Cancer treatment using prmt5 inhibitors in collaboration with mta

Abstract

Described herein are methods of treating MTAP-null lung cancer in a patient, comprising administering to the patient a PRMT5 inhibitor and an anti-PD1 antibody, optionally in combination with carboplatin and paclitaxel or pemetrexed. Further described herein are methods of treating MTAP-null cancer in a patient also having brain metastases, comprising administering to the patient a PRMT5 inhibitor.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to each of U.S. Provisional Patent Application No. 63 / 570,037, filed March 26, 2024, and U.S. Provisional Patent Application No. 63 / 569,967, filed March 26, 2024. Background Technology

[0003] Epigenetic regulation of gene expression is a crucial biological determinant of protein production and cell differentiation, and plays a significant pathogenic role in many human diseases. Epigenetic regulation involves heritable modifications of genetic material without altering its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modifications (e.g., methylation) of DNA and proteins (e.g., histones), which control conformational transitions between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., PRMT5), many of which are associated with specific genetic alterations that can cause human diseases. PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders.

[0004] Homozygous loss of tumor suppressor genes is a key driver in cancer, often leading to the incidental loss of passenger genes located in the genome adjacent to the tumor suppressor. The loss of these passenger genes can create therapeutically vulnerable vulnerabilities specific to tumor cells. Homozygous loss of the chromosome 9p21 locus (carrying the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A)) occurs in 15% of all tumors and typically includes the passenger gene MTAP (methionine phosphorylase, a key enzyme in the methionine and adenine rescue pathway). MTAP loss leads to the accumulation of its substrate, methionine (MTA). MTA shares close structural similarity with S-adenosylmethionine (SAM) (the methyl donor substrate of the type II methyltransferase PRMT5). Elevated MTA levels driven by MTAP loss selectively compete with SAM for binding to PRMT5, leaving the methyltransferase in a suballelic state, vulnerable to further PRMT5 inhibition. Multiple genome-wide drop-outscreening in large tumor cell lines has identified a strong correlation between MTAP loss and cell line dependence on PRMT5, further highlighting the intensity of this metabolic deficit. However, PRMT5 is a known cellular essential gene, and conditional PRMT5 knockout and siRNA knockdown studies have shown that significant burdens (e.g., pancytopenia, infertility, skeletal muscle loss, cardiac hypertrophy, etc.) may be associated with PRMT5 inhibition in normal tissues. Therefore, novel strategies are needed to exploit this metabolic deficit and preferentially target PRMT5 in MTAP-null tumors without impairing PRMT5 in normal tissues (MTAP WT). Targeting PRMT5 with a small molecule inhibitor that works in conjunction with MTA can preferentially target the MTA-binding state of PRMT5 enriched in MTAP-null tumor cells, while providing an improved therapeutic index beyond that of normal cells (where MTAP is intact and MTA levels are low). Summary of the Invention

[0005] In one respect, this article describes a method for treating MTAP-resistant cancers in patients in need, comprising administering to the patient a therapeutically effective amount of each of the following: (a) Compound G: (G), or a pharmaceutically acceptable salt thereof; and (b) anti-PD1 antibody.

[0006] In some embodiments, the MTAP-ineffective cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC)). In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the method described herein further includes administering carboplatin to the patient. In some embodiments, the method described herein further includes administering paclitaxel to the patient. In various embodiments, the method described herein further includes administering paclitaxel and carboplatin to the patient. In some embodiments, the method described herein further includes administering pemetrexed to the patient. In various embodiments, the method described herein further includes administering pemetrexed and carboplatin to the patient. In some embodiments, the method described herein includes administering (a) compound G and (b) pembrolizumab to the patient. In some embodiments, the method described herein includes administering (a) compound G, (b) carboplatin, (c) paclitaxel, and (d) pembrolizumab to the patient. In some embodiments, the method described herein includes administering (a) compound G, (b) carboplatin, (c) pemetrexed, and (d) pembrolizumab to the patient.

[0007] In another aspect, this article describes methods for treating patients with MTAP-resistant cancer and brain metastases, which involve administering compound G to the patient: (G), or a pharmaceutically acceptable salt thereof. In some embodiments, MTAP-resistant cancer is lung cancer. In some embodiments, lung cancer is NSCLC. In some embodiments, NSCLC is locally advanced. In some cases, NSCLC is metastatic. In some embodiments, brain metastases are active, previously untreated brain metastases. In some cases, compound G is administered to the patient as a single therapy. Detailed Implementation

[0008] This disclosure provides information on the therapeutically effective administration of compound G to patients in need: (G), or a pharmaceutically acceptable salt thereof, to treat patients with MTAP-ineffective cancers (e.g., lung cancer (e.g., non-small cell lung cancer)).

[0009] The methods disclosed herein may further include administering a therapeutically effective amount of an anti-programmed death 1 (PD1) antibody (e.g., pembrolizumab) to a patient. In some cases, these methods further include administering a therapeutically effective amount of an anti-PD1 antibody (e.g., pembrolizumab) and one or more additional therapeutic agents to a patient. A “therapeutically effective amount” for a compound disclosed herein (e.g., compound G) means an amount that effectively treats existing symptoms in a patient being treated, or prevents the development of existing symptoms, or alleviates existing symptoms. Therefore, in several aspects, this disclosure provides methods for treating MTAP-ineffective cancers in patients, methods comprising administering a therapeutically effective amount of each of the following: (a) Compound G: (G), or a pharmaceutically acceptable salt thereof; and (b) an anti-programmed death 1 (PD1) antibody.

[0010] In some cases, compound G is administered to patients with brain metastases. The term “brain metastasis” refers to cancer that has spread from the original (primary, non-brain) tumor to the brain. Brain metastases are common in NSCLC patients, occurring in approximately 25% of patients. However, patients with brain metastases are often excluded from clinical trials due to concerns about poor functional status, increased risk of toxicity, poor prognosis, and shorter life expectancy. However, preclinical evidence based on in vivo rat pharmacokinetic studies suggests CNS penetrance of compound G. Therefore, NSCLC patients with homozygous MTAP-deficient and active brain metastases may benefit from therapy with compound G. Active brain metastases can be assessed by the presence of intracranial lesions. It should be understood that although “metastasis” is plural, a patient exhibiting only one intracranial lesion is also considered to have “active brain metastases” according to the criteria below. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion > 5 mm. In some embodiments, a patient with active brain metastases has at least one measurable intracranial lesion > 5 mm but < 10 mm. In some embodiments, patients with active brain metastases have at least one measurable intracranial lesion > 10 mm. See the National Cancer Institute Common Terminology Standards for Adverse Events v5.0 (NCI CTCAE), published November 27, 2017, which is incorporated herein by reference in its entirety. Also see Neuro-oncology Brain Metastasis Response Assessment (RANO-BM) (Lin et al., 2015). RANO-BM is an extension of the response assessment criteria for Remission Assessment of Solid Tumors for High-Grade Gliomas (RECIST) 1.1 (Eisenhauer et al., 2009) and Neuro-oncology Response Assessment (RANO) (Wen et al., J. Clin. Oncol. [Journal of Clinical Oncology], 28:1963-1972, 2010). Therefore, in several aspects, this disclosure provides methods for treating patients with MTAP-resistant cancer and brain metastases, methods comprising administering to the patient a therapeutically effective amount of compound G: (G), or a pharmaceutically acceptable salt thereof. In some cases, the brain metastases are active, previously untreated brain metastases. In some cases, compound G or a pharmaceutically acceptable salt thereof is administered as a monotherapy to patients with MTAP-resistant cancer and brain metastases.

[0011] Compound G was also provided: (G), or a pharmaceutically acceptable salt thereof, is used in the preparation of a medicament for treating patients with MTAP-ineffective cancer and brain metastases.

[0012] Compound G was also provided: (G), or a pharmaceutically acceptable salt thereof, for the treatment of patients with MTAP-ineffective cancer and brain metastases.

[0013] It also provides (a) compound G: (G), or a pharmaceutically acceptable salt thereof; and (b) the use of an anti-programmed death 1 (PD1) antibody in the manufacture of a medicament for the treatment of patients with MTAP-ineffective cancers in need.

[0014] It also provides (a) compound G: (G), or a pharmaceutically acceptable salt thereof; and (b) anti-programmed death 1 (PD1) antibody for the treatment of patients with MTAP-ineffective cancers in need.

[0015] In some cases, in the methods disclosed herein, compound G is administered as a free base. In some cases, in the methods disclosed herein, compound G is administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the compounds described herein (e.g., compound G) include those derived from suitable inorganic and organic acids and inorganic and organic bases. Pharmaceutically acceptable salts include those with inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and with organic acids (such as tartaric acid, acetic acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, formic acid, propionic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, camphor sulfonic acid, isothiocyanate, mucilage, gentianic acid, isonicotinic acid, succinic acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, etc.). Acid addition salts formed with phenylacetic acid, mandelic acid, embosic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, stearic acid, sulfinic acid, alginic acid, galacturonic acid, and arylsulfonic acids (e.g., benzenesulfonic acid and p-toluenesulfonic acid); base addition salts formed with alkali metals and alkaline earth metals, as well as organic bases (such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), lysine, and procaine); and salts formed internally. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002.

