WO2025207705A1

WO2025207705A1 - Cancer treatments using mta-cooperative prmt5 inhibitors

Info

Publication number: WO2025207705A1
Application number: PCT/US2025/021444
Authority: WO
Inventors: Brian BELKMONTES; Katherine SLEMMONS; Tobias Eggert
Original assignee: Amgen Inc
Current assignee: Amgen Inc
Priority date: 2024-03-26
Filing date: 2025-03-26
Publication date: 2025-10-02
Anticipated expiration: 2026-09-26
Also published as: TW202602455A

Abstract

Described herein are methods of treating a 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 either paclitaxel or pemetrexed. Further described herein are methods of treating a MTAP-null cancer in a patient also suffering from brain metastases comprising administering to the patient a PRMT5 inhibitor.

Description

CANCER TREATMENTS USING MTA-COOPERATIVE PRMT5 INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of 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

[0002] Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases. Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition 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 disease. PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders.

[0003] The homozygous deletion of tumor suppressor genes is a key driver of cancer, frequently resulting in the collateral loss of passenger genes located in close genomic proximity to the tumor suppressor. Deletion of these passenger genes can create therapeutically tractable vulnerabilities that are specific to tumor cells. Homozygous deletion of the chromosome 9p21 locus, which harbors the well-known tumor suppressor CDKN2A (cyclin dependent kinase inhibitor 2A), occurs in 15% of all tumors and frequently includes the passenger gene MTAP (methylthioadenosine phosphorylase), a key enzyme in the methionine and adenine salvage pathways. Deletion of MTAP results in accumulation of its substrate, methylthioadenosine (MTA). MTA shares close structural similarity to S-adenosylmethionine (SAM), the substrate methyl donor for the type II methyltransferase PRMT5. Elevated MTA levels, driven by loss of MTAP, selectively compete with SAM for binding to PRMT5, placing the methyltransferase in a hypomorphic state, vulnerable to further PRMT5 inhibition. Multiple genome scale shRNA drop out screens performed in large tumor cell line panels have identified a strong correlation between MTAP loss and cell line dependency on PRMT5, further highlighting the strength of this metabolic vulnerability. However, PRMT5 is a known cell essential gene and conditional PRMT5 knockout and siRNA knockdown studies suggest that significant liabilities could be associated with inhibiting PRMT5 in normal tissues (e.g. pan-cytopenia, infertility, skeletal muscle loss, cardiac hypertrophy, others). Therefore, novel strategies are required to exploit this metabolic vulnerability and preferentially target PRMT5 in MTAP-null tumors while sparing PRMT5 in normal tissues (MTAP WT). Targeting PRMT5 with an MTA-cooperative small molecule inhibitor could preferentially target the MTA bound state of PRMT5, enriched in MTAP-null tumor cells, while providing an improved therapeutic index over normal cells where MTAP is intact and MTA levels are low. SUMMARY

[0004] In one aspect, described herein are methods of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of (a) Compound G: pharmaceutically acceptable salt thereof; and (b) an anti-PD1 antibody.

[0005] In some embodiments, the MTAP-null 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 methods described herein further comprise administering carboplatin to the patient. In some embodiments, the methods described herein further comprise administering paclitaxel to the patient. In various embodiments, the methods described herein further comprise administering paclitaxel and carboplatin to the patient. In some embodiments, the methods described herein further comprise administering pemetrexed to the patient. In various embodiments, the methods described herein further comprise administering pemetrexed and carboplatin to the patient. In some embodiments, the methods described herein comprise administering to the patient (a) Compound G and (b) pembrolizumab. In some embodiments, the methods described herein comprise administering to the patient (a) Compound G, (b) carboplatin, (c) paclitaxel, and (d) pembrolizumab. In some embodiments, the methods described herein comprise administering to the patient (a) Compound G, (b) carboplatin, (c) pemetrexed, and (d) pembrolizumab.

[0006] In another aspect, described herein are methods of treating a patient suffering from a MTAP-null cancer and having brain metastases comprising administering to the patient Compound G: pharmaceutically acceptable salt thereof. In some embodiments, the

MTAP-null cancer is lung cancer. In some embodiments, the lung cancer is NSCLC. In some embodiments, the

NSCLC is locally advanced. In some cases, the NSCLC is metastatic. In some embodiments, the brain metastases are active, previously untreated brain metastases. In some cases, Compound G is administered to the patient as a monotherapy. DETAILED DESCRIPTION

[0007] The disclosure provides methods of treating a MTAP-null cancer in a patient in need thereof, such as lung cancer (e.g., non-small cell lung cancer), by administering a therapeutically effective amount of Compound pharmaceutically acceptable salt thereof, to the patient.

[0008] The methods disclosed herein can further comprise administering a therapeutically effective amount of an anti-Programmed Death 1 (PD1) antibody (e.g., pembrolizumab) to the patient. In some cases, the methods further comprise administering therapeutically effective amounts of an anti-PD 1 antibody (e.g., pembrolizumab) and one or more additional therapeutic agents to the patient. A "therapeutically effective amount” of a compound disclosed herein, such as Compound G, means an amount effective to treat or to prevent development of, or to alleviate the existing symptoms of, the patient being treated. Accordingly, in various aspects, the disclosure provides methods of treating a MTAP-null cancer in a patient a therapeutically effective amount of each of comprising administering to the patient (a) Compound pharmaceutically acceptable salt thereof; and (b) an anti-Programmed Death 1 (PD1) antibody.

