g., 240 mg) is administered in two equal doses twice daily (e.g., 2 x 120 mg). In various embodiments, sotorasibel is administered in a solid dosage form. In some embodiments, the solid dosage form is tablets. In various embodiments, 240 mg of sotorasibel is administered in one tablet containing 240 mg of sotorasibel or in two tablets each containing 120 mg of sotorasibel. In various embodiments, 960 mg of sotorasibel is administered in three tablets each containing 320 mg of sotorasibel, four tablets each containing 240 mg of sotorasibel, or eight tablets each containing 120 mg of sotorasibel.

[0022] In various embodiments, sotorasirb is taken daily at approximately the same time, with or without food. In some embodiments, the sotorasirb tablet is dispersed in 120 mL (4 ounces) of non-carbonated room temperature water in a container, without crushing it. The liquid is stirred for approximately 3 minutes until the tablet is dispersed into small pieces and administered to the subject immediately or within 2 hours. Afterward, the container is rinsed with an additional 120 mL (4 ounces) of water and administered to the subject. This method can be used to administer sotorasirb to subjects who have difficulty swallowing solid dosage forms, such as tablets.

[0023] Carboplatin

[0024] This article provides methods for treating cancer containing a KRAS G12C mutation in a subject of need, comprising administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasirb, (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 sotorasirb and (ii) a therapeutically effective amount of pemetrexed. In various embodiments, the therapeutically effective amount of sotorasirb is 240 mg. In various embodiments, the therapeutically effective amount of sotorasirb is 960 mg.

[0025] Carboplatin is a platinum coordination compound. Its chemical name is diamine[1,1-cyclobutane-dicarboxylic acid (2-)-O,O']-,(SP-4-2)platinum or cis-(1,1-cyclobutane-dicarboxylic acid)-diamine-platinum(II), and it has the following structural formula:

[0026]

[0027] Carboplatin works by cross-linking deoxyribonucleic acid (DNA) chains, thereby inhibiting DNA synthesis and function. Carboplatin was introduced in 1981 as an analogue of cisplatin, exhibiting reduced non-hematologic toxicity compared to cisplatin in experimental models. (Calvert et al., 1989). In some cases, platinum-based chemotherapy has been a 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 recently the introduction of combinations of immunotherapy and chemotherapy (e.g., pembrolizumab combined with pemetrexed and platinum-based chemotherapy; see KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ, 07033 (revised March 2023), which is incorporated herein by reference in its entirety). Other chemotherapy agents that can be combined with platinum may include pemetrexed (for non-squamous NSCLC), gemcitabine (for squamous NSCLC), or taxanes (paclitaxel, albumin-bound paclitaxel, or docetaxel).

[0028] Carboplatin administration

[0029] Carboplatin is commercially available as PARAPLATIN®, BLASTOCARB®, BLASTOPLATIN®, CARBOKEM®, CARBOMAX®, PARAPLATIN®, CARBOPA®, KARPLAT®, and others. Complete information on the preparation, reconstitution, dosage, and administration of carboplatin is available in the local packaging insert (for the United States, see, for example, CARBOplatin Injection, US Prescribing Information, Fresenius KABI, Lake Zurich, Illinois, 60047 (revised May 2021), which is incorporated herein by reference in its entirety).

[0030] This article provides methods for administering a therapeutically effective dose of carboplatin. The Calvert formula [Total dose of carboplatin (mg) = (Target area under concentration-time curve (AUC) x (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 the amount corresponding to 5 mg / (mL x min) (AUC 5) multiplied by the subject's GFR in mL / min, plus an increase of 25 mL / min. The GFR used in the Calvert formula to calculate the AUC-based dosing should not exceed 125 mL / min, which is calculated using the Cockcroft-Gault formula (see Calvert et al., 1989; Cockcroft et al., 1976; and 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 x 150 mL / min). Therefore, methods are also provided herein for a therapeutically effective dose of carboplatin of 750 mg or less.

[0031] In various embodiments, carboplatin is administered intravenously.

[0032] Carboplatin is administered during the first regimen of the method provided herein, but not during the second regimen, i.e., the method provided herein includes a method in which carboplatin is not administered to the subject during the second regimen. In various embodiments, administration of the first regimen continues for multiple cycles. In some embodiments, administration of the first regimen continues for 4 cycles (each cycle lasting 21 days). In various embodiments, carboplatin is administered on day 1 of each cycle during the first regimen. In some embodiments, when administered on the same day (i.e., day 1 of each cycle of the first regimen), sotorasirb is administered before carboplatin.

[0033] Pemetrexed and other medications

[0034] This article provides methods for treating cancer containing a KRAS G12C mutation in a subject of need, comprising administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasirb, (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 sotorasirb and (ii) a therapeutically effective amount of pemetrexed. In various embodiments, the therapeutically effective amount of sotorasirb is 240 mg. In various embodiments, the therapeutically effective amount of sotorasirb is 960 mg.

[0035] This document also provides methods that further include administering other medications to a subject. In various embodiments, the methods provided herein further include administering a therapeutically effective amount of folic acid to a subject. In various embodiments, the methods provided herein further include administering a therapeutically effective amount of vitamin B12 to a subject. In various embodiments, the methods provided herein further include administering a therapeutically effective amount of a corticosteroid, such as dexamethasone or its equivalent, to a subject.

[0036] Pemetrexed is a folate analogue metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. The FDA has approved pemetrexed, for example, in combination with pembrolizumab and platinum-based chemotherapy (carboplatin or cisplatin) as initial treatment for patients with metastatic non-squamous NSCLC without EGFR or ALK tumor genomic abnormalities.

[0037] Pemetrexed is available commercially as ALIMTA® and others. Complete information on the preparation, reconstitution, dosage, and administration schedule of pemetrexed can be found in the local packaging insert (for the United States, see, for example, ALIMTA® US Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revised August 2022), which is incorporated herein by reference in its entirety). The active pharmaceutical ingredient of ALIMTA (pemetrexed for injection) is disodium pemetrexed heptahydrate, chemically named N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamate disodium salt heptahydrate, with the molecular formula C0. 20 H 19 The compound is N5Na2O6•7H2O, with a molecular weight of 597.49. Its structural formula is as follows:

[0038]

[0039] ALIMTA is a sterile white to pale yellow or greenish-yellow lyophilized powder in single-dose vials for reconstitution for intravenous infusion.

[0040] Pemetrexed administration

[0041] This article provides a method in which the effective therapeutic dose of pemetrexed is 500 mg / m². 2 In various embodiments, pemetrexed is administered intravenously. In some embodiments, pemetrexed is administered intravenously over 10 minutes.

[0042] In the method provided herein, pemetrexed is administered on day 1 of the first cycle of the first regimen, and then at 21-day intervals throughout the treatment course (i.e., on day 1, day 22, day 43, etc.), until the administration of pemetrexed is completed. 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 carboplatin administration has been stopped. In some embodiments, sotorasiib is administered before pemetrexed when administered on the same day (e.g., day 1 of each cycle of the first regimen and day 1 of the second regimen).

[0043] In various embodiments, pemetrexed was administered to the subject, wherein the subject’s creatinine clearance (CrCl, calculated by the Cockcroft-Gault equation (see Cockcroft et al., 1976; and Example 2 below)) was 45 mL / min or greater.

[0044] Therefore, this paper provides a method in which pemetrexed administration begins on day 1 of the first regimen. This paper further provides a method in which pemetrexed is administered at 21-day intervals during the period between administration of the first and second regimens to the subject.

[0045] Other drugs and their administration

[0046] As discussed above, this article also provides the following methods, which further include administering a therapeutically effective amount of folic acid to the subject; and the following methods, which further include administering a therapeutically effective amount of vitamin B to the subject. 12 See, for example, ALIMTA® US Prescribing Information, Eli Lilly, LLC, Indianapolis, 46285, Indiana (revised August 2022).

[0047] This document provides a method in which a therapeutically effective dose of folic acid is 350 µg to 1000 µg once daily. In some embodiments, a therapeutically effective dose of folic acid is 400 µg once daily. In various embodiments, a therapeutically effective dose of folic acid is 400 µg to 1000 µg once daily. In various embodiments, folic acid administration begins 7 days before pemetrexed administration and ends 21 days after pemetrexed administration is stopped.

[0048] This article also provides methods, including vitamin B. 12The therapeutically effective dose is 1 mg. In various embodiments, vitamin B12 is administered one week prior to the first pemetrexed administration and thereafter every 9 weeks (± 2 weeks) until pemetrexed administration is discontinued. In some embodiments, vitamin B... 12 Administer one week before the first pemetrexed administration, and thereafter every nine weeks until pemetrexed administration is discontinued. In various embodiments, vitamin B12 is administered intramuscularly.

[0049] As discussed above, this article also provides methods that further include administering a therapeutically effective amount of a corticosteroid, such as dexamethasone or its equivalent, to the subject.

[0050] Pemetrexed-induced rashes were reported more frequently in subjects who did not receive pretreatment with corticosteroids. Pretreatment with a corticosteroid (dexamethasone or an equivalent) reduced the incidence and severity of skin reactions. In clinical studies, dexamethasone 4 mg was administered orally twice daily, one day before, one day after, and one day after pemetrexed administration. See, for example, ALIMTA® US Prescribing Information, Eli Lilly, LLC, Indianapolis, 46285, Indiana (as approved August 19, 2004), available at https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2004 / 021677lbl.pdf (last accessed March 30, 2023). Therefore, this document also provides methods that further include administering a therapeutically effective amount of corticosteroid to a 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 one day before, on, and one day after each administration of pemetrexed to the subject.

[0051] Companion therapy

[0052] In various embodiments, the subject may also be treated with an acid reducing agent. Acid reducing agents include, but are not limited to, proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and locally acting antacids. In some embodiments, the subject may also be treated with a PPI or an 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 locally acting antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide. In some embodiments, a combination of a proton pump inhibitor or H2 receptor antagonist and sotorasibel was not administered to subjects requiring further acid-reducing therapy. In some embodiments, a combination of a proton pump inhibitor or H2 receptor antagonist and sotorasibel was not administered to subjects requiring further acid-reducing therapy, but a combination of a locally acting antacid and sotorasibel was administered. In some embodiments, sotorasibel was administered approximately 4 hours before or approximately 10 hours after the locally acting antacid. In some embodiments, if a subject requires further acid-reducing therapy, sotorasibel and an acidic beverage (such as cola) were administered to the subject. In some embodiments, no PPIs or H2RAs were administered to the subject within 7 days prior to the start of the first regimen (i.e., prior to day 1 of cycle 1 of the first regimen).

[0053] In various embodiments, the subject also requires treatment with a CYP3A4 inducer. In some embodiments, the combination of a CYP3A4 inducer and sotoraraxib is not administered to the subject. Exemplary CYP3A4 inducers include, but are not limited to, barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, and lorlatin. Sotorazib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, 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, the combination of a strong CYP3A4 inducer and sotorazib was not administered to the subject. Exemplary strong 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, strong CYP3A4 inducers include, but are not limited to, rifampin, phenytoin, mitotane, carbamazepine, avamepiride, enzalutamide, rifapentine, St. John's wort extract, apalutamide, rumacator, and evanib.In some embodiments, no strong CYP3A4 inducer was administered to the subject within 14 days prior to the start of the first protocol (i.e., prior to day 1 of cycle 1 of the first protocol).

[0054] In various embodiments, the subject also requires treatment with a CYP3A4 substrate. In some embodiments, the combination of a CYP3A4 substrate and sotoraraxib is not administered to the subject. Exemplary CYP3A4 substrates include, but are not limited to, abexicillin, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boprevir, bosutinib, epipiperazole, brigatinib, buspirone, gafplaza, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazanol, clopidogrel, cobitinib, cocaine, codeine, colchicine, curapanil, crizotinib. Nitroglycerin, Cyclosporine, Dabrafenib, Daclatasvir, Dapsone, Deficodine, Dexamethasone, Dextromethorphan, Diazepam, Diltiazem, Docetaxel, Dolutegravir, Domperidone, Doxepin, Oxlagoribé, Elbasvir / Gzopivir, Ilustat, Enzalutamide, Eplerenone, Erythromycin, Escitalopram, Esomeprazole, Estradiol, Felodipine, Fentanyl, Finasteride, Flubanceline, Gleevec, Haloperidol, Hydrocortisone, Ibrutinib, Adalaris, Indacaterol, Indinavir, Irinotecan, Isaconazole, Ivabradine, Ivacaptor, Lansoprazole, Lenvatinib, Lencanidipine, Ribavirin Docaine, liraristine, lovastatin, macitentan, methadone, midazolam, naldemeton, naloxetine, nateglinide, nelfinavir, neratinib, netupirant / palonosetron, nevirapine, nifedipine, nisodipine, nifedipine, olaparib, omeprazole, ondansetron, osimertinib, opemifene, palbociclib, palbistat, pantoprazole, perampanel, pipemacerine, paimidine, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, rebociclib, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast, lorapidan, roflumilastine ... Midesin, Ruxotinib, Salmeterol, Saquinavir, Celexapa, Sildenafil, Smepiride, Simvastatin, Sirolimus, Sonexamer, Sorafenib, Sunitinib, Suvorexan, Tacrolimus (FK506), Tamoxifen, Tasminone, Taxol, Telapir, Telimycin, Terfenadine, Testosterone, Ticagrelor, Tofacitinib, Tovapron, Torecell, Tramadol, Trazodone, Valbenazine, Vandetanib, Velpatasvir, Vermuprin, Venetocin, Venlafaxine, Verapamil, Verazordone, Vincristine, Vorapamil, Voriconazole, Zaleplon, and Ziprasidone.See, for example, Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007), https: / / drug-interactions.medicine.iu.edu, last accessed May 2021.

[0055] In some embodiments, the combination of a CYP3A4 substrate and sotorasidib was not administered to the subject, wherein the CYP3A4 substrate is a CYP3A4 substrate with a narrow therapeutic index. Exemplary CYP3A4 substrates with a narrow therapeutic index include, but are not limited to, alfentanil, fentanyl, cyclosporine, paimizoline, dihydroergotamine, quinidine, ergotamine, sirolimus, everolimus, and tacrolimus. In some embodiments, a CYP3A4 with a narrow therapeutic index was not administered to the subject for 14 days prior to the start of the first regimen (i.e., prior to day 1 of cycle 1 of the first regimen).

[0056] In various embodiments, the subject also requires treatment with a P-glycoprotein (P-gp) substrate. In some embodiments, the combination of a P-gp substrate and sotorasirb is not administered to the subject. 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, the combination of a P-gp substrate and sotorasirb is not administered to the subject, wherein the P-gp substrate is a P-gp substrate with a narrow therapeutic index. Exemplary P-gp substrates with a narrow therapeutic index include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, tacrolimus, and vincristine. P-gp substrates with a narrow therapeutic index are compounds to which even minimal concentration variations may result in serious toxicity. In some embodiments, a P-gp substrate with a narrow therapeutic index was not administered to the subject for 14 days prior to the start of the first regimen (i.e., prior to day 1 of cycle 1 of the first regimen).