[0016] Pharmaceutical compositions containing compound G can be manufactured in a conventional manner, such as by conventional mixing, dissolving, granulation, sugar-coated pellet preparation, grinding, emulsification, encapsulation, embedding, or lyophilization processes. In various cases, compound G is administered orally. In various cases, compound G is administered once daily. In some embodiments, compound G is administered twice daily. In some cases, compound G is administered orally once daily. In some cases, compound G is administered as a tablet formulation.

[0017] In some embodiments, compound G is administered orally and once daily to a patient in need. The intended “patient” or “subject” includes, but is not limited to, humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “patient” and “subject” are used interchangeably herein.

[0018] In some embodiments, a total daily dose of 100 mg, 120 mg, 200 mg, 240 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or 1600 mg of compound G is administered to the patient based on the weight of the free base of compound G. In some embodiments, a total daily dose of 120 mg, 200 mg, 240 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg of compound G is administered to the patient based on the weight of the free base of compound G. In some embodiments, a total daily dose of 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg of compound G is administered to the patient based on the weight of the free base of compound G. In some embodiments, a total daily dose of 500 mg, 800 mg, 900 mg, or 1200 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 500 mg, 800 mg, or 1200 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 800 mg, 900 mg, or 1200 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 800 mg or 1200 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 120 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 200 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 240 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 300 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 400 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 480 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 500 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 600 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 700 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 800 mg of compound G is administered to the patient based on the weight of its free base.In some embodiments, a total daily dose of 900 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 1000 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 1100 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 1200 mg of compound G is administered to the patient based on the weight of its free base. In some embodiments, a total daily dose of 1600 mg of compound G is administered to the patient based on the weight of its free base.

[0019] In some embodiments, compound G is administered once daily. In some embodiments, compound G is administered once daily for 21 consecutive days. In some embodiments, based on the weight of the free base of compound G, 100 mg, 120 mg, 200 mg, 240 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or 1600 mg of compound G is administered once daily for 21 consecutive days. In some embodiments, based on the weight of the free base of compound G, 120 mg, 200 mg, 240 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg of compound G is administered once daily for 21 consecutive days. In some embodiments, based on the weight of the free base of compound G, 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg of compound G is administered to the patient once daily for 21 consecutive days. In some embodiments, based on the weight of the free base of compound G, 500 mg, 800 mg, 900 mg, or 1200 mg of compound G is administered to the patient once daily for 21 consecutive days. In some embodiments, based on the weight of the free base of compound G, 500 mg, 800 mg, or 1200 mg of compound G is administered to the patient once daily for 21 consecutive days. In some embodiments, based on the weight of the free base of compound G, 800 mg, 900 mg, or 1200 mg of compound G is administered to the patient once daily for 21 consecutive days. In some embodiments, based on the weight of the free base of compound G, 800 mg or 1200 mg of compound G is administered to the patient once daily for 21 consecutive days. In some embodiments, 120 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 200 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 240 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 300 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 400 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 480 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base.In some embodiments, 500 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 600 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 700 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 800 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 900 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 1000 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 1100 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 1200 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the weight of its free base. In some embodiments, 1600 mg of compound G is administered to the patient once daily for 21 consecutive days, based on the free base weight of compound G.

[0020] In some embodiments, compound G is administered during a treatment cycle. In some embodiments, the treatment cycle is 21 days. In some embodiments, the cycle may be repeated. In various embodiments, the patient experiences 1, 2, 3, or more treatment cycles. In some embodiments, the patient experiences at least 3 treatment cycles, at least 5 treatment cycles, at least 8 treatment cycles, at least 10 treatment cycles, or at least 15 treatment cycles.

[0021] anti-PD1 antibody

[0022] In various respects, the methods described herein include administering an anti-programmed death 1 (PD1) antibody to a patient. TsPD-1 antibodies and methods of use in the treatment of the disease are described in U.S. Patent Nos. 7,595,048; 8,168,179; 8,728,474; 7,722,868; 8,008,449; 7,488,802; 7,521,051; 8,088,905; 8,168,757; 8,354,509; and U.S. Publications Nos. US 20110171220; US 20110171215; and US 20110271358. In some cases, the anti-PD1 antibody is administered every three weeks. In some cases, the anti-PD1 antibody is administered intravenously (IV).

[0023] Pembrolizumab (KEYTRUDA®) is an anti-PD-1 antibody marketed by Merck & Co. for the treatment of lung cancer. The amino acid sequence and method of administration of pembrolizumab are disclosed in U.S. Patent No. 8,168,757. See also KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ, 07033 (revised March 2023), which is incorporated herein by reference in its entirety.

[0024] Nivolumab (OPDIVO®) is a fully human monoclonal antibody marketed by Bristol Myers Squibb. It targets the human cell surface receptor PD-1 (programmed cell death 1 or PCD-1), which has immunomodulatory and inhibitory effects, and also possesses immunomodulatory activity. Nivolumab binds to PD-1 (an Ig superfamily transmembrane protein) via its ligands PD-L1 and PD-L2, blocking its activation and thereby activating T cells and triggering a cell-mediated immune response against tumor cells or pathogens. Activated PD-1 negatively regulates T cell activation and effector function by inhibiting the activation of the PI3k / Akt signaling pathway. Other names for nivolumab include BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence of nivolumab, as well as its use and preparation methods, are disclosed in U.S. Patent No. 8,008,449. See also OPDIVO® US Prescribing Information, Bristol-Myers Squibb Co., Princeton, NJ, 08543 (revised February 2023), which is incorporated herein by reference in its entirety.

[0025] Cimiprimab (LIBTAYO®) is an anti-PD-1 antibody marketed by Regeneron Pharmaceuticals for the treatment of squamous cell carcinoma (CSCC), basal cell carcinoma (BSC), and non-small cell lung cancer (NSCLC). The amino acid sequence of cimiprimab is disclosed in U.S. Patent No. 11,292,842. See also LIBTAYO® US Prescribing Information, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591 (revised November 2022), which is incorporated herein by reference in its entirety.

[0026] In some embodiments, the anti-PD1 antibody is tislelizumab, dostarlimab, or toripalimab.

[0027] In some embodiments, the methods described herein include administering an anti-PD-L1 antibody. Exemplary anti-PD-L1 antibodies include, but are not limited to, atezolizumab and durvalumab.

[0028] Therefore, this document provides methods that include administering a therapeutically effective amount of an anti-PD1 antibody to a patient. In some embodiments, the methods described herein further include administering pembrolizumab. In some embodiments, 200 mg of pembrolizumab is administered to the patient. In various embodiments, pembrolizumab is administered intravenously. In some cases, pembrolizumab is administered every three weeks.

[0029] Carboplatin

[0030] In some embodiments, the methods described herein include further administration of carboplatin to the patient. Carboplatin is a platinum coordination compound. The chemical name of carboplatin is diamino[1,1-cyclobutane-dicarboxylic acid (2-)-O,O']platinum, (SP-4-2). Carboplatin works by cross-linking deoxyribonucleic acid (DNA) chains, thereby inhibiting DNA synthesis and function. Platinum-based chemotherapy has been a preferred 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, when combinations of immunotherapy and chemotherapy were introduced (e.g., pembrolizumab combined with pemetrexed and platinum-based chemotherapy; see KEYTRUDA® USPrescribing Information, Merck, Kennillworth, NJ 07033 (revised March 2023), which is incorporated herein by reference in its entirety). Other chemotherapy agents that are combined with platinum typically include pemetrexed (for non-squamous NSCLC), gemcitabine (for squamous NSCLC), or taxanes (paclitaxel, albumin-bound paclitaxel, or docetaxel).

[0031] Carboplatin is commercially available as PARAPLATIN®, BLASTOCARB®, BLASTOPLATIN®, CARBOKEM®, CARBOMAX®, PARAPLATIN®, CARBOPA®, KARPLAT®, and others. Complete information on the preparation, reconstitution, dosage, and administration schedule of carboplatin is available in the local packaging insert (for the United States, see, for example, CARBOplatinInjection, US Prescribing Information, Fresenius KABI, Lake Zurich, Illinois, 60047 (revised May 2021), which is incorporated herein by reference in its entirety).

[0032] Therefore, this document provides methods that include administering a therapeutically effective amount of carboplatin to a patient. In some embodiments, the methods described herein include administering AUC5 or AUC6 carboplatin to a patient. In some embodiments, the methods described herein include administering AUC5 carboplatin to a patient. In some embodiments, the methods described herein include administering AUC6 carboplatin to a patient. In various embodiments, carboplatin is administered intravenously. In some cases, carboplatin is administered every three weeks.

[0033] Paclitaxel

[0034] In some embodiments, the methods described herein include further administration of paclitaxel to the patient. Paclitaxel is a semi-synthetic taxane, a class of anticancer agents that bind to β-tubulin, thereby stabilizing microtubules and inducing cell cycle arrest and apoptosis. Paclitaxel 200 mg / m² in combination with carboplatin 2 Intravenous administration every 3 weeks over 3 hours is the standard treatment option for patients with advanced or metastatic, previously untreated NSCLC who are in good physical condition.