[0009] In some cases, Compound G is administered to a patient suffering from brain metastases. The term "brain metastases” refers to a cancer that has spread from the original (primary, non-brain) tumor to the brain. Brain metastases are common in patients with NSCLC, occurring in approximately 25% of patients. Nevertheless, patients with brain metastases are often excluded from clinical trials due to concerns of poor functional status, increased risk of toxicity, poorer prognosis, and shorter life expectancy. However, preclinical evidence based on an in vivo rat pharmacokinetic study suggests CNS penetrance of Compound G. Thus, patients with NSCLC with homozygous MTAP-deletion and active brain metastases may benefit from therapy with Compound G. Active brain metastases can be assessed by the presence of intracranial lesions. It is to be understood that while "metastases” is plural, patients exhibiting only one intracranial lesion under the criteria noted below is a patient who has "active brain metastases.” In some embodiments, a patient having active brain metastases has at least one measurable intracranial lesion > 5 mm. In some embodiments, a patient having active brain metastases has at least one measurable intracranial lesion >5 mm but < 10 mm. In some embodiments, a patient having active brain metastases has at least one measurable intracranial lesion > 10 mm. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety. See also Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) (Lin et al, 2015). RANO-BM is an extension of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Eisenhauer et al, 2009) and the Response Assessment in Neuro Oncology (RANO) (Wen et al, J. Clin. Oncol., 28:1963-1972, 2010) response assessment criteria for high-grade gliomas. Accordingly, in various aspects, the disclosure provides methods of treating a patient suffering from a MTAP-null cancer and having brain metastases comprising administering to the patient a therapeutically effective amount of Compound pharmaceutically acceptable salt thereof. In some cases, the brain metastases are active, previously untreated brain metastases. In some cases, the patient suffering from a MTAP-null cancer and having brain metastases is administered Compound G, or pharmaceutically acceptable salt thereof, as a monotherapy.

[0010] Also provided is a use of Compound pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a patient suffering from a MTAP-null cancer and having brain metastases.

[0011] Also provided is a use of Compound pharmaceutically acceptable salt thereof, for treating a patient suffering from a MTAP-null cancer and having brain metastases. [0012] Also provided is a use of (a) Compound acceptable salt thereof; and (b) an anti-Programmed Death 1 (PD1) antibody in the manufacture of a medicament for treating a MTAP-null cancer in a patient in need thereof.

[0013] Also provided is a use of (a) Compound pharmaceutically acceptable salt thereof; and (b) an anti-Programmed Death 1 (PD1) antibody for treating a MTAP-null cancer in a patient in need thereof.

[0014] 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 bases. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002.

[0015] Pharmaceutical compositions containing Compound G can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing 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. [0016] In some embodiments, Compound G is administered to a patient in need thereof orally and once a day. A "patient” or "subject” to which administration is contemplated includes, but is not limited to, humans, i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomologus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "patient” and "subject” are used interchangeably herein.

[0017] In some embodiments, the patient is administered 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, based upon free base weight of Compound G. In some embodiments, the patient is administered 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, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 500 mg, 800 mg, 900 mg, or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 500 mg, 800 mg, or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 800 mg, 900 mg, or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 800 mg or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 120 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 240 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 300 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 400 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 480 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 500 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 600 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 700 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 800 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 900 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 1000 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 1100 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 1600 mg of Compound G, based upon free base weight of Compound G.

[0018] 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, the patient is administered 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, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 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, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 500 mg, 800 mg, 900 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 500 mg, 800 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 800 mg, 900 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 800 mg or 1200 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 120 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 200 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 240 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 300 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 400 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 480 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 500 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 600 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 700 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 800 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 900 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 1000 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 1100 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 1200 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days. In some embodiments, the patient is administered 1600 mg of Compound G, based upon free base weight of Compound G, once daily for 21 consecutive days.

[0019] In some embodiments, Compound G is administered in treatment cycles. In some embodiments, the treatment cycle is 21 days. In some embodiments, the cycle may be repeated. In various embodiments, the patient undergoes 1, 2, 3, or more treatment cycles. In some embodiments, the patient undergoes 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.

Anti-PD1 Antibodies

[0020] In various aspects, the methods described herein comprise administering an anti-Programmed Death 1 (PD1) antibody to the patient. TsPD-1 antibodies and methods of using in treatment of disease are described in U.S. Pat. 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 US Publication Nos. US20110171220; US20110171215; and US20110271358. In some cases, the anti-PD1 antibody is administered every three weeks. In some cases, the anti-PD1 antibody is administered via IV.

[0021] Pembrolizumab (KEYTRUDA®) is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using are disclosed in U.S. Pat. No. 8,168,757. See also KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ 07033 (revision 3/2023), which is herein incorporated by reference in its entirety.