[0057] Pembrolizumab

[0058] Pembrolizumab is a non-investigative product used as a comparator for sotorazib in the study described in Example 2 below.

[0059] Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody (mAb) with high specificity to bind to the PD-1 receptor, thereby inhibiting its interaction with PD-L1 and programmed cell death ligand-2 (PD-L2). Pembrolizumab is approved as a first-line monotherapy for patients with metastatic NSCLC expressing PD-L1 (TPS ≥ 1%) (as determined by an FDA-approved test), and as a monotherapy for disease progression during or after platinum-based chemotherapy (see, for example, KEYTRUDA® US Prescribing Information, Merck, Kenniworth, 07033, NJ (revised March 2023), which is incorporated herein by reference in its entirety). Patients with EGFR or ALK genomic tumor abnormalities should have experienced disease progression while receiving an FDA-approved targeted therapy for these abnormalities before receiving pembrolizumab.

[0060] The comparative group (a combination of pembrolizumab with carboplatin and pemetrexed) in the study described in Example 2 is the therapy of choice for non-squamous NSCLC subjects without actionable oncogenic driver mutations (e.g., subjects with low or negative PD-L1 expression levels) (NCCN Guidelines, 2022).

[0061] Based on the results of the KEYNOTE-021 cohort G and the confirmatory KEYNOTE 189 study (Gandhi et al., 2018; Langer et al., 2016), the combination of pembrolizumab and pemetrexed-platinum chemotherapy was approved. Initial results from KEYNOTE 189 showed significant improvements in overall survival (OS), with a hazard ratio (HR) of 0.49 (95% CI: 0.38, 0.64; p < 0.001), and significant improvements in progression-free survival (PFS), with an HR of 0.52 (95% CI: 0.43, 0.64; p < 0.001). The overall response rate (ORR) was 18.9% compared to the control group, and 47.6% (p < 0.001) in subjects treated with the combination of immunotherapy and chemotherapy (Gandhi et al., 2018; Gadgeel et al., 2020). These and other data led to the approval of pembrolizumab in the U.S., EU, and other countries in combination with pemetrexed and platinum-based chemotherapy as first-line treatment for patients with metastatic non-squamous NSCLC without EGFR or ALK genomic tumor abnormalities (see, for example, KEYTRUDA® US Prescribing Information, Merck, Kenniwell, 07033, NJ (revised March 2023)). Therefore, pembrolizumab dual chemotherapy with platinum (current standard of care) was selected as the investigational comparative agent.

[0062] patient group

[0063] In various embodiments, the subjects are adults. In some embodiments, the subjects are 18 years of age or older.

[0064] In various embodiments, the subject had not received prior systemic anticancer therapy for the cancer prior to treatment with the methods provided herein. In some cases, the patient had not received prior therapy for KRAS G12C-mutant cancers (e.g., metastatic colorectal and pancreatic cancer). In some embodiments, the patient had not previously received therapy using an anti-angiogenic agent. In some embodiments, the patient was not treated concurrently 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 was not treated concurrently with bevacizumab. In some embodiments, the patient had not received prior therapy for metastatic disease. The methods disclosed herein are first-line or frontline treatments.

[0065] In various embodiments, the subject's creatinine clearance (CrCl) was equal to or greater than 45 mL / min, as calculated using the Cockcroft-Gault formula. See Cockcroft et al., 1976. In various embodiments, the subject's creatinine clearance (CrCl) was equal to or greater than 45 mL / min and equal to or less than 125 mL / min.

[0066] In various embodiments, the subject's Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1. See, for example, Oken et al., 1982. Status 0 indicates full activity and the ability to perform all pre-illness activities without restriction. Status 1 indicates limited physical activity but the ability to walk and perform light or sedentary work. Status 2 indicates the ability to walk and be fully self-sufficient but unable to perform any work activities; able to get up and walk more than 50% of waking hours. Status 3 indicates limited self-sufficiency; confined to bed or sitting for more than 50% of waking hours. Status 4 indicates complete disability, incapable of any self-sufficiency, and confined to bed or sitting. Status 5 indicates death.

[0067] KRAS G12C mutant cancer

[0068] This article provides methods for treating cancer containing a KRAS G12C mutation in a subject of need, comprising administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasirb, (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 sotorasirb and (ii) a therapeutically effective amount of pemetrexed. In various embodiments, the therapeutically effective amount of sotorasirb is 240 mg. In various embodiments, the therapeutically effective amount of sotorasirb is 960 mg.

[0069] Additionally, this article provides methods for treating non-small cell lung cancer containing KRAS G12C mutations in subjects in need, comprising administering to the subject (a) a first regimen comprising (i) 240 mg of sotorasirb, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed; and then (b) a second regimen comprising (i) 240 mg of sotorasirb and (ii) a therapeutically effective dose of pemetrexed; wherein (1) the therapeutically effective dose of carboplatin is the amount corresponding to 5 mg / (mL x min) (AUC 5) multiplied by an increase of 25 mL / min in the subject's glomerular filtration rate (GFR) in mL / min, and wherein (2) the therapeutically effective dose of pemetrexed is 500 mg / m 2 And (3) prior to treatment, the subject had not received prior systemic anticancer therapy (first-line treatment) for the cancer, and (4) the cancer showed (a) a tumor cell (TC) score of less than 1% or (b) a PD-L1 tumor proportion score (TPS) of less than 1%.

[0070] Furthermore, this article provides methods for treating non-small cell lung cancer containing KRAS G12C mutations in subjects in need, comprising administering to the subject (a) a first regimen comprising (i) 960 mg of sotorasirb, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed; and then (b) a second regimen comprising (i) 960 mg of sotorasirb and (ii) a therapeutically effective dose of pemetrexed; wherein (1) the therapeutically effective dose of carboplatin is the amount corresponding to 5 mg / (mL x min) (AUC 5) multiplied by an increase of 25 mL / min in the subject's glomerular filtration rate (GFR) in mL / min, and wherein (2) the therapeutically effective dose of pemetrexed is 500 mg / m 2 And (3) prior to treatment, the subject had not received prior systemic anticancer therapy (first-line treatment) for the cancer, and (4) the cancer showed (a) a tumor cell (TC) score of less than 1% or (b) a PD-L1 tumor proportion score (TPS) of less than 1%.

[0071] Without being bound by any particular theory and as previously discussed, note the following: Sotorasirb is a small molecule that specifically and irreversibly inhibits KRAS. G12C(Hong et al., 2020). Hong et al. reported that “preclinical studies showed that [sotorasibu] inhibited almost all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, leading to durable and complete tumor regression in mice carrying KRAS p.G12C tumors.” (Ibid., see also Canon et al., 2019 and Lanman et al., 2020).

[0072] Sotorasirb was evaluated in a phase 1 dose-escalation and expansion trial in 129 subjects with histologically confirmed locally advanced or metastatic cancer with KRAS G12C mutations (identified by local molecular testing of tumor tissue), including 59 subjects with non-small cell lung cancer, 42 subjects with colorectal cancer, and 28 subjects with other tumor types (Hong et al., 2020, pp. 1208-1209). Hong et al. reported a disease control rate (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 remission (PR), as reported by Hong et al., are non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small bowel cancer, sinus cancer, bile duct cancer, or melanoma (Hong et al., 2020, p. 1212 (Figure A) and supplementary appendices (p. 59 (Figure S5) and p. 63 (Figure S6))).

[0073] The frequency of alterations in KRAS G12C mutations is shown in the table below (Cerami et al., 2012; Gao et al., 2013). For example, the table shows that 11.6% of non-small cell lung cancer patients had cancers containing KRAS G12C mutations. Therefore, specific and irreversible binding to KRAS... G12C Sotorasibu can be used to treat subjects with cancer, including but not limited to the following cancers:

[0074]

[0075] In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, small bowel cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, ampullary cancer, gastric cancer, sinus cancer, or bile duct cancer. In some embodiments, the cancer is non-small cell lung cancer, small bowel cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinus cancer, or bile duct cancer. In various embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.

[0076] Non-small cell lung cancer

[0077] 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 lung cancer) is the second most common cancer overall, with an estimated 2.21 million cases in 2020 (World Health Organization statistics, 2020). In 2020, North America, Europe, and Asia reported over 253,537, 477,543, and 1,315,136 new cases of lung cancer, respectively. The estimated number of lung cancer deaths 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).

[0078] The selection of systemic therapy for patients with advanced NSCLC is based on the molecular characteristics of the cancer, particularly the presence of actionable driver gene alterations and the expression level of PD-L1 in tumor cells (NCCN Guidelines, 2022; Besse et al., 2014).

[0079] In NSCLC patients without functional mutations in the EGFR or ALK genes, PD-L1 expression levels on tumor cells, as measured by TPS or tumor cell (TC) scores, were positively correlated with response rates and duration of response to either a single programmed cell death protein 1 / ligand-1 (PD-1 / L1) checkpoint inhibitor or its combination with platinum-based dual chemotherapy (Reck et al., 2019; Gandhi et al., 2018; Paz-Ares et al., 2018). The combination of immune checkpoint inhibitors (such as pembrolizumab) and platinum-based dual chemotherapy is a treatment option for advanced NSCLC that is PD-L1 negative and lacks functional mutations in the EGFR or ALK genes.

[0080] Conversely, the presence of actionable driver mutations in the EGFR or ALK genes, regardless of PD-L1 expression levels in tumors, indicates low efficacy of PD-1 / L1 checkpoint inhibitors. Therefore, oral tyrosine kinase inhibitors (TKIs) of EGFR or ALK proteins are a Class 1 NCCN front-line therapy option for such subjects. Immune checkpoint inhibitors have limited efficacy in these subject groups and are typically used in combination with chemotherapy, usually beyond second-line treatment (NCCN Guidelines, 2022).

[0081] Subjects with advanced non-squamous NSCLC without EGFR or ALK driver mutations were treated with pembrolizumab alone or cimiprizumab-rwlc alone or immunotherapy (pembrolizumab, atezolizumab or cimiprizumab) in combination with platinum chemotherapy (Reck et al., 2019; Gandhi et al., 2018; Sezer et al., 2021; Gogishvili et al., 2022).

[0082] In a randomized, multicenter, double-blind study, the efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy was investigated 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 had no EGFR or ALK genomic tumor abnormalities (KEYNOTE-189). Although the 2-year overall survival (OS) was significantly improved in the KEYNOTE-189 intention-to-treat population (45.5%; hazard ratio [HR] 0.56), the response rate in the pembrolizumab-chemotherapy group was only 48% (95% CI 43.1–53.0) (Gadgeel et al., 2020). As recently analyzed, response rate, PFS, and OS are strongly associated with higher levels of PD-L1 expression in tumors (Rodríguez-Abreu et al., 2021). Specifically, the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in the PD-L1 < 1% group were 33.1% (95% CI: 25.0, 42.0), 6.2 months (HR 0.67, 95% CI: 0.49, 0.93), and 17.2 months (HR 0.51, 95% CI: 0.36, 0.71), respectively. In contrast, the ORR, PFS, and OS in the PD-L1 < 1% group were 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, and in the PD-L1 > 50% group were 62% (95% CI: 53.3, 70.4), 6.2 months (HR 0.67, 95% CI: 0.49, 0.93), and 17.2 months (HR 0.51, 95% CI: 0.36, 0.71), respectively. The mean morbidity rate (HR) was 0.35 (95% CI: 0.25, 0.49) and the mean morbidity rate (HR) was 27.7 months (HR 0.59, 95% CI: 0.40, 0.86). Similar observations were also seen with the combination of cimiprimab and carboplatin-pemetrexed (Gogishvili et al., 2022), suggesting that PD-L1-negative NSCLC patients may benefit from alternative therapies and / or additional biomarkers may help in further selection of patients in this group who will benefit from novel therapeutic options.

[0083] Over the past 20 years, numerous driver mutations have been identified in specific genes, namely EGFR, ERBB2, BRAF, ROS1, ALK, METex14 skipping, NTRK, and RET. Improved outcomes have been observed in subjects with driver mutations compared to those who did not receive targeted therapy (Kris et al., 2017). Immunotherapy, particularly in the frontline setting, is less effective in subjects with most driver mutations than in NSCLC subjects without them, and in some groups (especially ALK and EGFR-driven cancers), immune checkpoint inhibitors have low response rates (Addeo et al., 2021).

[0084] Combinations of targeted small molecule therapies (e.g., EGFR inhibitors, BRAF inhibitors, or vascular endothelial growth factor inhibitors) with immunotherapeutic agents (e.g., anti-PD[L]-1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]) have led to an unexpected increase in the frequency and / or severity of adverse events. Some examples include elevated liver enzymes with or without elevated bilirubin (ipilimumab and vemurafenib, devalumab and gefitinib, pembrolizumab and axitinib, devalumab 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 devalumab) (Ahn et al., 2016). Even when oral targeted agents are administered following immunotherapy, an increased frequency and severity of immune-mediated toxicity has been observed, which may be due to the persistence and effects of anti-PD-1 / L1 therapeutic antibodies.

[0085] Therefore, the NCCN and ESMO recommend the use of targeted therapy as a first-line treatment for patients with advanced or metastatic NSCLC who have targetable 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.

[0086] Subjects with KRAS mutations (often associated with a history of heavy smoking) have shown similar responses to combinations of immune checkpoint inhibitor chemotherapy 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 as first-line therapy, just like subjects without other molecularly defined targets. Therefore, previously untreated subjects with locally advanced or metastatic KRAS G12C-mutant NSCLC treated with first-line targeted therapy, especially those with <1% PD-L1-expressing tumor cells (Herbst et al., 2019; Gadgeel et al., 2019), represent a population in need of novel treatment approaches, such as those disclosed in this article.

[0087] Therefore, this article provides a method for treating cancer containing a KRAS G12C mutation, wherein the cancer is non-small cell lung cancer, in subjects of need. 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. See, for example, AJCC Cancer Staging Manual, 8th edition, 2017.

[0088] Determine KRAS G12C mutation status

[0089] Methods and tests are known in the art for determining whether a subject has cancer containing a KRAS G12C mutation. KRAS G12C mutation status can be determined using Guardant360® NGS (plasma) and Qiagen's therascreen® KRAS RGQ PCR (tissue; from formalin-fixed paraffin-embedded (FFPE) tissue or cell blocks). The KRAS G12C mutation status of cancer can be determined using any test approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA).

[0090] Determine PD-L1 expression status

[0091] As background, PD-L1 is a transmembrane protein that downregulates immune responses by binding to its 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 its expression persists under chronic stimulation conditions, such as in chronic infection or cancer. (Blank et al., 2007) Binding of PD-L1 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. Binding of PD-L1 to B7.1 on T cells and antigen-presenting cells can mediate the downregulation of immune responses, including inhibition of T cell activation and cytokine production. (Butte et al., 2007) PD-L1 expression has been observed in both immune cells and malignant cells (Dong et al., 1999; Massard et al., 2016), and aberrant PD-L1 expression on malignant cells has been reported to impede antitumor immunity, leading to immune escape (Blank et al., 2007; Massard et al., 2016). Therefore, blocking the PD-L1 / PD-1 pathway represents an attractive strategy to revitalize tumor-specific T-cell immunity suppressed by PD-L1 expression in the tumor microenvironment. Associations between PD-L1 expression in TC or tumor-infiltrating immune cells (IC) and the clinical benefits of PD-L1 / PD-1 pathway inhibitors have been reported in various 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, United States. Available at https: / / www.accessdata.fda.gov / cdrh_docs / pdf16 / P160046S010C.pdf, last accessed March 31, 2023.