[0035] Complete information on the preparation, reconstitution, dosage, and administration of paclitaxel (TAXOL®) can be found in the local package insert (for the United States, see, for example, TAXOL® INJECTION US Prescribing Information, Bristol Myers Squibb, Princeton, NJ 08543 (revised April 2011), which is incorporated herein by reference in its entirety). Complete information on the preparation, reconstitution, dosage, and administration of albumin-bound paclitaxel (ABRAXANE®) can be found in the local package insert (for the United States, see, for example, ABRAXANE® US Prescribing Information, Bristol Myers Squibb, NJ 08543 (revised August 2020), which is incorporated herein by reference in its entirety).

[0036] Therefore, this article provides methods that include administering a therapeutically effective amount of paclitaxel to a patient. In some embodiments, 200 mg / m² is administered to the patient. 2 Paclitaxel. In various embodiments, paclitaxel is administered intravenously (“via IV”). In some embodiments, paclitaxel is administered intravenously over 24 hours. In some cases, paclitaxel is administered every three weeks.

[0037] Pemetrexed

[0038] In some embodiments, the methods described herein include further administration of pemetrexed to the patient. Pemetrexed is a folate analogue metabolism inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. The U.S. Food and Drug Administration (FDA) has approved pemetrexed in combination with pembrolizumab and platinum-based chemotherapy (carboplatin or cisplatin) as initial treatment for subjects with metastatic non-squamous NSCLC without EGFR or ALK tumor genomic abnormalities. Pemetrexed in combination with cisplatin is also approved for initial treatment of subjects with locally advanced or metastatic non-squamous NSCLC. In a maintenance setting, pemetrexed is approved as monotherapy for subjects with locally advanced or metastatic non-squamous NSCLC whose disease has not progressed after four cycles of first-line platinum-based doublet chemotherapy. Pemetrexed is also approved as monotherapy for subjects with recurrent metastatic non-squamous NSCLC following prior chemotherapy.

[0039] Pemetrexed may be commercially available, for example, as ALIMTA®. Complete information on the preparation, dispensing, dosage, and administration schedule of pemetrexed can be found in the local package insert (for the United States, see, for example, ALIMTA® USPrescribing Information, Lilly, USA, LLC, Indianapolis, Indiana 46285 (revised August 2022), which is incorporated herein by reference in its entirety).

[0040] 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 (“via IV”). In some embodiments, pemetrexed is administered intravenously over 10 minutes.

[0041] This document also provides methods that further include administering other medications to a subject while being treated with pemetrexed. In various embodiments, the methods provided herein further include administering a therapeutically effective amount of folic acid to the subject. In various embodiments, the methods provided herein further include administering a therapeutically effective amount of vitamin B12 to the 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 the subject.

[0042] Anti-PD1 dosing regimen

[0043] In some embodiments, the methods described herein include administering compound G and pembrolizumab to a patient. In some embodiments, the methods described herein include administering (a) 120 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 200 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 240 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 300 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 400 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 480 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 500 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 600 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 700 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 800 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 900 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 1000 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks.In some embodiments, the methods described herein include administering (a) 1100 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 1200 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks. In some embodiments, the methods described herein include administering (a) 1600 mg of compound G (once daily) and (b) 200 mg of pembrolizumab to a patient, wherein pembrolizumab is administered intravenously every three weeks.

[0044] In some embodiments, the methods described herein include administering (a) compound G, (b) carboplatin, (c) paclitaxel, and (d) pembrolizumab to a patient. In some embodiments, the methods described herein include administering (a) 120 mg of compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m² of compound G to a patient. 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 200 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 240 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 300 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 400 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 480 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 500 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 600 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 700 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 800 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 900 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 1000 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 1100 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 1200 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 1600 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein carboplatin, paclitaxel, and pembrolizumab are administered intravenously every three weeks. In some embodiments, carboplatin is AUC5 carboplatin. In some embodiments, carboplatin is AUC6 carboplatin.

[0045] In some embodiments, the methods described herein include administering (a) compound G, (b) carboplatin, (c) pemetrexed, and (d) pembrolizumab to a patient. In some embodiments, the methods described herein include administering (a) 120 mg of compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m² of compound G to a patient. 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 200 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 240 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 300 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 400 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 500 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 600 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 700 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 800 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 900 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m². 2Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 1000 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 1100 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 1200 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, the method described herein includes administering to the patient (a) 1600 mg compound G (once daily), (b) AUC5 or AUC6 carboplatin, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein carboplatin, pemetrexed, and pembrolizumab are administered intravenously every three weeks. In some embodiments, carboplatin is AUC5 carboplatin. In some embodiments, carboplatin is AUC6 carboplatin.

[0046] Other drugs and their administration

[0047] As discussed above, this disclosure provides methods that further include administering to a patient a therapeutically effective amount of folic acid, a therapeutically effective amount of vitamin B12, or a therapeutically effective amount of each of folic acid and vitamin B12.

[0048] Pemetrexed is a component of platinum-based dual chemotherapy for patients with non-squamous NSCLC. Singh et al., Cancer, 125:2203-2212, 2019. Because pemetrexed is an antifolate drug that works primarily by interfering with folate-dependent metabolic processes and inhibiting multiple enzymes involved in purine and pyrimidine synthesis, myelosuppression is its main drug toxicity. Ibid. It has been shown that adding vitamin B12 and folic acid to pemetrexed-containing chemotherapy regimens can reduce the incidence of serious adverse events, especially hematologic toxicity, without reducing antitumor efficacy. Ibid. Additional recommendations include starting oral folic acid (400-1000 μg daily) one week before the first dose of pemetrexed and continuing oral folic acid for at least 3 weeks after the end of treatment (ibid., and see, for example, ALIMTA® USPrescribing Information, Lilly, USA, LLC, Indianapolis, Indiana, 46285 (revised August 2022)). In conjunction with folic acid, vitamin B12 can be administered intramuscularly (1000 μg) and repeated every 9 weeks thereafter until the end of treatment. (ibid.)

[0049] Therefore, the therapeutically effective dose of folic acid administered in the methods provided herein is 350 µg to 1000 µg once daily. In some embodiments, the therapeutically effective dose of folic acid is 400 µg once daily. In various embodiments, the therapeutically effective dose of folic acid is 400 µg to 1000 µg once daily. In various embodiments, folic acid administration begins 7 days before pemetrexed administration and ends 21 days after pemetrexed administration is stopped.

[0050] In some embodiments, the therapeutically effective amount of vitamin B12 administered in the methods provided herein is 1 mg. In various embodiments, vitamin B12 is administered one week prior to the first administration of pemetrexed, and thereafter every 9 weeks (± 2 weeks) until pemetrexed administration is discontinued. In some embodiments, vitamin B12 is administered one week prior to the first administration of pemetrexed, and thereafter every 9 weeks until pemetrexed administration is discontinued. In various embodiments, vitamin B12 is administered intramuscularly.

[0051] 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.

[0052] 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 on the day before, the day of, and the day after pemetrexed administration. See, for example, ALIMTA® US Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revised August 2022). 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 amount of dexamethasone is 4 mg twice daily. In some embodiments, dexamethasone is administered to the subject one day before, on the same day, and the day after each administration of pemetrexed.

[0053] In some cases, antiemetics are administered to patients as part of an anti-PD1 dosing regimen.

[0054] The patient's previous treatment plan

[0055] In various cases, patients have received at least one prior treatment regimen before initiating the methods disclosed herein (e.g., administration of compound G)—that is, the disclosed methods are second-line (or higher) therapy, and these patients are not first-time treatments for the cancer being treated by the methods disclosed herein. In some embodiments, patients have received chemotherapy prior to treatment with compound G. In some embodiments, patients have received at least one systemic therapy for locally advanced or metastatic disease prior to administration of compound G. In some embodiments, systemic therapy includes platinum-based dual chemotherapy and an immune checkpoint inhibitor. In some cases, systemic therapy includes platinum-based chemoimmunotherapy, chemotherapy, or immunotherapy. In some embodiments, patients have received treatment with an immune checkpoint inhibitor prior to treatment with compound G. In some embodiments, patients with targetable mutations have received at least one approved targeted therapy against those mutations (e.g., EGFR, ALK, KRASG12C).

[0056] In some cases, for locally advanced or metastatic NSCLC, patients have not received prior systemic therapy. In some cases, patients have received prior systemic therapy, and the first dose of the prior systemic therapy was administered within 56 days (28 days of pre-screening + 28 days of screening) of the first dose of compound G.

[0057] In some embodiments, the patient has not received antitumor therapy within 28 days of receiving the first dose of compound G. In some embodiments, the patient has not received antitumor therapy within 21 days of receiving the first dose of compound G. Exemplary antitumor therapies include chemotherapy, antibody therapy, molecularly targeted therapy, or hormone therapy. In some embodiments, the patient has not previously been treated with a MAT2A inhibitor (i.e., the patient is MAT2A inhibitor-naïve). A MAT2A inhibitor is a compound that inhibits methionine adenosine transferase II α. An exemplary MAT2A inhibitor used in the methods provided herein is AG 270 ((3-(cyclohexyl-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-zetidindin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one).