[0022] Nivolumab (OPDIVO®) is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity. Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands PD-L1 and PD-L2, resulting in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of P13k/Akt pathway activation. Other names for nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence for nivolumab and methods of using and making are disclosed in U.S. Pat. No. 8,008,449. See also, OPDIVO® US Prescribing Information, Bristol-Myers Squibb Co., Princeton, NJ 08543 (revision 02/2023), which is herein incorporated by reference in its entirety.

[0023] Cemiplimab (LIBTAYO® is an anti-PD 1 antibody marketed for the treatment of cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BSC), and non-small cell lunch cancer (NSCLC) by Regeneron Pharmaceuticals. The amino acid sequences for cemiplimab are disclosed in U.S. Patent No. 11,292,842. See also LIBTAYO® US Prescribing Information, Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 (revision 11/2022), which is herein incorporated by reference in its entirety.

[0024] In some embodiments, the anti-PD1 antibody is tislelizumab, dostarlimab and toripalimab.

[0025] In some embodiments, methods described herein comprise administering an anti-PD-L1 antibody.

Exemplary anti-PD-L1 antibodies include, but are not limited to, atezolizumab and durvalumab.

[0026] Accordingly, provided herein are methods comprising the administration of a therapeutically effective amount of an anti-PD 1 antibody to the patient. In some embodiments, the methods described herein comprise administering to the pembrolizumab. In some embodiments, 200 mg pembrolizumab is administered to the patient. In various embodiments, the pembrolizumab is administered intravenously. In some cases, the pembrolizumab is administered every three weeks.

Carbopl atin

[0027] In some embodiments, the methods described herein comprise further administering carboplatin to the patient. Carboplatin is a platinum coordination compound. The chemical name for carboplatin is platinum, diammine [1 ,1 -cyclobutane-dicarboxylato(2-)-0,0']-, (SP-4-2). Carboplatin acts by crosslinking deoxyribonucleic acid (DNA) strands, thereby inhibiting DNA synthesis and function. Platinum-containing chemotherapy has been the preferred front-line regimen for subjects with advanced or metastatic non-small cell lung cancer (NSCLC) without genomic epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALA) tumor aberrations until the recent introduction of immunotherapy in combination with chemotherapy (e.g., pembrolizumab in combination with pemetrexed and platinum chemotherapy; see KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ 07033 (revision 03/2023), which is herein incorporated by reference in its entirety). The other chemotherapy agent combined with platinum typically includes pemetrexed (for nonsquamous NSCLC), gemcitabine (for squamous NSCLC), or taxanes (paclitaxel, nab-paclitaxel, or docetaxel).

[0028] Carboplatin is commercially available as PARAPLATIN®, BLASTOCARB®, BLASTOPLATIN®, CARBOKEM®, CARBOMAX®, PARAPLATIN®, CARBOPA®, KARPLAT®, and others. Complete information about carboplatin preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g., CARBOplatin Injection, U.S. Prescribing Information, Fresenius KABI, Lake Zurich, Illinois, 60047 (revision 5/2021), which is herein incorporated by reference in its entirety).

[0029] Accordingly, provided herein are methods comprising the administration of a therapeutically effective amount of carboplatin to the patient. In some embodiments, the methods described herein comprise administering to the patient AUC5 or AUC6 carboplatin. In some embodiments, the methods described herein comprise administering to the patient AUC5 carboplatin. In some embodiments, the methods described herein comprise administering to the patient AUC6 carboplatin. In various embodiments, carboplatin is administered intravenously. In some cases, the carboplatin is administered every three weeks. Paclitaxel

[0030] In some embodiments, the methods described herein comprise further administering paclitaxel to the patient. Paclitaxel is a semisynthetic taxane, a class of anticancer agents that bind to beta tubulin, thereby stabilizing microtubules and inducing cell cycle arrest and apoptosis. Paclitaxel 200 mg/m² administered intravenously over 3 hours every 3 weeks in combination with carboplatin is a standard of care option for the treatment of patients with good performance status, advanced or metastatic, previously untreated NSCLC.

[0031] Complete information about paclitaxel (TAXOL®) preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g., TAXOL® (paclitaxel) INJECTION U.S. Prescribing Information, Bristol-Myers Squibb Company, Princeton, New Jersey, 08543 (revision 4/2011), which is herein incorporated by reference in its entirety). Complete information about nab- paclitaxel (ABRAXANE®) preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g., ABRAXANE® U.S. Prescribing Information, Bristol-Myers Squibb Company, New Jersey, 08543 (revision 8/2020), which is herein incorporated by reference in its entirety).

[0032] Accordingly, provided herein are methods comprising the administration of a therapeutically effective amount of paclitaxel to the patient. In some embodiments, 200 mg/m² paclitaxel is administered to the patient. In various embodiments, paclitaxel is administered intravenously ("via IV administration”). In various embodiments, the paclitaxel is administered intravenously over 24 hours. In some cases, the paclitaxel is administered every three weeks.