[0092] PD-L1 expression can be determined using methods known in the art. For example, PD-L1 expression can be detected using the PD-L1 IHC22C3 pharmDx, an FDA-approved in vitro diagnostic immunohistochemical (IHC) assay developed by Dako and Merck as a companion assay for treatment with pembrolizumab. See PD-L1 IHC 22C3pharmDx, Dako North America, Inc., 6392 ViaReal, Carpinteria, California 93013, United States, available at https: / / www.accessdata.fda.gov / cdrh_docs / pdf15 / p150013c.pdf (version 09 / 15), last accessed on March 31, 2023, which is incorporated herein by reference in its entirety. The PD-L1 IHC 22C3 pharmDx assay is a qualitative immunohistochemical assay using monoclonal mouse anti-PD-L1 clone 22C3, intended for detection of PD-L1 protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissues on an Autostainer Link 48 using the EnVision FLEX visualization system. PD-L1 protein expression was determined using tumor proportion score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining.

[0093] For example, PD-L1 expression can also be detected using the Ventana SP263 assay (developed in collaboration between Ventana and AstraZeneca). This assay is a qualitative immunohistochemical assay using the rabbit monoclonal anti-PD-L1 clone SP263, intended for evaluating programmed death-ligand-1 (PD-L1) protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens via optical microscopy. The assay is used in conjunction with the OptiViewDAB IHC assay kit for staining on a BenchMark ULTRA instrument. PD-L1 protein expression in NSCLC is determined by the percentage of tumor cells with membrane staining above background (%TC). This assay is indicated to aid in the identification of subjects eligible for treatment with, for example, atezolizumab (TECENTRIQ®) for NSCLC with a TC score ≥ 1%. See VENTANA PD-L1 (SP263) Assay, Instructions 2021-10-10, 1020514US Rev 1, Ventana Medical Systems, Inc. 1910 Innovation Park Blvd East, Tucson, ARE 85755, USA, available at https: / / www.accessdata.fda.gov / cdrh_docs / pdf16 / P160046S010C.pdf, last accessed March 31, 2023, which is incorporated herein by reference in its entirety.

[0094] In some embodiments, PD-L1 negativity is determined using a test approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA), by using PD-L1 TPS or TC scores for cancer as described in the methods disclosed herein. In various embodiments, PD-L1 TPS or TC scores are determined using an immunohistochemical (IHC) test. In various embodiments, the IHC test is performed using samples obtained by, for example, excision, needle biopsy (CNB), or fine-needle aspiration (FNA). In some embodiments, the IHC test is the PD-L1 IHC 22C3 pharmDx test to determine TPS. In some embodiments, the IHC test is the Ventana PD-L1 (SP263) IHC assay to determine TC scores.

[0095] In various embodiments, cancer exhibits PD-L1 TPS less than the following: 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In various embodiments, cancer exhibits less than 1% PD-L1 TPS. In some embodiments, cancer exhibits PD-L1 TPS in the range of greater than or equal to 0% and less than 1%. In some embodiments, cancer exhibits a PD-L1 TPS score of 1%–49%. In some embodiments, cancer exhibits a PD-L1 TPS score of 50% or greater (i.e., 50%–100%). In some embodiments, the PD-L1 TPS range is determined using the PD-L1 IHC 22C3 pharmDx test.

[0096] In various embodiments, cancer exhibits TC scores less than the following: 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In various embodiments, cancer exhibits a TC score less than 1%. In some embodiments, cancer exhibits a TC score greater than or equal to 0% and less than 1%. In some embodiments, cancer exhibits a TC score of 1%–49%. In some embodiments, cancer exhibits a TC score of 50% or greater (i.e., 50%–100%). In some embodiments, the TC score is determined using a Ventana PD-L1 (SP263) IHC assay.

[0097] Determine the state changes of EGFR, ALK, and ROS1.

[0098] Compared with platinum-based dual chemotherapy or immune checkpoint inhibitors alone or in combination with chemotherapy, small molecule targeted therapy has shown superior results in patients with advanced non-small cell lung cancer (NSCLC) with actionable mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and several other genes (European Society for Medical Oncology [ESMO] Clinical Practice Guidelines, 2020; National Comprehensive Cancer Network [NCCN] Guidelines, 2022).

[0099] Therefore, this article provides methods for treating cancer in which the cancer does not involve EGFR alterations. In some embodiments, the cancer does not involve ALK alterations. In some embodiments, the cancer does not involve ROS 1 alterations. In some embodiments, the cancer does not involve either EGFR or ALK alterations.

[0100] Methods for determining EGFR, ALK, and ROS1 altered states are known in the art (see, for example, Thermo Fisher Scientific’s Oncomine Dx target test 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).

[0101] Example

[0102] 1. A method of treating cancer containing a KRAS G12C mutation in a subject in need, the method comprising: administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasirb, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed; and then administering (b) a second regimen comprising (i) a therapeutically effective amount of sotorasirb and (ii) a therapeutically effective amount of pemetrexed.

[0103] 2. The method as described in Example 1, wherein the application of the first solution lasts for a period of 4 cycles.

[0104] 3. The method as described in Example 2, wherein each cycle is a 21-day period.

[0105] 4. The method as described in any one of Examples 1 to 3, wherein the therapeutically effective dose of sotorasidub is 240 mg.

[0106] 5. The method as described in any one of Examples 1 to 3, wherein the therapeutically effective dose of sotorasidub is 960 mg.

[0107] 6. The method as described in any one of Examples 1 to 5, wherein the sotoprazib is administered orally.

[0108] 7. The method as described in any one of Examples 1 to 6, wherein the sotorasid is administered once daily.

[0109] 8. The method as described in any one of Examples 1 to 7, wherein the sotorasid is administered in a solid dosage form.

[0110] 9. The method as described in Example 8, wherein the solid dosage form is a tablet.

[0111] 10. The method as described in Example 9, wherein the sotorasidib is administered as one tablet containing 240 mg of sotorasidib, two tablets each containing 120 mg of sotorasidib, three tablets each containing 320 mg of sotorasidib, four tablets each containing 240 mg of sotorasidib, or eight tablets each containing 120 mg of sotorasidib.

[0112] 11. The method as described in any one of Examples 1 to 10, wherein the therapeutically effective amount of carboplatin is the amount corresponding to 5 mg / (mL x min) (AUC 5) multiplied by an increase of 25 mL / min in the subject's glomerular filtration rate (GFR) in mL / min.

[0113] 12. The method as described in Example 11, wherein the therapeutically effective dose of carboplatin is 750 mg or less.

[0114] 13. The method as described in any one of Examples 1 to 12, wherein the carboplatin is administered intravenously.

[0115] 14. The method as described in any one of Examples 2 to 13, wherein the carboplatin is administered on day 1 of each cycle.

[0116] 15. The method as described in any one of Examples 1 to 14, wherein carboplatin is not administered to the subject during the second protocol.

[0117] 16. The method as described in any one of Examples 1 to 15, wherein the therapeutically effective dose of pemetrexed is 500 mg / m². 2 .

[0118] 17. The method as described in any one of Examples 1 to 16, wherein pemetrexed is administered intravenously.

[0119] 18. The method as described in any one of Examples 1 to 17, wherein pemetrexed is administered starting on day 1 of the first regimen.

[0120] 19. The method as described in any one of Examples 1 to 18, wherein the pemetrexed is administered at 21-day intervals during the first and second administrations.

[0121] 20. The method of any one of Examples 1 to 19, further comprising administering a therapeutically effective amount of folic acid to the subject.

[0122] 21. The method as described in Example 20, wherein the therapeutically effective dose of folic acid is 350 µg to 1000 µg once daily.

[0123] 22. The method as described in Example 20, wherein the therapeutically effective dose of folic acid is 400 µg once daily.

[0124] 23. The method as described in Example 20, wherein the therapeutically effective dose of folic acid is 400 µg to 1000 µg once daily.

[0125] 24. The method as described in Example 20 or Example 23, wherein the folic acid administration begins 7 days before pemetrexed administration and ends 21 days after pemetrexed administration is stopped.

[0126] 25. The method of any one of Examples 1 to 24, further comprising administering a therapeutically effective amount of vitamin B12 to the subject.

[0127] 26. The method as described in Example 25, wherein the therapeutically effective amount of vitamin B12 is 1 mg.

[0128] 27. The method as described in Example 25 or Example 26, wherein the vitamin B12 is administered one week before the first administration of pemetrexed and thereafter every 9 weeks (± 2 weeks) until the administration of pemetrexed is discontinued.

[0129] 28. The method as described in Example 25 or Example 26, wherein the vitamin B12 is administered one week before the first pemetrexed administration and thereafter every nine weeks until pemetrexed administration is discontinued.

[0130] 29. The method as described in any one of Examples 25 to 28, wherein the vitamin B12 is administered intramuscularly.

[0131] 30. The method of any one of Examples 1 to 29, further comprising administering a therapeutically effective amount of dexamethasone to the subject.

[0132] 31. The method as described in Example 30, wherein the therapeutically effective dose of dexamethasone is 4 mg twice daily.

[0133] 32. The method as described in Example 30 or Example 31, wherein the dexamethasone is administered one day before, on, and one day after each administration of pemetrexed to the subject.

[0134] 33. The method as described in any one of Examples 1 to 32, wherein the subject is an adult.

[0135] 34. The method as described in any one of Examples 1 to 33, wherein the subject has not received prior systemic anticancer therapy (first-line treatment) for the cancer prior to treatment.

[0136] 35. The method as described in any one of Examples 1 to 34, wherein the subject’s creatinine clearance (CrCl) is equal to or greater than 45 mL / min, as calculated by the Cockcroft-Gault formula.

[0137] 36. The method as described in any one of Examples 1 to 35, wherein the subject's ECOG performance status is 0 or 1.

[0138] 37. The method as described in any one of Examples 1 to 36, wherein the cancer exhibits a TC score of less than 1%.

[0139] 38. The method as described in Example 37, wherein the therapeutically effective dose of sotorasidub is 960 mg.

[0140] 39. The method as described in Example 37, wherein the TC score is determined using Ventana PD-L1 (SP263) IHC assay.

[0141] 40. The method as described in any one of Examples 1 to 36, wherein the cancer exhibits a PD-L1 tumor proportion score (TPS) of less than 1%.

[0142] 41. The method as described in Example 40, wherein the therapeutically effective dose of sotorasidub is 960 mg.

[0143] 42. The method as described in Example 40, wherein the TPS is determined using PD-L1 IHC 22C3 pharmDx assay.

[0144] 43. The method as described in any one of Examples 1 to 42, wherein the cancer does not contain EGFR or ALK alterations.

[0145] 44. The method as described in any one of Examples 1 to 43, wherein the cancer is lung cancer.

[0146] 45. The method as described in any one of Examples 1 to 43, wherein the cancer is non-small cell lung cancer.

[0147] 46. ​​The method as described in any one of Examples 1 to 43, wherein the cancer is non-squamous non-small cell lung cancer.

[0148] 47. The method as described in Example 46, wherein the non-squamous non-small cell lung cancer is stage IV or advanced stage IIIB / C.

[0149] 48. The method as described in any one of Examples 1 to 47, wherein no antibody is administered to the patient concurrently.

[0150] 49. The method as described in Example 48, wherein the antibody is an anti-VEGF antibody.

[0151] 50. The method as described in Example 49, wherein the anti-VEGF antibody is bevacizumab.

[0152] 51. Sotorasirb for use in the treatment of KRAS G12C mutant cancer, wherein the treatment comprises administering to the subject (a) a first regimen comprising (i) a therapeutically effective amount of sotorasirb, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed; and then administering to the subject (b) a second regimen comprising (i) a therapeutically effective amount of sotorasirb and (ii) a therapeutically effective amount of pemetrexed.

[0153] 52. Sotorasirb for use in the treatment of KRAS G12C mutant cancer, wherein the treatment comprises administering to the subject (a) a first regimen comprising (i) sotorasirb, (ii) carboplatin, and (iii) pemetrexed; and then administering to the subject (b) a second regimen comprising (i) sotorasirb and (ii) pemetrexed. Example

[0154] Example 1 - A phase 1b / 2 regimen (CodeBreak 101) evaluating the safety, tolerability, pharmacokinetics, and efficacy of sotorasiib monotherapy and its combination with other anticancer therapies in patients with advanced solid tumors possessing KRAS p.G12C mutations.

[0155] Research Design

[0156] Sub-regimen F is part of the master regimen of study 20190135 (study 20190135), which evaluates various investigational combinations of sottorazib 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). Group A of sub-regimen F of CodeBreaK 101 evaluates the safety, tolerability, and efficacy of sottorazib in combination with carboplatin and pemetrexed (for 4 cycles), followed by maintenance therapy with sottorazib plus pemetrexed.

[0157] This study comprises a dose-exploration phase (Part 1) and an extension phase (Part 2) and is being conducted at approximately 65 research centers in the United States. Part 1 of the study consists of two cohorts. Cohort A is evaluating the safety of the combination of sotorasirb with carboplatin and pemetrexed (4 cycles (21 days each), followed by maintenance therapy with sotorasirb and pemetrexed). Currently, subjects in Part 1 Cohort A, Part 2 Cohort A1, and Part 2 Cohort A2, in particular, have received treatment as listed below:

[0158] • Group A, Part 1 = Sotorasibu 960 mg QD + Carboplatin AUC5 Q3W + Pemetrexed 500 mg / m 2 Q3W (n = 7)

[0159] • Group A1 (Part 2) = Sotorasibu 960 mg QD + Carboplatin AUC5 Q3W + Pemetrexed 500 mg / m 2 Q3W: First treatment (n = 11)

[0160] • Group A2 (Part 2) = Sotorasibu 960 mg QD + Carboplatin AUC5 Q3W + Pemetrexed 500 mg / m 2 Q3W: Prior medical history (n = 8)

[0161] Vitamin B12 and dexamethasone were administered to study subjects according to the pemetrexed label instructions (for the United States, see, for example, ALIMTA® US Prescribing Information, Eli Lilly, LLC, Indianapolis, 46285, Indiana 46285 (revised August 2022), which is incorporated herein by reference in its entirety). The primary safety endpoint was the occurrence of dose-limiting toxicities, treatment-related adverse events, treatment-related adverse events, and changes in vital signs, electrocardiograms, 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), duration of disease stability, and pharmacokinetic (PK) parameters.

[0162] The combination of sotorazib with carboplatin and pemetrexed is planned to enroll up to 47 subjects.