[0058] In some embodiments, the patient has not previously been treated with a PRMT5 inhibitor (i.e., the patient is PRMT5 inhibitor-naïve). A PRMT5 inhibitor is a compound that inhibits the protein arginine methyltransferase 5. The term "PRMT5 inhibitor" includes PRMT5 inhibitors that cooperate with MTA. Exemplary PRMT5 inhibitors used in the methods provided herein include, but are not limited to, pemrametostat (6-[(1-acetylpiperidin-4-yl)amino]-N-[(2S)-3-(3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxypropyl]pyrimidin-4-carboxamide), GSK3203591 (2-(cyclobutylamino)-N-[(2S)-3-(3,4-dihydro-2(1-yl)amino]-N-[(2S)-3-(3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxypropyl]pyrimidin-4-carboxamide), and GSK3203591 (2-(cyclobutylamino)-N-[(2S)-3-(3,4-dihydro-2-yl)-2-hydroxypropyl]pyrimidin-4-carboxamide). [H)-isoquinolinyl]-2-hydropropyl]-4-pyridinecarboxamide dihydrochloride), LLY-283 ((R)-5′-phenyl-7-deadenine; 6-amino-9-[(R)-5′-phenyl(furanibosyl)]-7-deadenine, (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-hydroxy(phenyl)methyl)tetrahydrofuran-3,4-diol), PRT 811, and MRTX1719 (2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile).

[0059] In some embodiments, the patient is not treated with compounds that are strong inducers of CYP3A4. Exemplary strong inducers of CYP3A4 include, but are not limited to, rifampin, mitotane, avasimibe, rifapentine, apalutamide, ivosidenib, phenytoin, carbamazepine, enzalutamide, St. John's wort extract, lumacaftor, and phenobarbital.

[0060] In some embodiments, the patient is not treated with compounds that are strong inhibitors of CYP3A4. Exemplary strong CYP3A4 inhibitors include, but are not limited to, VIEKIRA PAK, indinavir / ritonavir, tipranavir / ritonavir, ritonavir, cobicistat, ketoconazole, troleandomycin, telaprevir, danoprevir / ritonavir, elvitegravir / ritonavir, saquinavir / ritonavir, lopinavir / ritonavir, itraconazole, indinavir, and vortex. Riconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, lonafarnib, posaconazole, telithromycin, grapefruit juice, conivaptan, tucatinib, nefazodone, ceritinib, nelfinavir, saquinavir, ribociclib, idelalisib, and boceprevir.

[0061] In some cases, compound G is not administered co-administered with antacids. In some embodiments, compound G is not administered co-administered with proton pump inhibitors, histamine 2 receptor antagonists (H2RAs), and / or locally acting antacids. In some cases, locally acting antacids or H2RAs are administered 10 hours before or 2 hours after the administration of compound G.

[0062] In some embodiments, the patient has not had an arterial thrombosis within 6 months prior to starting treatment with compound G. In some embodiments, the patient has not had a history of myocardial infarction and / or symptomatic congestive heart failure, congestive heart failure (NYHA Class II), unstable angina; or cardiac arrest, ventricular tachycardia, known Wolf-Parkinson-White Syndrome; or a genetic syndrome that increases the risk of sudden cardiac death (e.g., long QT syndrome, short QT syndrome, hereditary hypertrophic cardiomyopathy, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, or catecholamine polymorphic ventricular tachycardia).

[0063] In some embodiments, the patient does not have toxicity from previous anticancer therapies, defined as not having regressed to Grade 0 or 1 of the Common Terminology Standard for Adverse Events (CTCAE) version 5.0, or not having regressed to the level specified in the eligibility criteria, except for hair loss.

[0064] MTAP-ineffective cancers

[0065] This disclosure provides methods for treating MTAP-ineffective cancers in patients in need, methods comprising administering compound G to the patient, optionally in combination with an additional therapeutic agent. MTAP-ineffective cancers are cancers lacking expression of the enzyme methionine phosphorylase (MTAP). The MTAP gene, located at chromosome 9p21, is frequently co-deleted with the CDKN2A and CDKN2B genes. Selective MTAP deficiency refers to a deficiency in the absence of CDKN2 gene co-deletion, resulting from selective deletion of the MTAP locus or methylation of the MTAP promoter. MTAP-ineffective cancers include MTAP deficiency in at least 1% of disease cells and, in some cases, at least 20% of disease cells. The terms “MTAP-ineffective,” “MTAP-deficient,” “MTAP-negative,” and “MTAP-deficient” are used interchangeably.

[0066] The terms "MTAP deficiency-associated," "MTAP deficiency," or "MTAP-deficient" diseases (e.g., proliferative diseases such as cancer), "MTAP-associated" diseases (e.g., proliferative diseases such as cancer), or "characterized by MTAP deficiency" diseases (e.g., proliferative diseases such as cancer) refer to diseases in which a large number of cells are MTAP-deficient cells (e.g., proliferative diseases such as cancer). For example, in MTAP deficiency-associated diseases, one or more disease cells may have significantly reduced post-translational modifications, production, expression, levels, stability, and / or activity of MTAP. MTAP-ineffective cancers can be identified by any suitable diagnostic test. Exemplary diagnostic tests for MTAP loss or MTAP protein deficiency include local immunohistochemistry (IHC) and local or central next-generation sequencing (NGS).

[0067] Examples of MTAP deficiency-related diseases include, but are not limited to, cancers, including but not limited to: glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., cystourethral epithelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct cancer, brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, and colorectal cancer or sarcoma. In patients with MTAP deficiency-related diseases, some disease cells (e.g., cancer cells) may be MTAP-deficient cells, while others are not. Similarly, some disease cells may be MTA-accumulating cells, while others are not. Therefore, this disclosure covers treatment methods for diseases involving these tissues, or any other tissues, wherein the proliferation of MTAP-deficient and / or MTA-accumulating cells can be inhibited by administration of a PRMT5 inhibitor. Some MTAP-deficient cancer cells also lack CDKN2A; post-translational modifications, production, expression, level, stability, and / or activity of the CDKN2A gene or its product are attenuated in these cells. The genes for MTAP and CDKN2A are very close together on chromosome 9p21; MTAP is located at approximately 100 kb telomeres of CDKN2A. Many cancer cell types contain CDKN2A / MTAP loss (loss of both genes). Therefore, in some embodiments, MTAP-deficient cells also lack CDKN2A. In some embodiments, the patient does not have a tumor carrying a CDKN2A mutation.

[0068] In some embodiments, the MTAP-ineffective cancer in the methods disclosed herein is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is squamous NSCLC. In some embodiments, the lung cancer is non-squamous NSCLC. In some embodiments, the NSCLC is locally advanced. In some embodiments, the NSCLC is metastatic.

[0069] Monitoring treatment efficacy

[0070] The efficacy of a given cancer treatment can be determined by a skilled clinician. However, treatment is considered “effective” as used herein if, after treatment with agents as described herein, any or all signs or symptoms of the tumor, for example, show a beneficial change, or other clinically acceptable symptoms improve or even decrease by, for example, by at least 10%. Efficacy can also be measured by the absence of disease progression (i.e., cessation of disease progression) in individuals who are hospitalized or require medical intervention for evaluation. Methods for measuring these indicators are known to those skilled in the art and / or described herein.

[0071] As determined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer et al., 2009), a patient can respond to therapy as measured by at least stable disease (SD). RECIST v1.1 is discussed in detail in the following examples. At least stable disease is a stable disease that demonstrates a partial response (PR) or a complete response (CR) (i.e., "at least SD" = SD + PR + CR, often referred to as disease control). In various embodiments, stable disease is neither sufficiently reduced to qualify for a partial response (PR) nor sufficiently increased to qualify for progressive disease (PD). In various embodiments, the patient demonstrates at least a partial response (i.e., "at least PR" = PR + CR, often referred to as objective response). Alternatively or concurrently, patient response can be determined by the Response Assessment in Neuro-Oncology (RANO) criteria, see, for example, Chen et al., Front Oncol. [Frontiers in Oncology], 2021 11:679331.

[0072] The response can be measured by one or more of the following: reduction in tumor size, inhibition or reduction of tumor growth, reduction of target or neoplastic lesions, delay in progression time, absence of new tumors or lesions, reduction in new tumor formation, increase in survival or progression-free survival (PFS), and absence of metastasis. In various embodiments, the progression of a patient's disease can be assessed by measuring tumor size, neoplastic lesions, or the formation of new tumors or lesions, using computed tomography (CT) scans, positron emission tomography (PET) scans, magnetic resonance imaging (MRI) scans, X-rays, ultrasound, or some combination thereof.

[0073] Progression-free survival (PFS) can be assessed as described in the RECIST 1.1 protocol. In various embodiments, patients exhibit at least 1 month of PFS. In various embodiments, patients exhibit at least 3 months of PFS. In some embodiments, patients exhibit at least 6 months of PFS.

[0074] Example:

[0075] 1. A method for treating MTAP-resistant lung cancer in a patient in need, the method comprising administering to the patient...