Pemetrexed

[0033] In some embodiments, the methods described herein comprise further administering pemetrexed to the patient. Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. Pemetrexed is approved by the U.S. Food and Drug Administration (FDA), in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin), as initial treatment of subjects with metastatic nonsquamous NSCLC with no EGFR or ALK tumor genomic aberrations. It is also approved in combination with cisplatin for the initial treatment for subjects with locally advanced or metastatic nonsquamous NSCLC. In the maintenance setting, pemetrexed is approved as a single agent for treatment of subjects with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after 4 cycles of first-line platinum doublet chemotherapy. It is also approved as a single agent for the treatment of subjects with recurrent, metastatic nonsquamous NSCLC after prior chemotherapy.

[0034] Pemetrexed is commercially available as ALIMTA®, for example. Complete information about pemetrexed preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g., ALIMTA® U.S. Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revision 08/2022), which is herein incorporated by reference in its entirety). [0035] Provided herein are methods, wherein the therapeutically effective amount of pemetrexed is 500 mg/m². In various embodiments, pemetrexed is administered intravenously ("via IV administration”). In some embodiments, pemetrexed is administered intravenously over 10 minutes.

[0036] Also provided herein are methods further comprising administering other medications to the subject when treated with pemetrexed. In various embodiments, the methods provided herein are methods further comprising administering to the subject a therapeutically effective amount of folic acid. In various embodiments, the methods provided herein are methods further comprising administering to the subject a therapeutically effective amount of vitamin B12. In various embodiments, the methods provided herein are methods further comprising administering to the subject a therapeutically effective amount of a corticosteroid, such as dexamethasone or an equivalent thereof.

Anti-PD1 Dosage Regimens

[0037] In some embodiments, the methods described herein comprise administering Compound G and pembrolizumab to the patient. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 200 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 300 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 400 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 480 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 500 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 600 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 700 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 800 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 900 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1000 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1100 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1200 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1600 mg Compound G once daily and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0038] In some embodiments, the methods described herein comprise administering to the patient (a) Compound G, (b) carboplatin, (c) paclitaxel, and (d) pembrolizumab. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 200 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 300 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 400 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 480 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 500 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 600 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 700 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 800 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 900 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1000 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1100 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1200 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1600 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks. In some embodiments, the carboplatin is AUC5 carboplatin. In some embodiments, the carboplatin is AUC6 carboplatin.

[0039] In some embodiments, the methods described herein comprise administering to the patient (a) Compound G, (b) carboplatin, (c) pemetrexed, and (d) pembrolizumab. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 200 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 300 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 400 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 500 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 600 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 700 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 800 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 900 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1000 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1100 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1200 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the methods described herein comprise administering to the patient (a) 1600 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. In some embodiments, the carboplatin is AUC5 carboplatin. In some embodiments, the carboplatin is AUC6 carboplatin.

Other Medications and Their Dosing

[0040] As discussed above, the disclosure provides methods further comprising administering to the 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.

[0041] Pemetrexed is a drug to be used as a component of platinum-based doublet chemotherapy for subjects with nonsquamous NSCLC. Singh et al., Cancer, 125:2203-2212, 2019. Because pemetrexed is an antifolate drug that acts primarily by disrupting folate-dependent metabolism and inhibiting multiple enzymes involved in purine and pyrimidine synthesis, myelosuppression is its principal drug toxicity. Id. It has been demonstrated that the addition of vitamin B12 and folic acid to pemetrexed-containing chemotherapy regimens leads to a reduction of severe adverse events, especially hematologic toxicity, without diminishing antitumor efficacy. Id. Recommendations for supplementation include starting oral folic acid (400-1000 pg daily) one week before the first dose of pemetrexed and continuing the same for at least 3 weeks beyond cessation of therapy (id., and see, e.g., ALIMTA® U.S. Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revision 8/2022)). Along with folic acid, intramuscular vitamin B12 injection (1000 pg) can be administered and repeated every 9 weeks thereafter until end of treatment. Id.

[0042] Accordingly, the therapeutically effective amount of folic acid administered in the methods provided herein is 350 pig to 1000 pig once daily. In some embodiments, the therapeutically effective amount of folic acid is 400 pig once daily. In various embodiments, the therapeutically effective amount of folic acid is 400 pig to 1000 pig once daily. In various embodiments, the folic acid administration commences 7 days prior to pemetrexed administration and ends 21 days after cessation of pemetrexed administration.

[0043] In some embodiments, the therapeutically effective amount of vitamin B12 administered in the methods provided herein is 1 mg. In various embodiments, the vitamin B12 is administered in the week prior to first pemetrexed administration and once every 9 weeks (± 2 weeks) thereafter until cessation of pemetrexed administration. In some embodiments, the vitamin B12 is administered one week prior to first pemetrexed administration and once every 9 weeks thereafter until cessation of pemetrexed administration. In various embodiments, the vitamin B12 is administered intramuscularly.

[0044] As discussed above, also provided herein are methods, further comprising administering to the subject a therapeutically effective amount of a corticosteroid, such as dexamethasone or an equivalent thereof.