[0163] Subject distribution and demographics

[0164] As of the data snapshot date of December 1, 2022, a total of 26 subjects were enrolled in sub-protocol F, group A of study 20190135 and received at least one dose of any investigational product. Of these 26 subjects, 17 were male and 9 were female. Subjects were white (n = 23) or black / African American (n = 3), with a mean (SD) age of 65.3 (8.8) years. PD-L1 expression levels were reported as follows: ≥ 50% of tumor cells in 7 of the 26 subjects (26.9%), 1% to 49% of tumor cells in 4 of the 26 subjects (15.4%), and < 1% of tumor cells in 7 of the 26 subjects (8 subjects were unknown [30.8%]).

[0165] In Part 1, Group A, 5 out of 7 participants (71.4%) had no prior history of anticancer therapy for metastatic disease, and 3 of these participants (42.9%) had not received prior antiPD-1 / PD-L1 therapy. All participants in Part 2, Group A1 were treatment-naïve, and all participants in Part 2, Group A2 had a prior history of anticancer therapy, including 5 out of 8 participants (62.5%) who had received antiPD-1 / PD-L1 therapy.

[0166] Exposure

[0167] In Group A of Part 1, the median (minimum to maximum) exposure to sotorasibel was 148.0 (93 to 589) days. In Group A1 of Part 2, the median sotorasibel exposure was 85.0 (9 to 191) days, and in Group A2 of Part 2, the median sotorasibel exposure was 46.5 (7 to 233) days. The median (minimum to maximum) exposure to carboplatin ranged from 60.5 (15 to 85) to 84.0 (63 to 91) days, and the median (SD) exposure to pemetrexed ranged from 70.5 (15 to 253) to 105.0 (16 to 197) days.

[0168] Efficacy data

[0169] As of December 1, 2022, efficacy evaluations were available for 23 subjects in Part A based on having received at least one dose of the investigational product, having at least one measurable lesion assessed at baseline using RECIST 1.1 (Eisenhauer et al., 2009), and having the opportunity to be followed up for at least 7 weeks. Table 1 shows the investigator-assessed objective responses by cohort. For the analysis of best overall response (BOR), among these 23 subjects, 6 (26.1%) had a confirmed partial response (PR), 14 (60.9%) had stable disease (SD) (including 12 unconfirmed PRs awaiting confirmatory scans), 1 (4.3%) had progressive disease (PD), and 2 subjects were not assessed after baseline. The confirmed ORR for Group A in Part 1 was 42.9% (95% CI: 9.90 to 81.59), the confirmed ORR for Group A1 in Part 2 was 11.1% (95% CI: 0.28 to 48.25), and the confirmed ORR for Group A2 in Part 2 was 28.6% (95% CI: 3.67 to 70.96).

[0170] Table 1. Summary of objective responses assessed by investigators (ORR analysis set - Study 20170543, sub-regimen F)

[0171]

[0172] N = Number of subjects in the analysis set. n = Number of subjects with observational data.

[0173] CI = Confidence Interval.

[0174] The BOR of subjects included in the “confirmed and unconfirmed scans awaiting confirmation” category may also be summarized in one of the other categories.

[0175] a Calculate the precise 95% confidence interval using the Clopper Pearson method.

[0176] The ORR analysis set included all subjects who received at least one dose of the investigational product, had one or more measurable lesions at baseline assessment using RECIST 1.1, and had the opportunity to be followed up for at least 7 weeks from day 1. One subject in cohort A1 of Part 2 had a BOR of SD based on the first post-baseline scan but was not included in the ORR analysis set because they did not have the opportunity to be followed up for at least 7 weeks from day 1 at the data cutoff.

[0177] Data cutoff date: December 1, 2022.

[0178] Security data

[0179] As of December 1, 2022, 26 subjects had received at least one investigational product and were eligible for safety evaluation. Table 2 provides a summary of adverse events that occurred during treatment. Twenty-four subjects (92.3%) experienced at least one adverse event during treatment. The most common adverse events occurring in ≥ 50% of subjects in each cohort are as follows:

[0180] Group A, Part 1 (n = 7): Diarrhea (71.4%), nausea (71.4%), fatigue (71.4%), and anemia (57.1%) were observed in Group A, Part 1.

[0181] Part 2, group A1 (n = 11): There are no [elements] in part 2, group A1.

[0182] Group A2 (n = 8): 50.0% of the participants in Group A2 experienced decreased appetite.

[0183] Overall, 12 of the 26 subjects (46.2%) experienced one or more treatment-related 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, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase (ALP), COVID-19, decreased appetite, dental caries, febrile neutropenia, abnormal liver function, hepatotoxicity, hypertransaminasaemia, nausea, neutropenia, decreased neutrophil count, decreased platelet count, anal pain, and pulmonary embolism (n = 1 each). Three subjects experienced Grade 4 treatment-related adverse events (n = 2), decreased neutrophil count, and thrombocytopenia (n = 1 each). No fatal treatment-related adverse events were reported.

[0184] Twenty-four subjects (92.3%) experienced at least one treatment-related adverse event considered relevant to the study treatment. Six of the 26 subjects (23.1%) experienced one or more serious adverse events, and three of the 26 subjects (11.5%) discontinued sotorasirb due to adverse events. Overall, the reported adverse events were consistent with the individual safety characteristics of the investigational product, and no new safety issues were identified.

[0185] Table 2. Summary of adverse events during treatment (Safety Analysis Set - Sub-Program F).

[0186]

[0187] CRF = Case Report Form; CTCAE = Common Terminology Standard for Adverse Events; eCRF = Electronic Case Report Form; MedDRA = Medical Dictionary of Regulatory Activities; N = Number of subjects in the analysis set. n = Number of subjects with observational data.

[0188] An adverse event occurring during treatment is defined as an adverse event (AE) that begins on or after the first dose of the investigational product, as determined by the flag. The flag indicates on the event CRF whether the adverse event began before the first dose and continues up to and including 30 days after the last dose of the investigational product or the study end date (whichever is earlier).

[0189] Treatment-related adverse events (AEs) are any AEs that occur during treatment if the relationship flag on the event's eCRF indicates a reasonable likelihood that the event was caused by an investigational medical product. In unlikely events where the relationship is missing, events occurring during treatment are considered treatment-related.

[0190] For subjects with multiple events in the same category, only the worst level is reported.

[0191] Encoding was performed using MedDRA version 25.1. Severity was graded using CTCAE version 5.0.

[0192] Data cutoff date: December 1, 2022

[0193] The updated data is current as of February 3, 2023.

[0194] As of February 3, 2023, 30 participants (median age 67 years; 60% male; ECOG 0 / 1: 47% / 53%) received sotorasidubrax in combination with carboplatin and pemetrexed. Nineteen participants were treatment-naïve (Part 2, Group A1, first-line (1L)) and 11 participants had prior therapy in metastatic / locally advanced cases (Part 2, Group A2, second-line and higher (2L+)). Treatment-related adverse events (TRAEs) occurred in 29 (97%) participants, with 19 (63%) being grade 3-4 (Table 3). The most common grade 3-4 TRAEs were neutropenia (9 [30%]), anemia, and thrombocytopenia (both in 5 participants [17%]). No fatal adverse events occurred. In first-line (1L) care, treatment-naïve patients treated with sotorasiib in combination with carboplatin and pemetrexed achieved an ORR (objective response rate, confirmed + unconfirmed) of 73% (95% CI: 45, 92) and a DCR (disease control rate, Table 3) of 100%. For patients with a PD-L1 tumor proportion score (TPS) < 1% treated at 1L, 8 out of 11 patients achieved a response (ORR 73%). In second-line (2L+) care, the ORR was 55%. The median DOR (duration of response) was not estimable among all confirmed responses. PFS and OS data are immature.

[0195] The combination of sotorasibil with carboplatin and pemetrexed is safe and well-tolerated, with a grade 3-4 TRAE incidence generally consistent with other platinum-based dual therapy approaches. Promising efficacy was observed, most notably in treatment-naïve patients with low PD-L1 expression and high unmet needs.

[0196] Table 3.

[0197]

[0198] TRAE = Treatment-related adverse events; ORR = Objective response rate; DCR = Disease control rate.

[0199] a This includes reported neutropenia and TRAE with a decreased neutrophil count.

[0200] b This includes reported thrombocytopenia and decreased platelet counts in TRAE (transmissible thrombocytopenic purpura).

[0201] c This includes all patients who have received at least one dose of the investigational product, have ≥ 1 measurable lesion at baseline according to RECIST 1.1, and have the opportunity to be followed up for ≥ 7 weeks.

[0202] d ORR is based on 9 - confirmed partial response (PR), 2 - unconfirmed PR; the remaining best overall response (BOR) is 4 - stable disease (SD).

[0203] e ORR is based on 1-unconfirmed complete response (CR) and 5-confirmed PR; the remaining BOR is 3-SD, 1-disease progression (PD) and 1-no treatment.

[0204] The updated data is current as of May 7, 2023.

[0205] As of May 7, 2023, 38 subjects received combination therapy with sotorasiib, carboplatin, and pemetrexed.

[0206] Baseline characteristics

[0207] Patients were enrolled in three groups: Group A (pre-existing anti-PD-1 / L1 immunotherapy and / or platinum-based combination chemotherapy, or those who refused standard therapy), Group A1 (no prior anti-PD-1 / L1 immunotherapy and no platinum-based combination chemotherapy), and Group A2 (pre-existing anti-PD-1 monotherapy, platinum-based chemotherapy, or neoadjuvant / adjuvant chemotherapy) (Group A: n = 2 (29%) first-line patients, n = 5 (71%) second-line patients; Group A1: n = 22 (100%) first-line patients; Group A2: n = 1 (11%) first-line patients, n = 8 (89%) second-line patients). In locally advanced / metastatic cases, data were pooled and analyzed based on exposure to prior therapy (n = 25 first-line patients; n = 13 second-line patients).

[0208] Twenty-five participants were treatment-naïve (first-line (1L)) and 13 participants had received prior therapy in cases of metastatic / locally advanced disease (second-line or higher (2L+)). The median age of treatment-naïve participants was 64 years (48% male), and the median age of previously treated participants was 67 years (62% male). Baseline characteristics of the patient population are as follows:

[0209]

[0210] Security

[0211] Treatment-related adverse events (TRAEs) occurred in 36 (95%) subjects, with 22 (58%) being grade 3-4. The most common grade 3-4 TRAEs occurring in ≥5% of all patients were neutropenia / decreased neutrophil count (32%), anemia (21%), and thrombocytopenia / decreased platelet count (16%), elevated ALT (5%, grade 304 ALT elevation observed only in second-line cases), diarrhea (5%), febrile neutropenia (5%), and nausea (5%). No fatal adverse events occurred. TRAEs were consistent with regimens based on sotorasirb and platinum dual therapy.

[0212]

[0213] effect

[0214] In first-line (1L) treatment of newly diagnosed patients using sotorasirb in combination with carboplatin and pemetrexed, the objective response rate (ORR) was 65%, the disease control rate (DCR) was 100%, and the 95% confidence interval (CI) was 83.2%–100%. In second-line (2L+) treatment, the ORR was 54%, and the DCR was 85%, with a 95% CI of 54.6%–98.1%.

[0215]

[0216] This includes all patients who received ≥ 1 dose of the study drug, had ≥ 1 measurable lesion at baseline according to RECIST v 1.1, and were followed up for ≥ 7 weeks from day 1.

[0217] † An additional patient developed an unconfirmed partial response (PR) at week 6.

[0218] As shown below, the ORR was similar between 1L (n = 20) and 2L+ (n = 13) subjects at PD-L1 expression levels. For (A) 1L subjects with PD-L1 expression < 1%, the ORR was 62% (n = 8 / 13); for (B) 1L subjects with PD-L1 expression between 1% and 49%, the ORR was 75% (n = 3 / 4); and for (C) 1L subjects with PD-L1 expression ≥ 50%, the ORR was 67% (n = 2 / 3). For (A) 2L+ subjects with PD-L1 expression level < 1%, the ORR was 50% (n = 2 / 4); for (B) 2L+ subjects with PD-L1 expression level of 1%-49%, the ORR was 67% (n = 2 / 3); and for (C) 2L+ subjects with PD-L1 expression level ≥ 50%, the ORR was 50% (n = 3 / 6).

[0219] The median follow-up time was 3.0 months, and initial rapid and durable remission was observed. PFS and OS data are immature. This includes all patients who received ≥ 1 dose of the investigational drug in first- or second-line settings, had ≥ 1 measurable lesion at baseline according to RECIST v 1.1, and were followed up for ≥ 7 weeks from day 1.

[0220] The updated data is current as of December 1, 2023.

[0221] As of December 1, 2023, 58 patients (median age 65.5 years; 45% male; ECOG status 0 / 1, 38% / 62%) were treated with sotoraraci, buprofen, carboplatin, and pemetrexed; 37 (64%) patients were in first-line (1L) care and 21 (36%) patients were in second-line plus (2L+) care. Among the 2L+ patients, 18 / 21 (86%) had previously received anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 54 patients (93%); 30 (52%) patients experienced grade 3-4 TRAEs, and 1 (2%) patient experienced a fatal TRAE (see the table 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 [f / u], 9.2 months). In the PD-L1 < 1% subgroup (n = 19), the median PFS was 11.9 months (95% CI, 5.3–NE). 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 are still immature.

[0222] Table. Key Safety Results

[0223]

[0224] The fatal TRAE is febrile neutropenia caused by carboplatin and pemetrexed.

[0225] In CodeBreaK 101, sotorasi-butaplatin dual chemotherapy provided robust and durable remission with manageable safety profiles, which supports the evaluation of this regimen in the ongoing CodeBreaK 202 Phase 3 trial (NCT05920356) for treatment-naïve, PD-L1-negative, KRAS G12C-mutant advanced NSCLC.

[0226] Example 2 - A Phase 3 study comparing first-line platinum dual therapy and sotorasibi versus pembrolizumab in PD-L1 negative KRAS p.G12C positive advanced / metastatic non-small cell lung cancer (NSCLC) (CodeBreaK 202)

[0227] This is a phase 3, international, multicenter, randomized, open-label study (CodeBreaK 202) designed to evaluate the efficacy and safety of sotorasirb in combination with carboplatin and pemetrexed versus pembrolizumab in combination with carboplatin and pemetrexed as a first-line treatment in patients 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) as a first-line treatment. The study evaluated sotorasirb-platinum dual therapy versus pembrolizumab-platinum dual therapy as a first-line treatment in participants with stage IV or advanced stage IIIB / C non-squamous NSCLC (CodeBreaK202), https: / / clinicaltrials.gov / study / NCT05920356, last accessed February 29, 2024.

[0228] The study will consist of a pre-treatment period (pre-screening period (optional for subjects with available molecular data) and a screening period), a treatment period (4 platinum-based cycles followed by maintenance therapy) and a post-treatment period (safety follow-up [SFU] period and long-term follow-up [LTFU] period).