[0076] (a) Chemical G, namely the PRMT5 inhibitor: (G), or a pharmaceutically acceptable salt thereof; and

[0077] (b) Anti-PD1 antibody, administered every three weeks.

[0078] 2. The method as described in Example 1, wherein compound G is applied as a free base.

[0079] 3. The method as described in Example 1, wherein the method comprises administering 400 mg of compound G to the patient once daily based on the free base weight of compound G.

[0080] 4. The method as described in Example 1, wherein the method comprises administering 500 mg of compound G to the patient once daily based on the free base weight of compound G.

[0081] 5. The method as described in Example 1, wherein the method comprises administering 600 mg of compound G to the patient once daily based on the free base weight of compound G.

[0082] 6. The method as described in Example 1, wherein the method comprises administering 800 mg of compound G to the patient once daily based on the free base weight of compound G.

[0083] 7. The method as described in Example 1, wherein the method comprises administering 1200 mg of compound G to the patient once daily based on the free base weight of compound G.

[0084] 8. The method as described in any one of Examples 1-6, wherein the lung cancer is non-squamous cell lung cancer (NSCLC).

[0085] 9. The method as described in Example 8, wherein the NSCLC is transferable.

[0086] 10. The method of any one of claims 1-9, wherein the anti-PD1 antibody is pembrolizumab.

[0087] 11. The method as described in Example 10, comprising administering 200 mg of pembrolizumab to the patient every three weeks via intravenous administration.

[0088] 12. The method of Example 10, comprising administering to the patient (a) 400 mg of compound G once daily and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0089] 13. The method of Example 10, comprising administering to the patient (a) 500 mg of compound G once daily and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0090] 14. The method of Example 10, comprising administering to the patient (a) 600 mg of compound G once daily and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0091] 15. The method of Example 10, comprising administering to the patient (a) 800 mg of compound G once daily and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0092] 16. The method of Example 10, comprising administering to the patient (a) 1200 mg of compound G once daily and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0093] 17. The method as described in any one of Examples 1-16, further comprising administering carboplatin to the patient.

[0094] 18. The method as described in Example 17, wherein the method comprises administering AUC5 or AUC6 carboplatin to the patient via IV every three weeks.

[0095] 19. The method as described in any one of Examples 1-18, further comprising administering paclitaxel to the patient.

[0096] 20. The method as described in Example 19, comprising administering 200 mg / m² to the patient via IV every three weeks. 2 Paclitaxel.

[0097] 21. The method of any one of Examples 1-20, further comprising administering pemetrexed to the patient.

[0098] 22. The method as described in Example 21, wherein the method comprises administering 500 mg / m² to the patient via IV every three weeks. 2 Pemetrexed.

[0099] 23. The method of any one of Examples 1-20, comprising administering (a) compound G, (b) carboplatin, (c) paclitaxel and (d) pembrolizumab to the patient.

[0100] 24. The method of Example 23, comprising administering to the patient (a) 400 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0101] 25. The method of Example 23, comprising administering to the patient (a) 500 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0102] 26. The method of Example 23, comprising administering to the patient (a) 600 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0103] 27. The method of Example 23, comprising administering to the patient (a) 800 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0104] 28. The method of Example 23, comprising administering to the patient (a) 1200 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0105] 29. The method as described in any one of Examples 1-18, 21 and 22, the method comprising administering to the patient (a) compound G, (b) carboplatin, (c) pemetrexed and (d) pembrolizumab.

[0106] 30. The method of Example 29, comprising administering to the patient (a) 500 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0107] 31. The method of Example 29, comprising administering to the patient (a) 600 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0108] 32. The method of Example 29, comprising administering to the patient (a) 800 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0109] 33. The method of Example 29, comprising administering to the patient (a) 1200 mg of compound G once daily, (b) carboplatin with AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0110] 34. A method of treating a patient with MTAP-resistant cancer and brain metastases, the method comprising administering compound G to the patient: (G), or a pharmaceutically acceptable salt thereof.

[0111] 35. The method as described in Example 34, wherein the MTAP-ineffective cancer is lung cancer.

[0112] 36. The method as described in Example 35, wherein the lung cancer is non-squamous cell lung cancer (NSCLC).

[0113] 37. The method as described in any one of Examples 34-36, wherein the method comprises administering 400 mg of compound G to the patient once daily.

[0114] 38. The method as described in any one of Examples 34-36, wherein the method comprises administering 500 mg of compound G to the patient once daily.

[0115] 39. The method as described in any one of Examples 34-36, wherein the method comprises administering 600 mg of compound G to the patient once daily.

[0116] 40. The method as described in any one of Examples 34-36, the method comprising administering 800 mg of compound G to the patient once daily.

[0117] 41. The method of any one of claims 34-36, the method comprising administering 1200 mg of compound G to the patient once daily.

[0118] 42. The method of any one of claims 34-41, wherein the brain metastasis is an active, previously untreated brain metastasis.

[0119] 43. The method of any one of claims 34-42, wherein the method comprises administering compound G to the patient as a single therapy.

[0120] Another embodiment:

[0121] 1A. A method for treating MTAP-resistant lung cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of each of the following: (a) compound G, (G), or a pharmaceutically acceptable salt thereof; and (b) anti-PD1 antibody.

[0122] 2A. The method of claim 1A, wherein compound G is applied as a free base.

[0123] 3A. The method as described in Example 1A or 2A, wherein the method comprises administering a total daily dose of 500 mg of compound G to the patient based on the free base weight of compound G.

[0124] 4A. The method as described in Example 1A or 2A, wherein the method comprises administering a total daily dose of 600 mg of compound G to the patient based on the free base weight of compound G.

[0125] 5A. The method as described in Example 1A or 2A, wherein the method comprises administering a total daily dose of 800 mg of compound G to the patient based on the free base weight of compound G.

[0126] 6A. The method as described in Example 1A or 2A, wherein the method comprises administering a total daily dose of 900 mg of compound G to the patient based on the free base weight of compound G.

[0127] 7A. The method as described in Example 1A or 2A, wherein the method comprises administering a total daily dose of 1200 mg of compound G to the patient based on the free base weight of compound G.

[0128] 8A. The method as described in Example 1A or 2A, wherein the method comprises administering a total daily dose of 1600 mg of compound G to the patient based on the free base weight of compound G.

[0129] 9A. The method as described in any one of Examples 1A-8A, wherein compound G is administered once daily.

[0130] 10A. The method as described in any one of Examples 1A-9A, wherein compound G is administered orally.

[0131] 11A. The method as described in any one of Examples 1A-10A, wherein compound G is administered as a tablet formulation.

[0132] 12A. The method as described in any one of Examples 1A-11A, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0133] 13A. The method as described in Example 12A, wherein the NSCLC is a scaly NSCLC.

[0134] 14A. The method as described in Example 12A, wherein the NSCLC is a non-squamous NSCLC.

[0135] 15A. The method as described in any one of Examples 12A-14A, wherein the NSCLC is locally late.

[0136] 16A. The method as described in any one of Examples 12A-14A, wherein the NSCLC is transferable.

[0137] 17A. The method as described in any one of Examples 1A-16A, wherein the anti-PD1 antibody is administered every three weeks.

[0138] 18A. The method as described in any one of Examples 1A-17A, wherein the anti-PD1 antibody is administered via IV.

[0139] 19A. The method as described in any one of Examples 1A-18A, wherein the anti-PD1 antibody is pembrolizumab.

[0140] 20A. The method as described in Example 19A, comprising administering 200 mg of pembrolizumab to the patient via IV every three weeks.

[0141] 21A. The method of Example 19A, comprising administering to the patient (a) 500 mg of compound G once daily based on the free base weight of compound G and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0142] 22A. The method of Example 19A, comprising administering to the patient (a) 600 mg of compound G once daily based on the free base weight of compound G and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0143] 23A. The method of Example 19A, comprising administering to the patient (a) 800 mg of compound G once daily based on the free base weight of compound G and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered intravenously every three weeks.

[0144] 24A. The method of Example 19A, comprising administering to the patient (a) 900 mg of compound G once daily based on the free base weight of compound G and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0145] 25A. The method of Example 19A, comprising administering to the patient (a) 1200 mg of compound G once daily based on the free base weight of compound G and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0146] 26A. The method as described in any one of Examples 1A-25A, further comprising administering carboplatin to the patient.

[0147] 27A. The method as described in Example 26A, wherein the method comprises administering AUC5 or AUC6 carboplatin to the patient via IV every three weeks.

[0148] 28A. The method as described in any one of Examples 1A-27A, further comprising administering paclitaxel to the patient.

[0149] 29A. The method as described in Example 28A, comprising administering 200 mg / m² to the patient via IV every three weeks. 2 Paclitaxel.

[0150] 30A. The method as described in any one of Examples 1A-27A, further comprising administering pemetrexed to the patient.

[0151] 31A. The method as described in Example 30A, wherein the method comprises administering 500 mg / m² to the patient via IV every three weeks. 2 Pemetrexed.

[0152] 32A. The method as described in any one of Examples 1A-19A, comprising administering to the patient (a) compound G, (b) carboplatin, (c) paclitaxel and (d) pembrolizumab.