[0045] Skin rash due to pemetrexed has been reported more frequently in subjects not pretreated with a corticosteroid. Pretreatment with corticosteroids (dexamethasone or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical studies, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after pemetrexed administration. See, e.g., ALIMTA® U.S. Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revision 8/2022). Accordingly, also provided herein are methods further comprising administering to the subject a therapeutically effective amount of a corticosteroid. 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, the dexamethasone is administered the day before, the day of, and the day after each pemetrexed administration to the subject.

[0046] In some cases, an antiemetic is administered to the patient as part of the anti-PD 1 dosage regimen. Prior Therapeutic Regimens of Patients

[0047] In various cases, the patients have been subject to a least one prior therapeutic regimen before beginning a method as disclosed herein (e.g., administration of Compound G) - i.e. , the disclosed methods are a second (or higher) line of therapy, and the patients are not treatment naive for the cancer being treated by the methods disclosed herein. In some embodiments, the patient has previously been treated with chemotherapy prior to treatment with Compound G. In some embodiments, the patient had received at least one systemic therapy for locally advanced or metastatic disease prior to administration of Compound G. In some embodiments, the system therapy comprises a platinum-based doublet chemotherapy and checkpoint inhibitor. In some cases, the system therapy comprises platinum chemoimmunothereapy, chemotherapy, or immunotherapy. In some embodiments, the patient was previously treated with a checkpoint inhibitor prior to treatment with Compound G. In some embodiments, patients with actionable mutations have received at least one approved targeted therapy for the treatment of these mutations, e.g., EGFR, ALK, KRASG12C.

[0048] In some cases, patients have not received prior systemic therapy for locally advanced or metastatic NSCLC. In some cases, patients have received prior systemic therapy, and the first dose of prior systemic therapy was administered within 56 days (28 days pre-screening + 28 days screening) of the first dose of Compound G.

[0049] In some embodiments, the patient did not receive anti-tumor therapy within 28 days of receiving the first dose of Compound G. In some embodiments, the patient did not receive anti-tumor therapy within 21 days of receiving the first dose of Compound G. Exemplary anti-tumor therapies include, chemotherapy, antibody therapy, molecular targeted therapy or hormonal therapy. In some embodiments, the patient had not previously been treated with a MAT2A inhibitor (i.e., the patient is MAT2A inhibitor naive). An MAT2A inhibitor is a compound that inhibits methionine adenosyltransferase II alpha. An exemplary MAT2A inhibitor for use in the methods provided herein is AG 270 (3-(cyclohex-1 -en-1 -yl)-6-(4-methoxyphenyl)-2-phenyl-zetidindin-2- ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one).

[0050] In some embodiments, the patient had not previously been treated with a PRMT5 inhibitor (i.e., the patient is PRMT5 inhibitor naive). A PRMT5 inhibitor in a compound that inhibits protein arginine methyltransferase 5. The term "PRMT5 inhibitor” includes MTA-cooperative PRMT5 inhibitors. Exemplary PRMT5 inhibitors for use in the methods provided herein include, but are not limited to, pemrametostat (6-[(1- acetylpiperidin-4-yl)amino]-N-[(2S)-3-(3,4-dihydro-1 H-isoquinolin-2-yl)-2-hydroxypropyl]pyrimidine-4- carboxamide), GSK3203591 (2-(Cyclobutylamino)-N-[(2S)-3-(3,4-dihydro-2(1 H)-isoquinolinyl)-2-hydropropyl]-4- pyridinecarboxamide dihydrochloride)), LLY-283 ((R)-5'-phenyl-7-deazaadenosine; 6-amino-9-[(R)-5'- phenyl(ribofuranosyl)]-7-deazapurine, (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-1 H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile). [0051] In some embodiments, the patient is not being treated with a compound that is a strong inducer 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.

[0052] In some embodiments, the patient is not being treated with a compound that is a strong inhibitor of CYP3A4. Exemplary strong inhibitors of CYP3A4 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, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, lonafarnib, posaconazole, telithromycin, grapefruit juice, conivaptan, tucatinib, nefazodone, ceritinib, nelfinavir, saquinavir, ribociclib, idelalisib, and boceprevir.

[0053] In some cases, Compound G is not co-administered with an acid-reducing agent. In some embodiments, Compound G is not co-administered with proton pump inhibitors, histamine 2 receptor antagonists (H2RA), and/or locally acting antacids. In some cases, a locally acting antacid or an H2RA is administered 10 hours before or 2 hours after Compound G administration.

[0054] In some embodiments, the patient has not had an arterial thrombosis within 6 months before starting Compound G therapy. In some embodiments, the patient has not had myocardial infarction and/or symptomatic congestive heart failure congestive heart failure (New York Heart Association © class II), unstable angina, or history of cardiac arrest, ventricular tachycardia, known Wolf-Parkinson White Syndrome, or a genetic syndrome with increased risk of sudden cardiac death, e.g., Long QT syndrome, short QT syndrome, hereditary hypertrophic cardiomyopathy, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, or catecholaminergic polymorphic ventricular tachycardia.

[0055] In some embodiments, the patient does not have toxicity from prior anti-cancer therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria, with the exception of alopecia.