[0229] The target population for this study will be non-squamous NSCLC patients who are PD-L1 immunohistochemistry (IHC) negative (tumor cell count (TC) or tumor percentage score (TPS) < 1%) and KRAS p.G12C mutation positive (as determined by the central laboratory or the local laboratory of selected cases). The central laboratory will use the VENTANA SP263 assay to determine PD-L1 negativity (TC < 1%) and therascreen® KRAS RGQ PCR (polymerase chain reaction) using Guardant360® next-generation sequencing (NGS) on plasma and therascreen® KRAS RGQ PCR (polymerase chain reaction) on formalin-fixed paraffin-embedded (FFPE) tissue to determine KRAS p.G12C. For enrollment, positivity for KRAS p.G12C from either test is sufficient. For subjects who require accelerated initiation of anticancer therapy due to progression of cancer-related symptoms, enrollment and randomization may be permitted using the results of local PD-L1 IHC and KRAS mutation analysis, provided that the results are obtained using qualified assays in one or more qualified laboratories, and that the subject completes and meets all other inclusion / exclusion criteria and submits the required samples for retrospective molecular pathological confirmation by the central laboratory.

[0230] Approximately 750 participants will be enrolled in the study, which will be conducted at approximately 350 sites worldwide. Participants will be randomized in a 1:1 ratio to receive either sotorasibi in combination with carboplatin and pemetrexed or pembrolizumab in combination with carboplatin and pemetrexed.

[0231] Subjects will be stratified by disease stage (stage IV or advanced stage IIIB / C, see AJCC Cancer Staging Manual, 8th edition, 2017), brain metastases (yes or no), 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.

[0232] Subjects in the sotorasirb (investigational) treatment group will receive sotorasirb 240 mg (or 960 mg) (once daily (QD), orally (PO)) with carboplatin and pemetrexed 500 mg / m², which have an area under the concentration-time curve of 5 mg / mL / min (AUC5). 2 The combination of intravenous (IV) therapy continued for 4 cycles, followed by sotorasiib 240 mg (or 960 mg) PO and pemetrexed 500 mg / m² every 21 days. 2 IV maintenance therapy (cycle 5 and beyond). Subjects in the pembrolizumab (control) treatment group received pembrolizumab 200 mg IV every 21 days with carboplatin AUC5 and pemetrexed 500 mg / m². 2 The combination was administered for four cycles, followed by pembrolizumab 200 mg IV every 21 days (up to 35 cycles) and pemetrexed 500 mg / m². 2 IV maintenance therapy (5th cycle and more).

[0233] Treatment with sotorasibi will continue until blinded independent central review (BICR) confirms disease progression, unacceptable toxicity, withdrawal of consent, study termination, or death according to RECIST v1.1 criteria, whichever occurs first. Pembrolizumab can be administered for up to 2 years. Subjects who discontinue study treatment for reasons other than BICR-confirmed disease progression will continue to undergo tumor evaluation (if clinically feasible) until BICR confirms disease progression.

[0234] Treatment after progression will only be permitted under certain circumstances, as detailed below.

[0235] Tumor remission will be evaluated using RECIST v1.1 criteria via radiographic imaging (computed tomography [CT] scans and / or magnetic resonance imaging [MRI]).

[0236] Goals and End Points

[0237]

[0238]

[0239] Estimation of the main objective

[0240] In patients with PD-L1-negative and KRAS p.G12C-positive stage IV or advanced stage IIIB / C non-squamous NSCLC requiring first-line therapy, the hazard ratio (HR) for progression-free survival (PFS) is as follows: patients receiving sotorasibi and platinum-based dual chemotherapy are compared to patients receiving pembrolizumab and platinum-based dual chemotherapy. A concurrent event is the initiation of a new anticancer therapy prior to a PFS event, and the primary analysis will review PFS at the last evaluable date before or at the start of a new anticancer therapy. Sensitivity analyses including all evaluable PFS will be performed after the initiation of a new anticancer therapy.

[0241] Estimation of key secondary objectives:

[0242] In patients with PD-L1-negative and KRAS p.G12C-positive stage IV or advanced stage IIIB / C non-squamous NSCLC requiring first-line therapy, the difference in the proportion of patients receiving sotorasibi and platinum-based dual chemotherapy compared to those receiving pembrolizumab and platinum-based dual chemotherapy was noted. Patients who started a new anticancer therapy before achieving an objective response were considered non-responders.

[0243] In patients with PD-L1-negative and KRAS p.G12C-positive stage IV or advanced stage IIIB / C non-squamous NSCLC who require first-line therapy, the hazard ratio (HR) of overall survival (OS) is estimated between patients receiving sotorasibi and platinum-based dual chemotherapy and those receiving pembrolizumab and platinum-based dual chemotherapy; the concurrent event is the initiation of a new anticancer therapy, and the primary analysis will estimate the HR of OS regardless of subsequent anticancer therapy.

[0244] In patients with PD-L1-negative and KRAS p.G12C-positive stage IV or advanced stage IIIB / C non-squamous NSCLC requiring first-line therapy, the change in the patient-reported outcome (PRO) endpoint from baseline to week 12 was measured between subjects receiving sotorasibi and platinum-based dual chemotherapy and those receiving pembrolizumab and platinum-based dual chemotherapy. PRO measurements prior to or at the start of a new anticancer therapy were used to estimate treatment efficacy.

[0245] Summary of Subject Eligibility Criteria

[0246] Participants aged ≥ 18 years (or the legal age of majority in China, whichever is older) who have provided informed consent before commencing any study-specific activity / procedure are eligible if they meet the following key inclusion criteria:

[0247] - Histological or cytological confirmation of non-squamous NSCLC (adenosquamous histology is permissible if non-squamous histology accounts for >50% of the tumor); the presence of small cell or large cell neuroendocrine components is an exclusion criterion.

[0248] - Stage IV or advanced Stage IIIB / C NSCLC (not a candidate for curative multimodal therapy due to the extent of the disease)

[0249] - No history of systemic anticancer therapy in metastatic / incurable cases.

[0250] - A tumor tissue sample must be provided (or the individual must be willing to undergo a biopsy) for central molecular analysis.

[0251] - Testing using the SP263 IHC assay requires tumor tissue to be PD-L1 expression negative (TC < 1%).

[0252] - Must be positive for circulating tumor DNA (ctDNA) in plasma and / or KRAS p.G12C mutation in tumor tissue.

[0253] - Must have a measurable disease as defined by the RECIST v1.1 criteria.

[0254] - Performance status of 0 or 1 in the Eastern Cooperative Oncology Group (ECOG)

[0255] The key exclusion criteria include the following:

[0256] - Mixed histological NSCLC with small cell or large cell neuroendocrine components (any percentage) or predominantly squamous cell histology (more than 50% of the available tumor).

[0257] - Tumors known to have locally approved molecular alterations for targeted therapy other than KRAS p.G12C (including but not limited to EGFR or ALK alterations).

[0258] - Active brain metastases, defined as symptomatic (treated or untreated) brain metastases; subjects with asymptomatic untreated or asymptomatic treated brain metastases are eligible if they meet all pre-specified criteria.

[0259] - Active autoimmune diseases

[0260] - Evidence of active hepatitis B or C (hepatitis series tests performed during screening).

[0261] - Known uncontrolled human immunodeficiency virus (HIV) infection, defined by detectable blood HIV levels and / or CD4 levels below 400; known controlled HIV infection is also permitted.

[0262] The complete list of eligibility criteria is shown below:

[0263] Full inclusion criteria:

[0264] A participant is eligible to be included in the study only if all of the following criteria apply:

[0265] Informed consent was provided by the participants before any study-specific activity / procedure began.

[0266] The participants must be ≥ 18 years old (or the legal age of adulthood in China, whichever is older).

[0267] Subjects had a histologically or cytologically confirmed diagnosis of non-squamous NSCLC.

[0268] - If the tumor has mixed histology including squamous components, the case is suitable for enrollment, provided that the squamous components constitute a small portion of the tumor in the sample (< 50% of the tumor present).

[0269] According to the AJCC Cancer Staging Manual, 8th edition, 2017, the subject had stage IV (metastatic) or advanced stage IIIB or IIIC NSCLC (not a candidate for curative multimodal therapy due to the extent of the disease).

[0270] In metastatic / incurable cases, the subject has no history of systemic anticancer therapy. Prior curative (curative intent) therapy is permitted for early-stage NSCLC if the following conditions are met:

[0271] - Neoadjuvant / adjuvant (for curative surgery) systemic anticancer therapy (with or without antiPD-1 / L1 therapy) was completed more than 6 months prior to the current diagnosis of metastatic disease.

[0272] - Radical concurrent chemotherapy with radiation therapy (with or without anti-PD-1 / L1 therapy) was completed more than 6 months prior to the current diagnosis of metastatic disease.

[0273] The subjects have provided blood for central analysis of KRAS p.G12C status.

[0274] Subjects have provided a sufficient number of tumor tissue samples for central analysis of KRAS p.G12C status.

[0275] Subjects have provided a sufficient number of tumor tissue samples for central analysis of PD-L1 status.

[0276] The tumor was negative for PD-L1 expression (TC or TPS < 1%), and this PD-L1 expression was assessed by a central or local laboratory (Clinical Laboratory Improvement Amendments [CLIA] - certified or equivalent according to regional standards) using a assay that conforms to research technical specifications.

[0277] Subjects must be positive for circulating tumor DNA (ctDNA) in plasma or KRAS p.G12C mutation in tumor tissue, as tested by a central laboratory. In selected cases, when central laboratory results are pending, results from a local laboratory may be used for study entry and randomization.

[0278] Subjects must have a measurable disease as defined by the RECIST v1.1 criteria.

[0279] Subjects had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0280] Researchers believe the subjects' life expectancy is greater than 3 months.

[0281] Subjects were able to take oral medications and were willing to record their daily adherence to the investigational product.

[0282] The subjects underwent thorough hematological laboratory evaluations:

[0283] - Absolute neutrophil count (ANC) ≥ 1.5 x 10⁻⁶ 9 / L.

[0284] - Hemoglobin ≥ 9.0 g / dL or > 5.6 mmol / L (no blood transfusion 1 week prior).

[0285] - Platelet count ≥ 100 x 10 9 / L.

[0286] Subjects underwent adequate renal laboratory assessments and were estimated to have creatinine clearance (CrCl) ≥ 45 mL / min (using the Cockcroft-Gault formula, see Cockcroft et al., 1976 and below).

[0287] - If the estimated CrCl is below 45 mL / min, CrCl can be measured directly, and if the actual creatinine clearance (CrCl) is ≥ 45 mL / min, the subject can be admitted to the study.

[0288] The subjects underwent thorough liver laboratory assessments, as follows:

[0289] - AST and ALT are < 2.5 x the upper limit of normal (ULN) or ≤ 5 x ULN for subjects with liver metastases.

[0290] - Total bilirubin ≤ 1.5 x ULN.

[0291] - Subjects with clinically confirmed Gilbert's syndrome who have total bilirubin > 1.5 x ULN are eligible if direct bilirubin is within the normal range.

[0292] Subjects underwent thorough coagulation laboratory assessments:

[0293] - If prophylactic anticoagulation therapy is received, the international normalized ratio (INR) should be ≤ 1.5 x ULN or within the target range.

[0294] The subject has sufficient or appropriately compensated thyroid function as recorded by:

[0295] - Thyroid-stimulating hormone (TSH) is within the normal limit (if TSH is not within the normal limit, the subject is eligible if total triiodothyronine [T3] [or free T3] and free thyroxine [T4] are within the normal limit).

[0296] Subjects with subclinical hypothyroidism or hyperthyroidism are allowed to participate in the study.

[0297] Complete Exclusion Criteria

[0298] Subjects will be excluded from the study if they meet any of the following criteria:

[0299] Related diseases

[0300] - Subjects have mixed histological NSCLC with either small cell or large cell neuroendocrine cell components (any percentage) or predominant squamous cell histology (more than 50% of the available tumor).

[0301] - Subjects have tumors with known locally approved molecular alterations for targeted therapy other than KRAS p.G12C (including but not limited to EGFR or ALK alterations).

[0302] - Subjects have active brain metastases, defined as symptomatic (treated or untreated) brain metastases. Subjects with untreated brain metastases are admitted to the study if they are asymptomatic without systemic steroid use and, as confirmed by a qualified radiation oncologist, are instructed not to undergo radiation therapy. Subjects with treated brain metastases are eligible if they have completed radical therapy (stereotactic radiotherapy after surgery, or stereotactic radiotherapy, or whole-brain radiotherapy) and meet all of the following criteria:

[0303] - There should be a clearance period of at least 7 days between the completion of radical therapy and day 1 of cycle 1, and

[0304] - Subjects have recovered to neurological baseline (except for residual signs or symptoms related to CNS treatment). Additionally, subjects must discontinue corticosteroids or reduce the dose to ≤ 10 mg prednisone daily (or equivalent) before day 1 of cycle 1.

[0305] - The subject had symptomatic spinal cord compression due to cancer metastasis.

[0306] - The subject had carcinomatous meningitis (leptomeningeal disease).

[0307] Other medical conditions

[0308] Subjects with a history of other malignant tumors within the past 3 years, except for the following:

[0309] - Malignant tumors treated for curative purposes and without known active disease for ≥ 2 years prior to enrollment, and whose treating physician considers the risk of recurrence to be low.

[0310] - Well-treated non-melanoma skin cancer or malignant freckle-like nevus, cervical cancer in situ or ductal carcinoma in situ of the breast, with no evidence of disease.

[0311] - Prostatic intraepithelial neoplasia without evidence of prostate cancer.

[0312] - Well-treated non-invasive papillary carcinoma or carcinoma in situ of the urothelial tract.

[0313] Other malignancies that have shown stability over the past 5 years or more and do not require systemic therapy may be considered after obtaining approval from a medical supervisor.

[0314] Subjects with acute illnesses or acute surgical conditions may need to undergo surgery during the first cycle of treatment (as assessed by the investigator).

[0315] Subjects who had undergone major surgery (e.g., intrathoracic, abdominal, or vascular surgery that, according to the surgeon's assessment, required up to 4 weeks for postoperative healing) or whose surgical wounds had not yet healed within 4 weeks prior to the first dose of study treatment.

[0316] The subjects had a severe active infection requiring antibiotic treatment.

[0317] Subjects had an active autoimmune disease that required systemic treatment with immunosuppressants / immunomodulators (i.e., corticosteroids, tumor necrosis factor-alpha inhibitors, or other agents) within the past 2 years. The following types of therapy were not considered forms of systemic immunosuppression and were not excluded from the study:

[0318] - Adrenal insufficiency replacement therapy (e.g., physiological doses of corticosteroids).

[0319] - Inhaled steroids.

[0320] Subjects with interstitial lung disease or a history of pneumonia require oral or IV glucocorticoids for management.

[0321] The subjects had a history of solid organ transplantation.

[0322] The subjects had a history of allogeneic bone marrow transplantation.

[0323] Subjects suffered from severe gastrointestinal disorders that resulted in severe malabsorption, required IV nutritional supplementation, or prevented them from taking oral medications.

[0324] Subjects had serious cardiovascular disease, such as New York Heart Association heart disease (Class III or above), myocardial infarction within 6 months prior to randomization, unstable arrhythmia, or unstable angina.