[0153] 33A. The method of Example 32A, comprising administering to the patient (a) 500 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin at AUC5 or AUC6; and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered via IV every three weeks.

[0154] 34A. The method of Example 32A, comprising administering to the patient (a) 600 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin at AUC5 or AUC6; and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0155] 35A. The method of Example 32A, comprising administering to the patient (a) 800 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin at AUC5 or AUC6; and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0156] 36A. The method of Example 32A, comprising administering to the patient (a) 900 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin with AUC5 or AUC6; and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0157] 37A. The method of Example 32A, comprising administering to the patient (a) 1200 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin with AUC5 or AUC6; and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

[0158] 38A. The method as described in any one of Examples 1A-19A, comprising administering to the patient (a) compound G, (b) carboplatin, (c) pemetrexed and (d) pembrolizumab.

[0159] 39A. The method of Example 38A, comprising administering to the patient (a) 500 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin at AUC5 or AUC6; and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0160] 40A. The method as described in Example 38A, comprising administering to the patient (a) 600 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin at AUC5 or AUC6; and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0161] 41A. The method of Example 38A, comprising administering to the patient (a) 800 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin at AUC5 or AUC6; and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0162] 42A. The method of Example 38A, comprising administering to the patient (a) 900 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin at AUC5 or AUC6; and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0163] 43A. The method of Example 38A, comprising administering to the patient (a) 1200 mg of compound G once daily, based on the free base weight of compound G; (b) carboplatin at AUC5 or AUC6; and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

[0164] 44A. A method for treating a patient with MTAP-resistant cancer and brain metastases, the method comprising administering to the patient a therapeutically effective amount of compound G: (G), or a pharmaceutically acceptable salt thereof.

[0165] 45A. The method as described in Example 44A, wherein the MTAP-ineffective cancer is lung cancer.

[0166] 46A. The method as described in Example 45A, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0167] 47A. The method as described in Example 46A, wherein the NSCLC is a scaly NSCLC.

[0168] 48A. The method as described in Example 46A, wherein the NSCLC is a non-squamous NSCLC.

[0169] 49A. The method as described in any one of Examples 46A-48A, wherein the NSCLC is locally late.

[0170] 50A. The method as described in any one of Examples 46A-48A, wherein the NSCLC is transferable.

[0171] 51A. The method as described in any one of Examples 44A-50A, wherein the brain metastasis is an active, previously untreated brain metastasis.

[0172] 52A. The method as described in any one of Examples 44A-51A, wherein compound G is administered once daily.

[0173] 53A. The method as described in any one of Examples 44A-51A, wherein compound G is administered orally.

[0174] 54A. The method as described in any one of Examples 44A-53A, wherein compound G is administered as a tablet formulation.

[0175] 55A. The method as described in any one of Examples 44A-54A, wherein the method comprises administering compound G to the patient as a single therapy.

[0176] Example

[0177] Example 1

[0178] This is a phase 1b, multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of the following combinations in patients with NSCLC who have homozygous MTAP deficiency (“MTAP-ineffective”): compound G in combination with carboplatin, pemetrexed, and pembrolizumab; or in combination with carboplatin, paclitaxel, and pembrolizumab; or in combination with pembrolizumab.

[0179] This study consisted of three groups. Group A evaluated the safety of compound G in combination with carboplatin, paclitaxel, and pembrolizumab. Group B evaluated the safety of compound G in combination with carboplatin, pemetrexed, and pembrolizumab. Group C evaluated the safety of compound G in combination with pembrolizumab.

[0180] The following investigated the dose levels of compound G:

[0181] Dosage level 2: 1200 mg once daily (QD)

[0182] Dosage level 1: 800 mg once daily (QD)

[0183] Dosage level - 1,500 mg once daily (QD)

[0184] Groups A and B will begin at dose level 1. Group C will begin at dose level 2.

[0185] Summary of subject eligibility criteria:

[0186] Adult subjects (≥ 18 years) with advanced NSCLC who have homozygous MTAP deficiency (i.e., MTAP-ineffective) as assessed by local or central NGS testing, or MTAP protein deficiency as determined by IHC, are eligible to participate in this study. Subjects in Group C must also have tumor PD-L1 expression levels that meet the levels specified on the locally approved label for pembrolizumab monotherapy as determined by local or central immunohistochemistry (IHC) (e.g., TPS ≥ 1% in the US, or TPS ≥ 50% in the EU). MTAP deficiency can be determined by local testing results or central pre-screening next-generation sequencing (NGS). Once consent is given, subjects will provide their medical history and undergo screening safety tests to confirm they meet all study eligibility requirements. Subjects must have adequate blood, kidney, and liver function. Subjects must provide archived tumor tissue samples (formalin-fixed, paraffin-embedded [FFPE] samples) collected within the past 5 years. If archived tumor tissue is unavailable, subjects must be willing to undergo a tumor biopsy prior to treatment, provided the investigator deems it safe.

[0187] treat

[0188] Compound G is administered once daily for 21 consecutive days. Food intake does not need to be considered when administering Compound G.

[0189] Carboplatin, pembrolizumab, and paclitaxel (or pemetrexed) were administered intravenously [IV] on day 1 of every 21-day cycle (all groups):

[0190] Group A:

[0191] Carboplatin and paclitaxel combination: AUC 5 or 6 (up to 4 cycles);

[0192] Paclitaxel: 200 mg / m 2 (Maximum 4 cycles); and

[0193] Pembrolizumab: 200 mg (to be administered before chemotherapy)

[0194] Group B:

[0195] Carboplatin and pemetrexed combination: AUC 5 (maximum 4 cycles);

[0196] Pemetrexed: 500 mg / m 2 (Together with vitamin supplements);

[0197] Pembrolizumab: 200 mg (to be administered before chemotherapy)

[0198] Group C:

[0199] Pembrolizumab: 200 mg

[0200] Exemplary inclusion criteria

[0201] Age ≥ 18 years old

[0202] Patients diagnosed with NSCLC by histology or cytology, and who have not previously received systemic therapy for metastatic or unresectable disease, except for those who meet the first-line therapy criteria outlined below for 28 days.

[0203] Group A: Predominantly squamous histological morphology.

[0204] Group B: Predominantly non-squamous histological morphology.

[0205] Group C: Regardless of histological morphology, PD-L1 positivity is indicated by the approved label for pembrolizumab monotherapy (e.g., TPS ≥ 1% in the United States or ≥ 50% in the European Union).

[0206] Exemplary exclusion criteria

[0207] Previous / companion therapy:

[0208] - Prior systemic therapy for metastatic NSCLC. To enable local or central pre-screening NGS testing and analysis, eligible subjects are those who have started first-line standard of care therapy (i.e., platinum-based chemoimmunotherapy, chemotherapy, or immunotherapy) and are within 28 days of their first dose when signing the primary informed consent form.

[0209] - Perform major surgery within 28 days of the first dose of compound G.

[0210] -Previously treated with MAT2A inhibitors or PRMT5 inhibitors.

[0211] - Toxicity caused by previous antitumor therapy has not improved to at least Grade 1 of the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, except for alopecia or stable and well-controlled toxicity.

[0212] - Subjects who have experienced a grade 2 or higher immune-mediated adverse event (irAE), including those who have permanently discontinued immuno-oncology drugs. The following exception is hypothyroidism.

[0213] -Previous irradiation > 25% of bone marrow.

[0214] - Receive radiation therapy within 28 days of the first dose (or local or focused radiation therapy for palliative purposes within 14 days of the first dose). All radiation therapy-related toxicities must improve to ≤ Grade 1 before the first dose of the study treatment.

[0215] - Live vaccine therapy was administered within 4 weeks prior to the study drug administration.

[0216] - Therapeutic anticoagulation is used to treat active thromboembolic events. Note: Subjects receiving a stable dose of anticoagulation therapy for thromboembolic events for a duration of ≥ 1 month may be eligible upon approval by the principal investigator in consultation with the medical supervisor.

[0217] - Use of unreviewed and unapproved prescription drugs that are known strong inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives (whichever is longer) prior to Day 1 of the study.

[0218] Related diseases:

[0219] - Targetable mutations exist, and for these mutations, there are already approved targeted therapies for first-line treatment of metastatic NSCLC, such as EGFR mutations or ALK rearrangements.

[0220] - Untreated symptomatic CNS metastatic disease with brain metastases > 2 cm / lesion, regardless of size or whether they are asymptomatic or non-asymptomatic. Note: Subjects with treated CNS metastases are eligible if they have maintained radiographic and neurological stability for ≥ 14 days prior to the first dose of study treatment and do not require corticosteroids for at least 7 days. Subjects with untreated asymptomatic brain metastases are eligible if each lesion (if more than one) is ≤ 2 cm in size and does not require corticosteroid treatment.

[0221] - Subjects with leptomeningeal disease were excluded regardless of whether symptoms were present or not, even after treatment.

[0222] - Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures more than once a month. Subjects with PleurX catheters placed may be included in this study upon approval.