MTAP-Null Cancer

[0056] The disclosure provides methods of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient Compound G, optionally with an additional therapeutic agent. A MTAP- null cancer refers to a cancer that lacks expression of the enzyme methylthioadenosine phosphorylase (MTAP). The MTAP gene, located at chromosomal locus 9p21 is frequently co-deleted with the CDKN2A and CDKN2B genes. Selective MTAP deficiency, refers to deficiency without co-deletion of the CDKN2 genes, due either to selective deletion of the MTAP locus or to methylation of the MTAP promoter. MTAP-null cancers include MTAP- deficiency in at least 1% of disease cells, and in some cases, at least 20% of disease cells. Terms "MTAP-null”, "MTAP-deficient”, "MTAP-negative”, and "MTAP-deleted” are used interchangeably. [0057] An "MTAP-deficiency-related” or "MTAP-deficiency” or "MTAP deficient” disease (for example, a proliferating disease, e.g., a cancer) or a disease (for example, a proliferating disease, e.g., a cancer) "associated with MTAP deficiency” or a disease (for example, a proliferating disease, e.g., a cancer) "characterized by MTAP deficiency” and the like refer to an ailment (for example, a proliferating disease, e.g., a cancer) wherein a significant number of cells are MTAP-deficient. For example, in a MTAP-deficiency-related disease, one or more disease cells can have a significantly reduced post-translational modification, production, expression, level, stability and/or activity of MTAP. MTAP-null cancers can be identified by any suitable diagnostic test. Exemplary diagnostic tests for MTAP-deletion or MTAP protein loss include local immunohistochemistry (IHC) and local or central next generation sequencing (NGS).

[0058] Examples of MTAP-deficiency-related diseases include, but are not limited to, cancers, including but not limited to: glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma. In a patient afflicted with a MTAP-deficiency-related disease, it is possible that some disease cells (e.g., cancer cells) can be MTAP-deficient while others are not. Similarly, some disease cells may be MTA-accumulating while others are not. Thus, the present disclosure encompasses methods of treatment involving diseases of 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 cancer cells which are MTAP-deficient are also deficient in CDKN2A; the post-translational modification, production, expression, level, stability and/or activity of the CDKN2A gene or its product are decreased in these cells. The genes for MTAP and CDKN2A are in close proximity on chromosome 9p21; MTAP is located approximately 100 kb telomeric to CDKN2A. Many cancer cell types harbor CDKN2A/MTAP loss (loss of both genes). Thus, in some embodiments, a MTAP-deficient cell is also deficient in CDKN2A. In some embodiments, the patient does not have a tumor harboring a CDKN2A mutation.

[0059] In some embodiments, the MTAP-null cancer in the methods disclosed herein is lung cancer. In various 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.

Monitoring Efficacy of Treatment

[0060] The efficacy of a given treatment for cancer can be determined by the skilled clinician. However, a treatment is considered "effective treatment," as the term is used herein, if any one or all of the signs or symptoms of e.g., a tumor are altered in a beneficial manner or other clinically accepted symptoms are improved, or even ameliorated, e.g., by at least 10% following treatment with an agent as described herein. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and/or described herein.

[0061] The patient can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). RECIST v1 .1 is discussed in detail in the examples below. An at least stable disease is one that is a stable disease, has shown a partial response (PR) or has shown a complete response (CR) (i.e., "at least SD” = SD+PR+CR, often referred to as disease control). In various embodiments, the stable disease has neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD). In various embodiments, the patient exhibits at least a partial response (i.e., "at least PR” = PR+CR, often referred to as objective response). Additionally or alternatively, patient response can be determined by Response Assessment in Neuro-Oncology (RANG) criteria, see, e.g., Chen et al., Front Oncol., 2021 11 :679331.

[0062] Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases. In various embodiments, the progression of a patient's disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof.

[0063] Progression free survival (PFS) can be assessed as described in the RECIST 1.1 protocol. In various embodiments, the patient exhibits a PFS of at least 1 month. In various embodiments, the patient exhibits a PFS of at least 3 months. In some embodiments, the patient exhibits a PFS of at least 6 months.

Embodiments:

[0064] 1 . A method of treating a MTAP-null lung cancer in a patient in need thereof comprising administering to the patient acceptable salt thereof; and

(b) an anti-PD 1 antibody administered every three weeks.

[0065] 2. The method of embodiment 1 , wherein Compound G is administered as a free base. [0066] 3. The method of embodiment 1 , comprising administering to the patient 400 mg Compound G once daily, based upon free base weight of Compound G.

[0067] 4. The method of embodiment 1 , comprising administering to the patient 500 mg Compound G once daily, based upon free base weight of Compound G.

[0068] 5. The method of embodiment 1 , comprising administering to the patient 600 mg Compound G once daily, based upon free base weight of Compound G.

[0069] 6. The method of embodiment 1 , comprising administering to the patient 800 mg Compound G once daily, based upon free base weight of Compound G.

[0070] 7. The method of embodiment 1, comprising administering to the patient 1200 mg Compound G once daily, based upon free base weight of Compound G.