[0325] Subjects have evidence of active hepatitis B or C as defined by the following (hepatitis series tests performed during screening): positive for hepatitis B surface antigen (HepBsAg); or positive for hepatitis C antibody and detectable hepatitis C virus RNA.

[0326] - Subjects who have previously been infected with HBV or whose HBV infection has regressed (defined as having hepatitis B core antibody [anti-HBc] and lacking HBsAg) are eligible.

[0327] - Subjects have a known uncontrolled human immunodeficiency virus (HIV) infection, defined by detectable blood HIV levels and / or CD4 levels below 400.

[0328] Subjects with known controlled HIV (undetectable by PCR) and adherent to highly active antiretroviral therapy (HAART) are eligible. These subjects must continue HAART throughout the study treatment in accordance with local standards.

[0329] Prior / concomitant therapy

[0330] Subjects received >30 Gy of radiation to the lungs within 6 months of the first dose of the study treatment.

[0331] Subjects completed palliative radiotherapy (for brain radiation) within 7 days of the first dose of the study treatment.

[0332] Subjects received treatment with sotorasibu or other KRAS. G12C Prior therapy with inhibitors.

[0333] Subjects who have received anticancer therapy (chemotherapy, antibody therapy (e.g., anti-VEGF antibody bevacizumab), molecularly targeted therapy, hormone therapy, retinoid therapy, or investigational drugs) within the past 2 years, except in the following circumstances:

[0334] - After complete resection of early-stage breast cancer, and with no known active disease for more than 2 years, the subject received or continued to receive anticancer hormone therapy in adjuvant settings, or

[0335] - Subjects had previously received neoadjuvant / adjuvant therapy for NSCLC.

[0336] Subjects used a known cytochrome P450 (CYP) 3A4-sensitive substrate or a P-glycoprotein (P-gp) substrate, both with a narrow therapeutic window, for 14 days prior to Day 1 of Cycle 1. Exemplary CYP3A-sensitive substrates with a narrow therapeutic index include, but are not limited to, alfentanil, fentanyl, cyclosporine, pamoate, dihydroergotamine, quinidine, ergotamine, sirolimus, everolimus, and tacrolimus. Exemplary P-gp substrates with a narrow therapeutic index include, but are not limited to, cyclosporine, sirolimus, digoxin, tacrolimus, everolimus, and vincristine.

[0337] Subjects used strong CYP3A4 inducers (including herbal supplements such as St. John's wort) for 14 days prior to Day 1 of Cycle 1. Examples of strong CYP3A inducers include, but are not limited to, rifampin, mitotane, avamebub, rifapentine, apalutamide, evanibub, phenytoin, carbamazepine, enzalutamide, St. John's wort extract, and rumacato.

[0338] Subjects used a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA) for 7 days prior to Day 1 of the Day 1 cycle.

[0339] Subjects received a live attenuated virus vaccine within 4 weeks of the first dose of the study treatment; vaccines without live virus were permitted.

[0340] Prior / parallel clinical research experience

[0341] Subjects are currently receiving treatment in another investigational device or drug study, or have completed treatment in another investigational device or one or more drug studies less than 4 weeks prior. Other concurrent investigational procedures are excluded from participation in this study.

[0342] Other exclusions

[0343] Subjects have known sensitivities to any product or component to be administered during the course of treatment.

[0344] To the best of the knowledge of the subjects and researchers, subjects may be unable to complete all protocol-required study accesses or procedures and / or comply with all required study procedures (e.g., clinical outcome assessment [COA]).

[0345] The subject has a history or evidence of any other clinically significant obstacle, condition, or disease (other than those outlined above) that, in the opinion of the investigator or medical monitor (if consulted), would pose a risk to the subject's safety or interfere with the evaluation, procedure, or completion of the study.

[0346] Female subjects of reproductive potential who are assessed as having a positive pregnancy test by a highly sensitive urine or serum pregnancy test at screening and / or on day 1 of cycle 1.

[0347] Female subjects of reproductive potential who do not wish to use the protocol-specified method of contraception during treatment with sotorrascib, carboplatin, pemetrexed, and pembrolizumab, and for additional periods of time:

[0348] - 7 days after the last dose of Sotoprazib;

[0349] - 4 months after the last dose of pembrolizumab; and

[0350] - Six months after the last dose of carboplatin and pemetrexed.

[0351] Female participants who plan to become pregnant or donate eggs while receiving treatment with sotoraraxib, carboplatin, pemetrexed, and pembrolizumab, and additionally during the following time periods:

[0352] - 7 days after the last dose of Sotoprazib;

[0353] - 4 months after the last dose of pembrolizumab; and

[0354] - Six months after the last dose of carboplatin and pemetrexed.

[0355] Female subjects who were breastfeeding or planned to breastfeed during the study period up to 7 days after the last dose of sotorasibi, carboplatin, and pemetrexed, and 4 months after the last dose of pembrolizumab.

[0356] Male subjects with fertile female partners who are unwilling to practice sexual abstinence (avoid heterosexual intercourse) or use contraception during treatment with sotorrasib, carboplatin, pemetrexed, and pembrolizumab, and for additional periods of time:

[0357] - 7 days after the last dose of sotoraraxib and pembrolizumab;

[0358] - 3 months after the last dose of pemetrexed; and

[0359] - 6 months after the last dose of carboplatin.

[0360] Male subjects with pregnant partners who were unwilling to abstain from sex or use condoms during treatment with sotorasib, carboplatin, pemetrexed, and pembrolizumab, and additionally during the following periods:

[0361] - 7 days after the last dose of sotoraraxib and pembrolizumab;

[0362] - 3 months after the last dose of pemetrexed; and

[0363] - 6 months after the last dose of carboplatin.

[0364] Male subjects who did not wish to withdraw their sperm donation during treatment with sotoraraxib, carboplatin, pemetrexed, and pembrolizumab, and additionally during the following periods:

[0365] - 7 days after the last dose of sotoraraxib and pembrolizumab;

[0366] - 3 months after the last dose of pemetrexed; and

[0367] - 6 months after the last dose of carboplatin.

[0368] Research Intervention

[0369] The administration and delivery of each treatment are summarized in detail below. The investigational products used during this study were sotorasibride and pembrolizumab.

[0370]

[0371] a Sotorazib will be manufactured and packaged by the trial sponsor and allocated using the sponsor's clinical investigational drug allocation procedure.

[0372] bIf the start of a future cycle is postponed, the ongoing cycle will continue until the next cycle begins. The start of the next cycle begins at the start of any study treatment. Once the next cycle begins, the 21-day cycle duration should be reset and maintained. However, if a dose is paused or missed within a cycle, the missed dose will not be made up and Day 1 of the subsequent cycle should not be adjusted. Additional information regarding the definition and duration of cycles is provided below.

[0373] c Or according to local label / packaging inserts

[0374] The non-investigative products (background therapies) used during this study were carboplatin and pemetrexed, as described below.

[0375]

[0376] AUC5 = Area under the concentration-time curve of 5 mg / mL / min; GFR = Glomerular filtration rate.

[0377] a The carboplatin dose should be calculated using the Calvert formula [Total dose (mg) = (Target AUC) x (GFR + 25)]. If an estimated GFR based on measured serum creatinine is used in the Calvert formula, the GFR used for calculation should not exceed 125 mL / min. Based on a target carboplatin AUC of 5, the maximum carboplatin dose for this study was 750 mg (i.e., AUC 5 mg / mL / min x 150 mL / min).

[0378] b If the start of a future cycle is postponed, the ongoing cycle will continue until the next cycle begins. The start of the next cycle begins at the start of any study treatment. Once the next cycle begins, the 21-day cycle duration should be resumed and maintained. However, if a dose is paused or missed within a cycle, the missed dose will not be made up and day 1 of the subsequent cycle should not be adjusted. Additional information regarding the definition and duration of cycles is provided below.

[0379] c The low-dose folic acid used in the studies ranged from 350 to 1000 μg. The most commonly used oral folic acid dose in clinical studies was 400 μg. At least five daily doses of folic acid must be taken during the 7-day period preceding the first dose of pemetrexed; and should continue throughout the entire treatment course and for 21 days after the last dose of pemetrexed. Folic acid can be administered according to standard care as per the approved local label for pemetrexed.

[0380] dSubjects must receive an intramuscular injection of vitamin B12 (1000 μg) once a week prior to the first dose of pemetrexed and every 9 weeks (± 2 weeks) thereafter. Subsequent vitamin B12 injections may be given on the same day as pemetrexed.

[0381] e Pemetrexed-induced rashes were reported more frequently in subjects who did not receive pretreatment with corticosteroids. Pretreatment with corticosteroids (dexamethasone or equivalents) reduced the incidence and severity of skin reactions. In clinical studies, dexamethasone 4 mg was administered orally twice daily on the day before, the day of, and the day after pemetrexed administration.

[0382] Other therapies required for the treatment plan

[0383] Other treatments required for the regimen may include antiemetic therapy to prevent nausea / vomiting prior to carboplatin administration (NCCN Guidelines, 2022; Multinational Association of Supportive Care in Cancer [MASCC] / ESMO guidelines, Roila et al., 2016), as well as folic acid, vitamin B12, and steroids (dexamethasone or equivalent) administered along with pemetrexed (see above and refer to the approved local label for pemetrexed).

[0384] Treatment period and its definition

[0385] The treatment period will begin on day 1 of cycle 1. Day 1 of cycle 1 will be defined as the first day the subject receives any treatment required for the study. Day 1 of the next cycle will be 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.

[0386] The formulation, dosage, frequency, route of administration, accountability, pre-treatment regimen (if any), dosage preparation, and dosage administration instructions for the research drug are as described above.

[0387] Dosage adjustment

[0388] For sotorasirb, carboplatin, or pemetrexed, a maximum of two dose reductions related to toxicity are permitted. Subjects requiring a third dose reduction of sotorasirb, carboplatin, or pemetrexed will discontinue the drug. Dose reductions for pembrolizumab are not permitted. Toxicity must resolve to ≤ grade 1 or baseline before resumption in subsequent cycles. The rationale for dose modifications and the relationship of toxicity to one or more study agents must be documented in the source documentation. Once a dose is reduced, it may not be increased again.

[0389] If one or more investigational agents are not associated with toxicity, the investigator may continue to use one or more agents at the current dose, assuming that the safety parameters of the agent are within the limits specified in the protocol (e.g., a subject may discontinue chemotherapy while continuing to receive sotorasibi or pembrolizumab alone; similarly, a subject may discontinue sotorasibi or pembrolizumab and continue chemotherapy alone), or suspend the one or more investigational agents until the safety parameters of the agent return to acceptable limits (at which point the non-inducing agent can be restarted at the current dose).

[0390] Chemotherapy and / or sotorasibi can be interrupted for up to 9 weeks; pembrolizumab can be interrupted for up to 12 weeks at a time. If the interruption exceeds the prescribed period, the medication must be permanently discontinued.

[0391] Table 4. Dosage levels of the studied drugs

[0392]

[0393] a For the United States, see LUMAKRAS® US Prescribing Information, Amgen, Thousand Oaks, California, 91320 (revised January 2023), the full text of which is incorporated herein by reference.

[0394] Dose reduction of sotorracib is not permitted. Sotorracib will be discontinued or terminated if the investigator believes the toxicity is attributable to sotorracib and the severity warrants intervention. Guidelines for the suspension and permanent discontinuation of sotorracib are listed in Table 5 below. The reasons for suspension and permanent discontinuation of sotorracib will be recorded on one or more case report forms (CRFs) for each subject.

[0395] Table 5. Guidelines for Sotorasirb Dosage Modifications in Response to Sotorasirb-Related Toxicity

[0396]

[0397] ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.

[0398] a For suspected hepatotoxicity, refer to the rules for stopping and re-triggering hepatotoxicity below.

[0399] bFor hepatotoxicity that does not meet the severity criteria listed in the table (e.g., grade 2 AST or ALT without associated symptoms), consider steroids such as prednisone 1.0 to 2.0 mg / kg / day, dexamethasone equivalent, or methylprednisolone equivalent, followed by gradual tapering over 4 to 6 weeks.

[0400] c Start with a steroid, such as prednisone 1.0 to 2.0 mg / kg / day, an equivalent dose of dexamethasone, or an equivalent dose of methylprednisolone, followed by gradual tapering over 4 to 6 weeks. Gradual tapering may continue while resuming sotorasibel (if criteria for resuming sotorasibel are met).

[0401] d Monitor closely when restarting (e.g., repeat liver function tests after 2 to 3 days, then 3 times a week).

[0402] Carboplatin and Pemetrexed

[0403] Complete blood cell counts, including platelet counts, should be performed on all subjects receiving carboplatin and pemetrexed or these compounds alone.

[0404] Dosage adjustments at the start of subsequent cycles should be based on the lowest hematologic count or maximum nonhematologic toxicity of the previous cycle of therapy.

[0405] Postpone the start of the next cycle of chemotherapy until:

[0406] - Non-hematologic toxicity recovered to grade 0 to 2, and

[0407] - ANC ≥ 1.5 x 10 9 / L, and

[0408] - Platelet count ≥ 100 x 10⁻⁶ 9 / L.

[0409] Table 6 below summarizes recommended dosage modifications for key chemotherapy toxicities.

[0410] Table 6. Dosage modifications for hematologic toxicity of chemotherapy a

[0411]

[0412] ANC = Absolute neutrophil count; ANY = Any value

[0413] a These dosage modifications serve as guidelines and, if more stringent, cannot replace investigator judgment and applicable local labeling recommendations.

[0414] Table 7. Dosage modifications for non-hematologic toxicities of chemotherapy a

[0415]

[0416] CTCAE = Common Terminology Standard for Adverse Events

[0417] a These dosage modifications serve as guidelines and, if more stringent, cannot replace investigator judgment and applicable local labeling recommendations.

[0418] Recurrence of grade 3 or 4 hematologic or non-hematologic toxicity after two dose reductions should lead to discontinuation of the chemotherapy agent causing the toxicity.

[0419] CrCl will be assessed before each cycle using the Cockcroft and Gault formula based on the original weight. If CrCl is less than 45 mL / min, chemotherapy (carboplatin and / or pemetrexed) will not be administered. Pemetrexed and / or platinum may be delayed to allow the subject to recover from toxicity (the therapy interruption period specified above).

[0420] If pemetrexed causes interstitial pneumonia or severe or life-threatening skin toxicity, it should be permanently discontinued. Please refer to the pemetrexed regional prescribing information (e.g., pemetrexed USPI, SmPC; for the United States, see, for example, ALIMTA® US Prescribing Information, Eli Lilly, LLC, Indianapolis, Indiana 46285 (revised August 2022), which is incorporated herein by reference in its entirety).

[0421] Pembrolizumab

[0422] Dosage reduction of pembrolizumab is not permitted.