[0223] Other medical conditions:

[0224] - History of other malignant tumors within the past 3 years, except for the following: malignant tumors treated for curative purposes and without known active disease for ≥ 2 years prior to recruitment, and the treating physician considers the risk of recurrence to be low. Non-melanoma skin cancer or malignant nevus with adequate treatment and no evidence of disease. Cervical cancer with adequate treatment and no evidence of disease. Breast ductal carcinoma in situ with adequate treatment and no evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer. Urothelial papillary noninvasive carcinoma or carcinoma in situ with adequate treatment. Evidence of any current interstitial lung disease or pneumonia, or a previous history of interstitial lung disease or non-infectious pneumonia. Active infection requiring systemic therapy. - History of arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months of the first dose of compound G.

[0225] - Myocardial infarction and / or symptomatic congestive heart failure (New York Heart Association class II), unstable angina, or cardiac arrest, ventricular tachycardia, a known history of Wolf-Parkinson-White syndrome, or a genetic syndrome that increases the risk of sudden cardiac death (e.g., long QT syndrome, short QT syndrome, hereditary hypertrophic cardiomyopathy, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, or catecholamine polymorphic ventricular tachycardia).

[0226] - Gastrointestinal diseases that cannot be treated with PO drugs, malabsorption syndrome, requiring IV high-energy nutrition, feeding via gastric tube / jejunal tube, and uncontrolled inflammatory gastrointestinal diseases (e.g., Crohn's disease, ulcerative colitis).

[0227] - A history of intestinal obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of entering the study (unless approved), or a history of one or more gastrointestinal procedures that lead to malabsorption.

[0228] -History of solid organ transplantation.

[0229] Prior / current clinical research experience: Currently receiving treatment in another research facility or drug study, or less than 21 days or 5 half-lives (whichever is shorter) after completing treatment in another research facility or one or more drug studies. Exclusion criteria include concurrent participation in other research procedures or observational studies.

[0230] Diagnostic assessment:

[0231] - A positive test for known human immunodeficiency virus. Note: Eligible subjects are those with HIV, undetectable viral load, adequate CD4 T cell count, and no history of opportunistic infections as defined in AIDS.

[0232] - Hepatitis B infection based on the following results and / or criteria: Positive hepatitis B surface antigen (HBsAg). If HBsAg is negative and hepatitis B core antibody is positive, then hepatitis B virus DNA detection by polymerase chain reaction (PCR) is required. Subjects with detectable hepatitis B virus DNA are ineligible. If hepatitis C virus antibody (HCVAb) is positive, then hepatitis C virus RNA detection by PCR is required. Subjects with detectable hepatitis C virus RNA are ineligible.

[0233] Other exclusions: Currently receiving or having received immunosuppressive corticosteroid therapy defined as 10 mg prednisone or its equivalent daily within 14 days of study day 1. Use of steroid medications with minimal systemic effects (e.g., topical or inhaled) is permitted.

[0234] Data as of February 9, 2025 (data cutoff date)

[0235]

[0236] Defined as at least 6 weeks of treatment and scanning.

[0237] Unconfirmed, subsequent scans showed PD.

[0238] Including a patient who developed PD in cycle 1

[0239] Example 2

[0240] This is a phase 1b, multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of compound G in subjects with homozygous MTAP deficiency (“MTAP-ineffective”) NSCLC and active, previously untreated brain metastases.

[0241] Compound G was administered orally once daily (QD) over a 21-day period. Food intake did not need to be considered when administering compound G. The following investigated the dose levels of compound G:

[0242] Dosage level 2: 1200 mg once daily (QD)

[0243] Dosage level 1: 800 mg once daily (QD)

[0244] Dosage level-1: 500 mg once daily (QD)

[0245] Summary of subject eligibility criteria:

[0246] Adult subjects (≥18 years) with advanced NSCLC and active brain metastases (at least one newly detected brain lesion) and homozygous MTAP deficiency as assessed by local or central NGS testing or MTAP protein deficiency as determined by local immunohistochemistry are eligible to participate in this study. MTAP deficiency can be determined by local testing results or central pre-screening next-generation sequencing (NGS). Once consent is given, subjects will provide their medical history and undergo screening safety tests to confirm that they meet all eligibility requirements for the study. Subjects must have adequate blood, kidney, and liver function. Subjects must provide archived tumor tissue samples (formalin-fixed, paraffin-embedded [FFPE] samples) collected within the past 5 years. If archived tumor tissue is unavailable, subjects must be willing to undergo a tumor biopsy prior to treatment, provided the investigator deems it safe.

[0247] Exemplary inclusion criteria

[0248] Subjects must be diagnosed with locally advanced or metastatic NSCLC with brain metastases by histology or cytology, provided that the attending physician determines that immediate CNS-specific treatment (e.g., radiation therapy or surgery) is unlikely. Note: Subjects are ineligible if small cell components are present.

[0249] At least one newly diagnosed and previously untreated (i.e., surgical or radiotherapy) brain lesion that meets the RANO-BM criteria for measurable disease by MRI. A subject is eligible if they meet all of the following criteria: a) neurological symptom grade ≤ 2; and b) currently receiving a stable or reduced dose of dexamethasone (if applicable). Note: Subjects requiring antiepileptic therapy or undergoing epilepsy prophylaxis are ineligible unless approved by a medical supervisor.

[0250] Subjects must have received at least one prior systemic therapy for locally advanced or metastatic disease and have experienced disease progression or relapse at or after receiving this treatment. Prior treatment must include platinum-based dual chemotherapy and a checkpoint inhibitor (if locally approved and considered standard of care), and may be administered as one line of therapy or as multiple lines of therapy individually, unless the subject has a medical contraindication to one of the required therapies. Subjects with targetable mutations must have received at least one approved targeted therapy for those mutations (e.g., EGFR, ALK, KRASG12C, etc.).

[0251] - If a subject shows progress within 6 months of receiving adjuvant therapy, the adjuvant therapy is counted as a line of therapy.

[0252] - If planned systemic therapy is performed after chemoradiotherapy, and there is no recorded progress between chemoradiotherapy and systemic therapy, the entire treatment process is counted as one therapy line.

[0253] - Maintenance therapy following platinum-based dual chemotherapy is not considered a separate line of treatment. Note: Bisphosphonates or denosumab are permitted for use in skeletal-related events, according to institutional guidelines.

[0254] (1) Homozygous MTAP loss as assessed by local or central NGS testing, or (2) MTAP protein loss as determined by local IHC testing.

[0255] Exemplary exclusion criteria

[0256] Previous / companion therapy:

[0257] - Antitumor therapy (chemotherapy, antibody therapy, molecularly targeted therapy, hormone therapy, or investigational agent) must be administered within 28 days of Day 1 of the study, unless the antitumor therapy has a half-life of less than 28 days (in which case recruitment may be permitted after appropriate consultation and upon washout from prior therapy < 28 days). Note: Bisphosphonates or denosumab are permitted for use in bone-related events, according to institutional guidelines.

[0258] -Previously treated with MAT2A inhibitors or PRMT5 inhibitors.

[0259] - Perform major surgery within 28 days of the first dose of compound G.

[0260] -Previous irradiation > 25% of bone marrow.

[0261] - Receive radiation therapy within 28 days of the first dose (or local or focused radiation therapy for palliative purposes within 14 days of the first dose). All radiation therapy-related toxicities must improve to ≤ Grade 1 before the first dose of the study treatment.

[0262] - Live vaccine therapy was administered within 4 weeks prior to the study drug administration.

[0263] - Therapeutic anticoagulation is used to treat active thromboembolic events. Note: Subjects receiving a stable dose of anticoagulation therapy for thromboembolic events for a duration of ≥ 1 month may be eligible upon approval. Note: For subjects receiving anticoagulation and undergoing a biopsy, safety precautions, such as discontinuation, may be considered if deemed necessary and safe.

[0264] - Use of unreviewed and unapproved prescription drugs that are known strong inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives (whichever is longer) prior to Day 1 of the study.

[0265] - Unresolved toxicities from previous anticancer therapies are defined as those that have not yet resolved to Grade 0 or 1 of the Common Criteria for Adverse Events (CTCAE) version 5.0, or have not resolved to the level specified in the eligibility criteria, except for alopecia. Grade 2 or 3 toxicities considered irreversible (defined as present and stable for ≥ 5 months) from previous anticancer therapies may be permitted if the exclusion criteria do not provide a separate description of the toxicity and with mutual agreement, such as endocrine disorders controlled by hormone replacement therapy.

[0266] Related disease: spinal cord compression.

[0267] Other medical conditions:

[0268] - History of other malignant tumors within the past 3 years, except for the following: malignant tumors treated for curative purposes and without known active disease for ≥ 2 years prior to recruitment, and the treating physician considers the risk of recurrence to be low. Non-melanoma skin cancer or malignant nevus with adequate treatment and no evidence of disease. Cervical cancer with adequate treatment and no evidence of disease. Breast ductal carcinoma in situ with adequate treatment and no evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer. Well-treated non-invasive papillary carcinoma or carcinoma in situ of the urothelial tract.

[0269] - There is evidence of any current interstitial lung disease or pneumonia, or a history of previous interstitial lung disease or non-infectious pneumonia.

[0270] - Active infection requiring systemic treatment.

[0271] - A history of arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months of the first dose of compound G.