[0071] 8. The method of any one of embodiments 1-6, wherein the lung cancer is non-squamous cell lung cancer (NSCLC).

[0072] 9. The method of embodiment 8, wherein the NSCLC is metastatic.

[0073] 10. The method of any one of claims 1-9, wherein the anti-PD1 antibody is pembrolizumab.

[0074] 11 . The method of embodiment 10, comprising administering to the patient 200 mg pembrolizumab via IV administration every three weeks.

[0075] 12. The method of embodiment 10, comprising administering to the patient (a) 400 mg Compound

G once daily, (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0076] 13. The method of embodiment 10, comprising administering to the patient (a) 500 mg Compound

[0077] 14. The method of embodiment 10, comprising administering to the patient (a) 600 mg Compound

[0078] 15. The method of embodiment 10, comprising administering to the patient (a) 800 mg Compound

[0079] 16. The method of embodiment 10, comprising administering to the patient (a) 1200 mg

Compound G once daily, (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0080] 17. The method of any one of embodiments 1-16, further comprising administering carboplatin to the patient.

[0081] 18. The method of embodiment 17, comprising administering to the patient AUC5 or AUC6 carboplatin via IV every three weeks. [0082] 19. The method of any one of embodiments 1-18, further comprising administering paclitaxel to the patient.

[0083] 20. The method of embodiment 19, comprising administering to the patient 200 mg/m² paclitaxel via IV every three weeks.

[0084] 21 . The method of any one of embodiments 1-20, further comprising administering pemetrexed to the patient.

[0085] 22. The method of embodiment 21 , comprising administering to the patient 500 mg/m² pemetrexed via IV every three weeks.

[0086] 23. The method of any one of embodiments 1-20, comprising administering to the patient (a) Compound G, (b) carboplatin, (c) paclitaxel, and (d) pembrolizumab.

[0087] 24. The method of embodiment 23, comprising administering to the patient (a) 400 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0088] 25. The method of embodiment 23, comprising administering to the patient (a) 500 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0089] 26. The method of embodiment 23, comprising administering to the patient (a) 600 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0090] 27. The method of embodiment 23, comprising administering to the patient (a) 800 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0091] 28. The method of embodiment 23, comprising administering to the patient (a) 1200 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0092] 29. The method of any one of embodiments 1-18, 21 and 22, comprising administering to the patient (a) Compound G, (b) carboplatin, (c) pemetrexed, and (d) pembrolizumab.

[0093] 30. The method of embodiment 29, comprising administering to the patient (a) 500 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. [0094] 31 . The method of embodiment 29, comprising administering to the patient (a) 600 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

[0095] 32. The method of embodiment 29, comprising administering to the patient (a) 800 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

[0096] 33. The method of embodiment 29, comprising administering to the patient (a) 1200 mg Compound G once daily, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab via IV every three weeks.

[0097] 34. A method of treating a patient suffering from MTAP-null cancer and having brain metastases acceptable salt thereof.

[0098] 35. The method of embodiment 34, wherein the MTAP-null cancer is lung cancer.

[0099] 36. The method of embodiment 35, wherein the lung cancer is non-squamous cell lung cancer

(NSCLC).

[0100] 37. The method of any one of embodiments 34-36, comprising administering to the patient 400 mg Compound G once daily

[0101] 38. The method of any one of embodiments 34-36, comprising administering to the patient 500 mg Compound G once daily.

[0102] 39. The method of any one of embodiments 34-36, comprising administering to the patient 600 mg Compound G once daily

[0103] 40. The method of any one of embodiments 34-36, comprising administering to the patient 800 mg Compound G once daily.

[0104] 41. The method of any one of claims 34-36, comprising administering to the patient 1200 mg Compound G once daily.

[0105] 42. The method of any one of claims 34-41, wherein the brain metastases are active, previously untreated brain metastases. [0106] 43. The method of any one of claims 34-42, comprising administering Compound G to the patient as a monotherapy.

Additional Embodiments:

[0107] 1 A. A method of treating a MTAP-null lung cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of (a) Compound G, pharmaceutically acceptable salt thereof; and (b) an anti-PD1 antibody.

[0108] 2A. The method of claim 1A, wherein Compound G is administered as a free base.

[0109] 3A. The method of embodiment 1A or 2A, comprising administering to the patient a total daily dose of 500 mg Compound G, based upon free base weight of Compound G.

[0110] 4A. The method of embodiment 1A or 2A, comprising administering to the patient a total daily dose of 600 mg Compound G, based upon free base weight of Compound G.

[0111] 5A. The method of embodiment 1A or 2A, comprising administering to the patient a total daily dose of 800 mg Compound G, based upon free base weight of Compound G.

[0112] 6A. The method of embodiment 1A or 2A, comprising administering to the patient a total daily dose of 900 mg Compound G, based upon free base weight of Compound G.

[0113] 7A. The method of embodiment 1A or 2A, comprising administering to the patient a total daily dose of 1200 mg Compound G, based upon free base weight of Compound G.

[0114] 8A. The method of embodiment 1A or 2A, comprising administering to the patient a total daily dose of 1600 mg Compound G, based upon free base weight of Compound G.