[0423] Pembrolizumab may be temporarily suspended as needed. Generally, pembrolizumab is suspended for severe (Grade 3) immune-mediated adverse reactions. Pembrolizumab is permanently discontinued in the following cases: life-threatening (Grade 4) immune-mediated adverse reactions, relapsed severe (Grade 3) immune-mediated reactions requiring systemic immunosuppression, or inability to reduce the corticosteroid dose to prednisone ≤ 10 mg / day (or equivalent) within 12 weeks of initiating steroid use. For specific management guidelines for immune-mediated adverse reactions and infusion-related reactions, see KEYTRUDA® regional prescribing information (e.g., KEYTRUDA® USPI, SmPC; for the United States, see KEYTRUDA® US Prescribing Information, Merck, Kennillworth, 07033, NJ (revised March 2023)).

[0424] Rules for the cessation and re-triggering of hepatotoxicity

[0425] This section details the rules regarding drug-induced liver injury. All investigational agents in this protocol (sottorazib, carboplatin, pemetrexed, and pembrolizumab) are known to cause elevations in liver enzymes. Investigators should carefully identify the causative agent in order to administer appropriate intervention. Guidelines for the management of subjects with elevated AST, ALT, or alkaline phosphatase (ALP) associated with sotoprazib, carboplatin, and / or pemetrexed or pembrolizumab are provided above.

[0426] Subjects with abnormal liver laboratory values ​​(i.e., alkaline phosphatase [ALP], aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]), and / or international normalized ratio (INR) and / or signs / symptoms of hepatitis (described below) may meet the criteria for suspending or permanently discontinuing other therapies required for the investigational product or protocol, as stated in Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 (US FDA, 2009).

[0427] Criteria for suspending and / or permanently discontinuing investigational products and protocols due to potential hepatotoxicity and requiring other therapies:

[0428] The following discontinuation and / or suspension rules apply to subjects for whom other causes of changes in liver biomarkers (TBL, INR, and transaminases) have not yet been identified. Important alternative causes of elevated AST / ALT and / or TBL values ​​include, but are not limited to:

[0429] - Hepatobiliary tract diseases

[0430] - Viral hepatitis (e.g., hepatitis A / B / C / D / E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus)

[0431] - Right-sided heart failure, low blood pressure, or any hypoxic cause leading to liver ischemia.

[0432] - Exposure to hepatotoxic agents / drugs or hepatotoxins, including herbs and dietary supplements, plants and mushrooms.

[0433] - Genetic disorders that lead to impaired glucuronidation (e.g., Gilbert syndrome, Krieger-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir).

[0434] - α-1 antitrypsin deficiency

[0435] - Alcoholic hepatitis

[0436] - Autoimmune hepatitis

[0437] - Wilson's disease and hemochromatosis

[0438] - Nonalcoholic fatty liver disease, including steatohepatitis

[0439] - Non-hepatic causes (e.g., rhabdomyolysis, hemolysis)

[0440] If one or more investigational products are suspended, subjects should be followed up for possible drug-induced liver injury (DILI) in accordance with the recommendations in the last part of this appendix.

[0441] If an alternative cause is found for elevated liver test results (ALT, AST, ALP) and / or TBL, and the laboratory abnormalities subside to normal or baseline, re-stimulation can be considered.

[0442] Table 8. Conditions for Suspension and / or Permanent Discontinuation of Investigational Products and Protocols Due to Potential Hepatotoxicity and Requirement of Other Therapies

[0443]

[0444] ALP = Alkaline phosphatase; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; INR = International Normalized Ratio; TBL = Total bilirubin; ULN = Upper Limit of Normal

[0445] Reactivation criteria for investigational products and protocols following potential hepatotoxicity:

[0446] The decision to re-stimulate a subject will be discussed and agreed upon by the subject, researcher, and medical monitor. If signs or symptoms recur with re-stimulation, other treatments required for the investigational product and protocol (as appropriate) will be permanently discontinued. Subjects who clearly meet the criteria for permanent discontinuation (as described in Table 8) will never be re-stimulated.

[0447] Evaluation criteria for response to solid tumors, version 1.1 (RECIST v1.1) (Eisenhauer et al., 2009; Schwartz et al., 2016; Therasse et al., 2000).

[0448] definition:

[0449] Measurable diseases

[0450] The presence of at least one measurable lesion is required. If the measurable lesion is limited to a single lesion, its tumor nature should be confirmed by cytology / histology.

[0451] Measurable lesions

[0452] Measurable non-nodular tumor lesions

[0453] Well-defined, non-nodular lesions that can be accurately measured in at least one dimension using computed tomography (CT) / magnetic resonance imaging (MRI) scans, with a maximum diameter ≥ 10 mm and a slice thickness not exceeding 5 mm. When the slice thickness is greater than 5 mm, the minimum measurable lesion size should be twice the slice thickness.

[0454] nodular lesions

[0455] When assessed by CT / MRI, lymph nodes are considered measurable if their short axis is ≥ 15 mm (slice thickness is recommended not to exceed 5 mm). Only the short axis will be measured and tracked at baseline and follow-up (Schwartz et al., 2009).

[0456] cystic lesions

[0457] If cystic lesions representing cystic metastases are considered to meet the definition of measurability described above for non-nodular lesions, then they can be considered measurable lesions.

[0458] Bone lesions with identifiable soft tissue components

[0459] If the soft tissue components meet the definition of measurability described above for non-nodular lesions, then a bone lesion with identifiable soft tissue components that can be evaluated by cross-sectional imaging techniques (such as CT or MRI) can be considered a measurable lesion.

[0460] lesions measured clinically

[0461] A lesion is considered measurable if the longest diameter of a non-nodule is ≥ 10 mm or the shortest diameter of a lymph node is ≥ 15 mm. For greater accuracy, the lesion should be measured radiographically; otherwise, it can be measured with calipers.

[0462] Irradiation lesions

[0463] Unless measurable progression has been demonstrated in the lesion prior to enrollment, tumor lesions located in previously irradiated areas or areas that have undergone other local therapies are not measurable.

[0464] Unmeasurable lesions

[0465] All other lesions, including small lesions (pathological lymph nodes with a longest diameter < 10 mm or a short axis of ≥ 10 mm to < 15 mm, where the CT scan section thickness is no greater than 5 mm), are considered unmeasurable. (When the section thickness is greater than 5 mm, the minimum size of a measurable lesion should be twice the section thickness).

[0466] Other examples of lesions that are typically considered unmeasurable include:

[0467] Lesions treated with prior local therapy: Unless lesion progression has been demonstrated, tumor lesions located in previously irradiated areas or areas that have undergone other local therapies should not be considered measurable.

[0468] Specifically, small lesion clusters, bone lesions without soft tissue components, inflammatory breast disease, ascites, pleural / pericardial effusion, cutaneous lymphangitis / pneumonia, and pia mater diseases are unmeasurable.

[0469] Measurement methods

[0470] All measurements should be performed and recorded using a ruler or calipers in metric notation. The same assessment methods and techniques should be used to characterize each identified and reported lesion at baseline and throughout the trial. Unless one or more lesions being tracked are not imageable but can be assessed by clinical examination, imaging-based assessment is preferred for evaluations performed by clinical examination. Clinical lesions (e.g., skin nodules) will be assessed using calipers. In the case of skin lesions, recording by color photography is recommended, including estimating lesion size with a ruler.

[0471] CT / MRI

[0472] Contrast-enhanced CT or MRI should be used to evaluate all lesions. Optimal visualization and measurement of solid tumor metastases require consistent intravenous (IV) contrast agent administration (dose and rate) and scan time. CT and MRI should be performed on serial slices ≤ 5 mm thick. The longest diameter of the selected lesion should be measured in the plane of image acquisition. Ideally, the same scanner or at least the same type of scanner should be used, and the image acquisition protocol should follow the previous scans as closely as possible.

[0473] PET-CT

[0474] Currently, the low-dose or attenuation-corrected CT portion of a combined PET-CT scan does not always possess optimal diagnostic CT quality for RECIST measurements. However, if a site can record a CT scan performed as part of a PET-CT scan with the same diagnostic quality as a diagnostic CT scan (using IV and oral contrast agents), the CT portion of the PET-CT scan can be used for RECIST measurements and can be used interchangeably with a regular CT scan for accurate measurement of cancerous lesions over time. However, it should be noted that the PET portion of the CT scan introduces additional data, which can introduce bias into the researcher's work if it is not performed routinely or continuously.

[0475] ultrasound

[0476] Ultrasound cannot be used to assess lesion size and should not be used as a measurement method. Ultrasound examinations cannot be fully replicated for independent review later, and because they are operator-dependent, there is no guarantee that the same techniques and measurements will be used from one assessment to the next. If a new lesion is identified by ultrasound during the investigation, confirmation by CT or MRI is recommended. If there are concerns about radiation exposure from CT, MRI can be used instead of CT in selected cases.

[0477] Endoscopic examination, laparoscopic examination

[0478] These techniques are not recommended for objective tumor evaluation. However, when a biopsy is obtained, such techniques may be used to confirm complete pathological remission or to determine recurrence in trials where complete remission (CR) or recurrence after surgical resection is the endpoint.

[0479] Tumor markers

[0480] Tumor markers cannot be used alone to assess remission. If a marker is initially above the upper limit of normal, it must be normalized in a subject with radiographic CR before the subject can be considered as having CR.

[0481] Cytology, Histology

[0482] If needed, these techniques can be used to differentiate between PR and CR in very rare cases, such as residual lesions in tumor types (e.g., germ cell tumors) where known residual benign tumors may remain.

[0483] When exudate is known to be a potential adverse reaction to treatment (e.g., the use of certain taxane compounds or angiogenesis inhibitors), cytological confirmation of the tumor origin of any exudate that appears or worsens during treatment may be considered if measurable tumors meet the criteria for remission or disease stabilization used to differentiate between remission (or disease stabilization) and disease progression.

[0484] FDG-PET

[0485] While fluorodeoxyglucose-positron emission tomography (FDG-PET) remission assessment requires additional research, it is sometimes reasonable to incorporate FDG-PET scans to supplement CT scans when assessing progression, especially potential “new” disease. New lesions based on FDG-PET imaging can be identified using the following algorithms:

[0486] A negative FDG-PET at baseline followed by a positive FDG-PET at follow-up is an indication of disease progression based on new lesions.

[0487] No FDG-PET at baseline, but positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new lesion site confirmed by CT, this indicates disease progression. If the positive FDG-PET at follow-up is not confirmed as a new lesion site on CT, an additional follow-up CT scan is required to determine if the site has actually progressed (if so, the date of disease progression will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing lesion site on CT (based on no progression on anatomical images), this does not indicate disease progression.

[0488] In cases where residual radiographic abnormalities are thought to represent fibrosis or scarring, FDG-PET can be used to upgrade remission to complete remission (CR) in a manner similar to a biopsy.

[0489] Note: "Positive" FDG-PET scan lesions refer to lesions with abundant FDG on attenuation-corrected images, where the FDG uptake is more than twice that of the surrounding tissue.

[0490] Lesion evaluation

[0491] Baseline records of “target” and “non-target” lesions

[0492] target lesions

[0493] All measurable lesions (up to two lesions per organ, and a total of five lesions representing all affected organs) should be identified as target lesions and recorded and measured at baseline.

[0494] Target lesions should be selected based on their size (the lesion with the longest diameter) and the suitability for accurate and repeatable measurements. All other measurable lesions will be tracked as non-target lesions.

[0495] A lymph node is considered an organ, so a maximum of two measurable lymph nodes can be identified as a target lesion.

[0496] Calculate the sum of the diameters of all target lesions (longest diameter of non-nodular lesions, short axis of nodular lesions) and report it as the baseline sum of diameters. Use the baseline sum of diameters as a reference to characterize objective tumor response.

[0497] Non-target lesions

[0498] All other lesions (or disease sites), including pathological lymph nodes, should be identified as non-target lesions and should be documented at baseline. Throughout the study, these lesions should be tracked as "present," "missing," "clearly progressive," or "not evaluable" (NE). Alternatively, multiple non-target lesions involving 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").

[0499] Table 9. Remission Criteria. Evaluation of Target Lesions.

[0500]

[0501] Table 10. Remission Criteria. Evaluation of Non-Target Lesions.

[0502]

[0503] a For a "definite progression" to be achieved on the basis of non-target disease, there must be an overall level of substantial worsening in the non-target disease, such that even if the target disease has SD or PR, the overall tumor burden has increased sufficiently to warrant discontinuation of therapy. A modest "increase" in the size of one or more non-target lesions is generally insufficient to qualify as a definitive progression.

[0504] Evaluation of best overall remission

[0505] Optimal response allocation for subjects will depend on the discovery of both target and non-target diseases, and will also take into account the occurrence of new lesions. BOR will be based on all post-baseline disease assessments prior to the initiation of subsequent anticancer therapy. Subjects must be free of radiological disease progression for at least 5 weeks from day 1 of cycle 1 to meet the minimum criteria for SD duration, thus allocating BOR for SD. Generally, subjects who cannot be classified into the RECIST v1.1 response category due to insufficient data or premature death will be classified as NE for BOR, but will be included in the denominator of all response rate calculations.

[0506] Table 11. Overall Relief at Different Time Points

[0507]

[0508] a For a "definite progression" to be achieved on the basis of non-target disease, there must be an overall level of substantial worsening in the non-target disease, such that even if the target disease has SD or PR, the overall tumor burden has increased sufficiently to warrant discontinuation of therapy. A modest "increase" in the size of one or more non-target lesions is generally insufficient to qualify as a definitive progression.

[0509] Table 12. Optimal overall response when complete response (CR) and partial response (PR) need to be confirmed.

[0510]

[0511] CR = Complete remission; PD = Disease progression; PR = Partial remission; NE = Not evaluable; SD = Stable disease.

[0512] a If complete remission (CR) is indeed achieved at the first time point, any disease at subsequent time points (see the confirmation section below for details on timing), even if it meets the partial remission (PR) criteria relative to baseline, will be considered a progressive disease (PD) at that point (because the disease must have reappeared after CR). The optimal response will depend on the shortest duration of stable disease (SD). However, a "CR" may sometimes be claimed when subsequent scans show that small lesions may still exist, and the subject actually had PR rather than CR at the first time point. In these cases, the original CR should be changed to PR, and the optimal response is PR.

[0513] Special Notes on Mitigation Assessment

[0514] Target lesions become “too small to measure” – In studies, all lesions (nodules and non-nodules) recorded at baseline should be measured at each subsequent evaluation, even if they are very small (e.g., 2 mm). However, sometimes lesions or lymph nodes recorded as target lesions at baseline become so faint on CT scans that radiologists may feel uncomfortable assigning precise measurements and may report them as “too small to measure.” When this occurs, it is important to record a value on the case report form. If the radiologist believes that a non-lymph node lesion may have disappeared, the measurement should be recorded as 0 mm. If the lesion is believed 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 apply to lymph nodes, as they typically have a definable size under normal conditions and are often surrounded by fat, such as in the retroperitoneal space; however, if a lymph node is considered present and faintly visible but too small to be measured, a default value of 5 mm should also be assigned in that case.) This default value is derived from a 5 mm CT slice thickness (but should not be changed with variations in CT slice thickness). Measurements of these lesions may be non-reproducible, so providing this default value will prevent erroneous remissions or progressions based on measurement errors. However, it should be reiterated that if the radiologist can provide an accurate measurement, even if it is less than 5 mm, it should be recorded.