[0272] - If myocardial infarction and / or symptomatic congestive heart failure (New York Heart Association Class II), unstable angina, or arrhythmia requiring medical treatment occurs within 12 months of the first dose of compound G.

[0273] - Gastrointestinal diseases that cannot be treated with PO drugs, malabsorption syndrome, requiring IV high-energy nutrition, feeding via gastric tube / jejunal tube, and uncontrolled inflammatory gastrointestinal diseases (e.g., Crohn's disease, ulcerative colitis).

[0274] - A history of intestinal obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of entering the study (unless approved), or a history of one or more gastrointestinal procedures that lead to malabsorption.

[0275] -History of solid organ transplantation.

[0276] - Diagnosis of congenital short QT syndrome.

[0277] Prior / current clinical research experience: Currently receiving treatment in another research facility or drug study, or less than 21 days or 5 half-lives after completing treatment in another research facility or one or more drug studies. Exclusion criteria include concurrent participation in other research procedures and observational studies.

[0278] Diagnostic assessment

[0279] - A positive test for known human immunodeficiency virus. Note: Eligible subjects are those with HIV, undetectable viral load, adequate CD4 T cell count, and no history of opportunistic infections as defined in AIDS.

[0280] - Viral hepatitis infection based on the following results and / or criteria:

[0281] • Positive for hepatitis B surface antigen (HepBsAg)

[0282] • HepBsAg is negative, and hepatitis B core antibody (HepBcAb) is positive.

[0283] - Polymerase chain reaction (PCR) is required for hepatitis B virus DNA. Subjects who test positive for hepatitis B virus DNA are ineligible.

[0284] • Positive hepatitis C virus antibody (HCVAb): PCR testing for hepatitis C virus RNA is required. Subjects testing positive for hepatitis C virus RNA are ineligible.

[0285] References:

[0286] ABRAXANE® US Prescribing Information, Bristol-Myers Squibb Company, New Jersey, 08543 (revision 8 / 2020).

[0287] ALIMTA® US Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revision 03 / 2023).

[0288] CARBOplatin Injection, U.S. Prescribing Information, Fresenius KABI,Lake Zurich, Illinois, 60047 (revision 5 / 2021).

[0289] Eisenhauer, et al., Eur. J. Cancer 2009 45:228-247.

[0290] KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ07033 (revision 3 / 2023).

[0291] LIBTAYO® US Prescribing Information, Regeneron Pharmaceuticals,Inc., Tarrytown, NY 10591 (revision 11 / 2022).

[0292] National Cancer Institute Common Terminology Criteria for AdverseEvents v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National CancerInstitute.

[0293] National Comprehensive Cancer Network. NCCN clinical practiceguidelines in oncology: non-small cell lung cancer. Version 3.2022, availableat https: / / www.nccn.org / .

[0294] OPDIVO® US Prescribing Information, Bristol-Myers Squibb Co.,Princeton, NJ 08543 (revision 02.2023).

[0295] Singh et al., Cancer, 125:2203-2212, 2019.

[0296] TAXOL® (paclitaxel) INJECTION U.S. Prescribing Information, Bristol-Myers Squibb Company, Princeton, New Jersey, 08543 (revision 4 / 2011).

Claims

1. A method for treating MTAP-resistant lung cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of each of the following: (a) Chemical G: (G), or a pharmaceutically acceptable salt thereof; and (b) Anti-PD1 antibody.

2. The method of claim 1, wherein compound G is applied as a free base.

3. The method of claim 1 or 2, wherein the method comprises administering a total daily dose of 500 mg of compound G to the patient based on the free base weight of compound G.

4. The method of claim 1 or 2, wherein the method comprises administering a total daily dose of 600 mg of compound G to the patient based on the free base weight of compound G.

5. The method of claim 1 or 2, wherein the method comprises administering a total daily dose of 800 mg of compound G to the patient based on the free base weight of compound G.

6. The method of claim 1 or 2, wherein the method comprises administering a total daily dose of 900 mg of compound G to the patient based on the free base weight of compound G.

7. The method of claim 1 or 2, wherein the method comprises administering a total daily dose of 1200 mg of compound G to the patient based on the free base weight of compound G.

8. The method of claim 1 or 2, wherein the method comprises administering a total daily dose of 1600 mg of compound G to the patient based on the free base weight of compound G.

9. The method of any one of claims 1-8, wherein compound G is administered once daily.

10. The method of any one of claims 1-9, wherein compound G is administered orally.

11. The method of any one of claims 1-10, wherein compound G is administered as a tablet formulation.

12. The method of any one of claims 1-11, wherein the lung cancer is non-small cell lung cancer (NSCLC).

13. The method of claim 12, wherein the NSCLC is a scaly NSCLC.

14. The method of claim 12, wherein the NSCLC is a non-squamous NSCLC.

15. The method of any one of claims 12-14, wherein the NSCLC is locally late.

16. The method of any one of claims 12-14, wherein the NSCLC is transferable.

17. The method of any one of claims 1-16, wherein the anti-PD1 antibody is administered every three weeks.

18. The method of any one of claims 1-17, wherein the anti-PD1 antibody is administered via IV.

19. The method of any one of claims 1-18, wherein the anti-PD1 antibody is pembrolizumab.

20. The method of claim 19, wherein the method comprises administering 200 mg of pembrolizumab to the patient via IV every three weeks.

21. The method of claim 19, the method comprising administering to the patient (a) 500 mg of compound G once daily based on the free base weight of compound G, and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered intravenously every three weeks.

22. The method of claim 19, comprising administering to the patient (a) 600 mg of compound G once daily, based on the free base weight of compound G, and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered intravenously every three weeks.

23. The method of claim 19, the method comprising administering to the patient (a) 800 mg of compound G once daily based on the free base weight of compound G, and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered intravenously every three weeks.

24. The method of claim 19, the method comprising administering to the patient (a) 900 mg of compound G once daily based on the free base weight of compound G, and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered intravenously every three weeks.

25. The method of claim 19, comprising administering to the patient (a) 1200 mg of compound G once daily, based on the free base weight of compound G, and (b) 200 mg of pembrolizumab, wherein the pembrolizumab is administered intravenously every three weeks.

26. The method of any one of claims 1-25, further comprising administering carboplatin to the patient.

27. The method of claim 26, wherein the method comprises administering AUC5 or AUC6 carboplatin to the patient via IV every three weeks.

28. The method of any one of claims 1-27, further comprising administering paclitaxel to the patient.

29. The method of claim 28, wherein the method comprises administering 200 mg / m² to the patient via IV every three weeks. 2 Paclitaxel.

30. The method of any one of claims 1-27, further comprising administering pemetrexed to the patient.

31. The method of claim 30, wherein the method comprises administering 500 mg / m² to the patient via IV every three weeks. 2 Pemetrexed.

32. The method of any one of claims 1-19, the method comprising administering to the patient (a) compound G, (b) carboplatin, (c) paclitaxel and (d) pembrolizumab.

33. The method of claim 32, wherein the method comprises administering to the patient (a) 500 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

34. The method of claim 32, wherein the method comprises administering to the patient (a) 600 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

35. The method of claim 32, wherein the method comprises administering to the patient (a) 800 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

36. The method of claim 32, wherein the method comprises administering to the patient (a) 900 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

37. The method of claim 32, wherein the method comprises administering to the patient (a) 1200 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Paclitaxel and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel and pembrolizumab are administered intravenously every three weeks.

38. The method of any one of claims 1-19, the method comprising administering to the patient (a) compound G, (b) carboplatin, (c) pemetrexed and (d) pembrolizumab.

39. The method of claim 38, wherein the method comprises administering to the patient (a) 500 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

40. The method of claim 38, wherein the method comprises administering to the patient (a) 600 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

41. The method of claim 38, wherein the method comprises administering to the patient (a) 800 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

42. The method of claim 38, wherein the method comprises administering to the patient (a) 900 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

43. The method of claim 38, wherein the method comprises administering to the patient (a) 1200 mg of compound G once daily, based on the free base weight of compound G, (b) carboplatin at AUC5 or AUC6, and (c) 200 mg / m². 2 Pemetrexed and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab are administered intravenously every three weeks.

44. A method for treating a patient with MTAP-resistant cancer and brain metastases, the method comprising administering to the patient a therapeutically effective amount of compound G: (G), or a pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein the MTAP-ineffective cancer is lung cancer.

46. ​​The method of claim 45, wherein the lung cancer is non-small cell lung cancer (NSCLC).

47. The method of claim 46, wherein the NSCLC is a scaly NSCLC.

48. The method of claim 46, wherein the NSCLC is a non-squamous NSCLC.

49. The method of any one of claims 46-48, wherein the NSCLC is locally late.

50. The method of any one of claims 46-48, wherein the NSCLC is transferable.

51. The method of any one of claims 44-50, wherein the brain metastasis is an active, previously untreated brain metastasis.

52. The method of any one of claims 44-51, wherein compound G is administered once daily.

53. The method of any one of claims 44-51, wherein compound G is administered orally.

54. The method of any one of claims 44-53, wherein compound G is administered as a tablet formulation.

55. The method of any one of claims 44-54, wherein the method comprises administering compound G to the patient as a single therapy.

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