[0515] New lesions – The term “new lesion” always refers to a newly discovered finding that is definitively a tumor. If a new lesion is identified by a modality other than CT or MRI, CT or MRI confirmation is recommended unless the new lesion is definitively identified as a tumor. New findings that are not necessarily tumors but may be benign (infection, inflammation, etc.) are not selected as new lesions until review determines that they represent a tumor.

[0516] If the new lesion is unclear (e.g., due to its small size), continued treatment and follow-up evaluation will clarify whether it represents a truly new disease. If additional imaging confirms the presence of a new lesion, the date of the initial scan should be used to declare progress.

[0517] Lesions at anatomically located sites identified in follow-up studies (not scanned at baseline) are considered new lesions and will indicate disease progression, regardless of any remissions that may be seen from target or non-target lesions present at baseline.

[0518] According to the protocol, no local treatments are permitted.

[0519] Any subject receiving local therapy to one or more target lesions selected when the protocol does not allow for a direct impact on baseline will be considered non-evaluable in all disease assessments occurring on or after the date of local therapy, except for disease progression. However, if the lesion is completely removed pathologically, the subject's response may still be evaluated, and a size of 0 will be reported.

[0520] If a non-target lesion is treated locally, the lesion will always be assessed as present unless the pathology is benign.

[0521] For split or merged lesions during treatment – ​​when a non-nodular lesion “fragments,” the longest diameters of the fragmented portions should be summed to calculate the total target lesion and identify fragments of the original lesion. Similarly, when lesions merge, maintaining the plane between them can help obtain the maximum diameter measurement for each individual lesion. If the lesions have indeed merged to the point that they are no longer separable, in this case, the vector of longest diameters should be the maximum longest diameter of the “merged lesions.”

[0522] "Symptom worsening" does not in itself meet the requirement of objective progression. If objective progression was not previously recorded, every effort should be made to record it even after treatment has been discontinued.

[0523] In some cases, it may be difficult to distinguish residual disease from scars or normal tissue. When the evaluation of CR depends on this determination, further investigation of residual lesions via fine-needle aspiration / biopsy or FDG-PET is recommended to confirm the CR status.

[0524] If a lesion disappears and then reappears at a subsequent time point, measurements should continue. However, at the time point of lesion reappearance, the subject's response will depend on the status of his / her other lesions. For example, if a subject's tumor has reached CR and the lesion reappears, the subject will be considered PD at the time of reappearance. In contrast, if the tumor status is PR or SD, and one lesion that has disappeared subsequently reappears, its largest diameter should be added to the sum of the remaining lesions to obtain the calculated response: in other words, the reappearance of a single lesion that has clearly "disappeared" among many remaining lesions is not sufficient on its own to meet the requirements of PD; the sum of all lesions must meet the PD criteria.

[0525] Confirmed measurement of relief / duration

[0526] Confirmation of CR and PR is required and must be performed no less than 4 weeks after the initial recording of CR or PR. If CR is pending confirmation and specified in an assessment, followed by one or more NE and / or PR assessments, resulting in target lesion remission of CR and non-target lesion remission of NE, then CR can be confirmed if non-target lesion remission subsequently returns to CR. Similarly, if PR is pending confirmation and specified in an assessment, followed by one or more NE and / or SD assessments, then PR can be confirmed. Subsequent target lesion remission after CR is limited to CR, PD, or NE; target lymph node PD is only satisfied if any lymph node target lesion reaches a short-axis measurement of ≥ 15 mm.

[0527] Neuro-oncology Brain Metastasis Response Assessment (RANO-BM) Criteria

[0528] This study will include an exploratory analysis of intracranial PFS according to the BICR Neuro-oncology Brain Metastasis Response Assessment (RANO-BM) criteria (Lin et al., 2015). RANO-BM is an extension of the Remission Assessment Criteria for Solid Tumors in High-Grade Gliomas (RECIST) 1.1 (Eisenhauer et al., 2009) and the Remission Assessment Criteria for Neuro-oncology (RANO) (Wen et al., 2010).

[0529] definition

[0530] Measurable central nervous system (CNS) disease is defined as contrast-enhanced CNS lesions that can be accurately measured in at least one dimension (minimum size 10 mm) and are visible on two or more axial sections, preferably spaced 5 mm or less with 0 mm skips (and ideally spaced ≤ 1.5 mm with 0 mm skips).

[0531] - The diameter of the longest diameter perpendicular to the measurement plane must be at least 5 mm for CNS lesions to be considered measurable.

[0532] - When there is more than one measurable CNS lesion at baseline, all CNS lesions (up to 5) should be recorded and measured at baseline.

[0533] - If CNS lesions ≥ 5 mm but < 10 mm are considered measurable, they should be measured using magnetic resonance imaging (MRI) with a slice thickness of 1.5 mm or less. Any CNS lesion with a longest diameter < 10 mm should be considered as unchanged relative to baseline unless the longest diameter measured shows a change of at least 3 mm.

[0534] Unmeasurable CNS lesions include all other CNS lesions, including lesions with a maximum size < 10 mm, lesions with unmeasurable borders, dural metastases, bony skull metastases, and cystic lesions only.

[0535] Measurement methods

[0536] Lesion measurement: The maximum diameter of the selected lesion should be measured on the plane in which the image is acquired.

[0537] Assessment methods: The same assessment methods and techniques should be used to characterize each identified and reported lesion at baseline and throughout the trial.

[0538] MRI: Gadolinium-enhanced MRI should be used to evaluate all CNS lesions. If MRI is contraindicated or unavailable, computed tomography (CT) with or without contrast agent may be performed.

[0539] CNS target lesion remission assessment

[0540]

[0541] For merged lesions, maintaining the plane between them can help obtain the maximum longest diameter of each individual lesion. If the lesions have merged and are no longer separable, then the vector of the longest diameter should be the maximum longest diameter, which in this case should be the maximum longest diameter of the merged lesions.

[0542] New CNS lesions not present in prior scans should be clearly identified and not due to technical or slide changes.

[0543] Each radiographic evaluation should include at least a qualitative assessment of non-target lesions.

[0544] Assessment of response to non-target lesions

[0545]

[0546] The CNS and non-CNS areas will be evaluated separately as follows:

[0547]

[0548] For the assessment of overall progression-free survival, the criteria for progression-free survival are met if progression occurs in one or two compartments. Subjects experiencing isolated CNS progression may be eligible to remain in the study after local therapy (e.g., whole-brain radiotherapy, stereotactic radiosurgery, or surgery).

[0549] Eastern Cooperative Oncology Group (ECOG) Performance Status

[0550]

[0551] ECOG = Eastern Cooperative Oncology Group

[0552] Source: Oken et al., 1982.

[0553] Calculate creatinine clearance rate

[0554] For the purposes of this protocol, the creatinine clearance rate is calculated as follows:

[0555] The original weight-based Cockcroft and Gault formula (see Cockcroft et al., 1976)

[0556] For men

[0557]

[0558] For women

[0559]

[0560] References:

[0561] Addeo, et al. Cancer Treat. Rev. 2021; 96(102179): 1-10.

[0562] Ahn, et al. J. Thorac. Oncol. 2016; 11(4): S115.

[0563] Amin, et al., eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.

[0564] ALIMTA® US Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revision 08 / 2022).

[0565] ALIMTA® U.S. Prescribing Information, Lilly USA, LLC, Indianapolis,Indiana 46285 (as approved August 19, 2004), available at https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2004 / 021677lbl.pdf, lastaccessed March 30, 2023.

[0566] Besse, et al. Annals of Oncology 2014; 25:1475-1484.

[0567] Blank, et al. Cancer Immunol. Immunother. 2007; 56(5):739-745.

[0568] Butte, et al. Immunity 2007; 27(1):111-122.

[0569] Calvert, et al. J. Clin. Oncol. 1989; 7:1748-1756.

[0570] Canon, et al. Nature 2019; 575(7781), 217.

[0571] CARBOplatin Injection, U.S. Prescribing Information, Fresenius KABI,Lake Zurich, Illinois, 60047 (revision 5 / 2021).

[0572] Cerami, et al. Cancer Discov. 2012;2(5):401-404.

[0573] Cockcroft, Gault, Nephron. 1976; 16:31-41.

[0574] CodeBreaK 101, ClinicalTrials.gov identifier: NCT04185883, https: / / clinicaltrials.gov / ct2 / show / NCT04185883, last accessed March 27, 2023.

[0575] Dong, et al. Nat. Med. 1999; 5(12): 1365-1369.

[0576] Eisenhauer, et al., Eur. J. Cancer 2009 45:228-247.

[0577] ESMO Clinical Practice Guidelines – metastatic NSCLC. UpdatedSeptember 2020, originally published Ann Oncol. 2018;29 (suppl 4):iv192-iv237https: / / www.esmo.org / guidelines / lung-and-chest-tumours / clinical-practice-living-guidelines-metastatic-non-small-cell-lung-cancer.

[0578] Gadgeel, et al. Ann. Oncol. 2019; 30(11). Late-breaking abstract 5.

[0579] Gadgeel, et al. J. Clin. Oncol. 2020; 38(14):1505-1517.

[0580] Gandhi, et al. N. Engl. J. Med. 2018; 378(22):2078-2092.

[0581] Gao, et al. Sci. Signal. 2013;6(269):pl1, pages 1-19.

[0582] Gibbons, et al. J. Thorac. Oncol. 2016; 11(4):S79.

[0583] GLOBOCAN 2020 – Lung. Available at http: / / gco.iarc.fr / today / home.Last accessed March 2022.

[0584] Gogishvili, et al. Nat. Med., 2022; 28:2374-2380.

[0585] Hendriks, et al. Ann. Oncol. 2023a. doi: https: / / doi.org / 10.1016 / j.annonc.2022.12.009.

[0586] Hendriks, et al. Ann. Oncol. 2023b. doi: https: / / doi.org / 10.1016 / j.annonc.2022.12.013.

[0587] Herbst, et al. Ann. Oncol. 2019; 30(11). Late-breaking abstract 4.

[0588] Hong, et al. N. Engl. J. Med. 2020; 383:1207-1217.

[0589] Janes et al. Cell. 2018; 172(3):578-589.

[0590] Jeanson, et al. J. Thorac. Oncol. 2019; 14(6):1095-1101.

[0591] Keir, et al. Annu. Rev. Immunol. 2008; 26:677-704.

[0592] KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ07033 (revision 3 / 2023).

[0593] Kris, et al. J. Clin. Oncol. 2017; 35(25):2960-2974.

[0594] Langer, et al. Lancet Oncol. 2016; 17(11):1497-1508.

[0595] Lanman, et al. J. Med. Chem. 2020; 63(1):52-65.

[0596] Lin, et al. Lancet Oncol. 2015; 16(6):e270-e278.

[0597] LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks,California, 91320 (revision 01 / 2023).

[0598] Massard, et al. J. Clin. Oncol. 2016; 34(26):3119-3125.

[0599] National Cancer Institute Common Terminology Criteria for AdverseEvents v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National CancerInstitute

[0600] National Comprehensive Cancer Network. NCCN clinical practiceguidelines in oncology: non-small cell lung cancer. Version 3.2022, availableat https: / / www.nccn.org / .

[0601] Oken, et al. Am J Clin Oncol. 1982; 5(6):649-655.

[0602] Ostrem, et al. Nature. 2013; 503:548-551.

[0603] Ostrem and Shokat. Nature Rev Drug Discov. 2016; 15(11):771-785.

[0604] Patricelli, et al. Cancer Discovery. 2016; 6:316-329.

[0605] Paz-Ares, et al. N. Engl. J. Med. 2018; 379:2040-2051.

[0606] 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, lastaccessed March 31, 2023.

[0607] Reck, et al. J. Clin. Oncol. 2019; 37(7):537-546.

[0608] Ribas, et al. N. Eng. J. Med., 2013; 368(14):1365-1366

[0609] Rini, et al. N. Engl. J. Med., 2019; 380:1116-1127.

[0610] Rodríguez-Abreu et al. Ann. Oncol. 2021 Jul;32(7):881-895.

[0611] Roila, et al. Ann. Oncol. 2016; 27(5):v119v133

[0612] Sezer, et al. Lancet 2021; 397(10274):592604.

[0613] Schwartz, et al. Time. J. Cancer. 2016; 62:132-137.

[0614] Schwartz, et al. Eur. J. Cancer. 2009; 45:261-267.

[0615] Surveillance, Epidemiology, and End Results (SEER) Program(www.seer.cancer.gov) SEER Stat Database: Incidence - SEER Research Data, 17Registries, Nov 2021 Sub (2000-2019) - Linked To County Attributes - TimeDependent (1990-2019) Income / Rurality, 1969-2020 Counties, National CancerInstitute, DCCPS, Surveillance Research Program, released April 2022, basedon the November 2021 submission. Kaplan-Meier, Ederer II Method. Lastaccessed May 5, 2022.

[0616] Simanshu, et al. Cell. 2017; 170:17-33.

[0617] Therasse, et al. J. Natl. Cancer Inst. 2000; 92(3):205-16.

[0618] VENTANA PD-L1 (SP263) Assay, Instructions 2021-10-10, 1020514US Rev1, 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.

[0619] Wen, et al. J. Clin. Oncol. 2010; 28:1963-1972.

[0620] World Health Organization. 2020 Statistics. https: / / www.who.int / news-room / fact-sheets / detail / cancer. Last accessed March 2022.

[0621] Yang, et al. J. Thorac. Oncol. 2019; 14(3):553-559.

Claims

1. A method for treating cancer containing a KRAS G12C mutation in a subject of need, the method comprising: The subject was administered (a) a first regimen comprising (i) a therapeutically effective amount of sotorasiib, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed; And then administer (b) the second regimen, which comprises (i) a therapeutically effective amount of sotorasibo and (ii) a therapeutically effective amount of pemetrexed.

2. The method of claim 1, wherein the application of the first scheme lasts for a period of 4 cycles.

3. The method of claim 2, wherein each cycle is a 21-day period.

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

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

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

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

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

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

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

11. The method of any one of claims 1 to 10, wherein the therapeutically effective amount of carboplatin is the amount corresponding to 5 mg / (mL x min) (AUC 5) multiplied by an increase of 25 mL / min in the subject's glomerular filtration rate (GFR) in mL / min.

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

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

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

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

16. The method of any one of claims 1 to 15, wherein the therapeutically effective dose of pemetrexed is 500 mg / m². 2 .

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

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

19. The method of any one of claims 1 to 18, wherein the pemetrexed is administered at 21-day intervals during the first and second regimens.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

35. The method of any one of claims 1 to 34, wherein the subject’s creatinine clearance (CrCl) is equal to or greater than 45 mL / min, as calculated by the Cockcroft-Gault formula.

36. The method of any one of claims 1 to 35, wherein the subject has an ECOG fitness level of 0 or 1.

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

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

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

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

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

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

43. The method of any one of claims 1 to 42, wherein the cancer does not contain EGFR or ALK alterations.

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

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

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

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

48. The method of any one of claims 1 to 47, wherein no antibody is administered to the patient concurrently.

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

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

Images