[0115] 9A. The method of any one of embodiments 1A-8A, wherein Compound G is administered once daily.

[0116] 10A. The method of any one of embodiments 1A-9A, wherein Compound G is administered orally.

[0117] 11 A. The method of any one of embodiments 1A-10A, wherein Compound G is administered as a tablet formulation.

[0118] 12A. The method of any one of embodiments 1A-11A, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0119] 13A. The method of embodiment 12A, wherein the NSCLC is squamous. [0120] 14A. The method of embodiment 12A, wherein in the NSCLC is non-squamous.

[0121] 15A. The method of any one of embodiments 12A-14A, wherein the NSCLC is locally advanced.

[0122] 16A. The method of any one of embodiments 12A-14A, wherein the NSCLC is metastatic.

[0123] 17A. The method of any one of embodiments 1 A-16A, wherein the anti-PD 1 antibody is administered every three weeks.

[0124] 18A. The method of any one of embodiments 1 A-17A, wherein the anti-PD 1 antibody is administered via IV.

[0125] 19A. The method of any one of embodiments 1 A-18A, wherein the anti-PD 1 antibody is pembrolizumab.

[0126] 20A. The method of embodiment 19A, comprising administering to the patient 200 mg pembrolizumab via IV every three weeks.

[0127] 21 A. The method of embodiment 19A, comprising administering to the patient (a) 500 mg Compound G once daily, based upon free base weight of Compound G, and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0128] 22A. The method of embodiment 19A, comprising administering to the patient (a) 600 mg Compound G once daily, based upon free base weight of Compound G, and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0129] 23A. The method of embodiment 19A, comprising administering to the patient (a) 800 mg Compound G once daily, based upon free base weight of Compound G, and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0130] 24A. The method of embodiment 19A, comprising administering to the patient (a) 900 mg Compound G once daily, based upon free base weight of Compound G, and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0131] 25A. The method of embodiment 19A, comprising administering to the patient (a) 1200 mg Compound G once daily, based upon free base weight of Compound G, and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV every three weeks.

[0132] 26A. The method of any one of embodiments 1 A-25A, further comprising administering carboplatin to the patient.

[0133] 27A. The method of embodiment 26A, comprising administering to the patient AUC5 or AUC6 carboplatin via IV every three weeks.

[0134] 28A. The method of any one of embodiments 1 A-27A, further comprising administering paclitaxel to the patient. [0135] 29A. The method of embodiment 28A, comprising administering to the patient 200 mg/m2 paclitaxel via IV every three weeks.

[0136] 30A. The method of any one of embodiments 1 A-27A, further comprising administering pemetrexed to the patient.

[0137] 31 A. The method of embodiment 30A, comprising administering to the patient 500 mg/m2 pemetrexed via IV every three weeks.

[0138] 32A. The method of any one of embodiments 1 A-19A, comprising administering to the patient (a) Compound G, (b) carboplatin, (c) paclitaxel, and (d) pembrolizumab.

[0139] 33A. The method of embodiment 32A, comprising administering to the patient (a) 500 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0140] 34A. The method of embodiment 32A, comprising administering to the patient (a) 600 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0141] 35A. The method of embodiment 32A, comprising administering to the patient (a) 800 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0142] 36A. The method of embodiment 32A, comprising administering to the patient (a) 900 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0143] 37A. The method of embodiment 32A, comprising administering to the patient (a) 1200 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

[0144] 38A. The method of any one of embodiments 1 A-19A, comprising administering to the patient (a) Compound G, (b) carboplatin, (c) pemetrexed, and (d) pembrolizumab.

[0145] 39A. The method of embodiment 38A, comprising administering to the patient (a) 500 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks. [0146] 40A. The method of embodiment 38A, comprising administering to the patient (a) 600 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

[0147] 41 A. The method of embodiment 38A, comprising administering to the patient (a) 800 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

[0148] 42A. The method of embodiment 38A, comprising administering to the patient (a) 900 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

[0149] 43A. The method of embodiment 38A, comprising administering to the patient (a) 1200 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m2 pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab via IV every three weeks.

[0150] 44A. A method of treating a patient suffering from a MTAP-null cancer and having brain metastases comprising administering to the patient a therapeutically effective amount of Compound G: pharmaceutically acceptable salt thereof.

[0151] 45A. The method of embodiment 44A, wherein the MTAP-null cancer is lung cancer.

[0152] 46A. The method of embodiment 45A, wherein the lung cancer is non-small cell lung cancer

(NSCLC).

[0153] 47A. The method of embodiment 46A, wherein the NSCLC is squamous.

[0154] 48A. The method of embodiment 46A, wherein in the NSCLC is non-squamous.

[0155] 49A. The method of any one of embodiments 46A-48A, wherein the NSCLC is locally advanced.

[0156] 50A. The method of any one of embodiments 46A-48A, wherein the NSCLC is metastatic.

[0157] 51 A. The method of any one of embodiments 44A-50A, wherein the brain metastases are active, previously untreated brain metastases. [0158] 52A. The method of any one of embodiments 44A-51 A, wherein Compound G is administered once daily.

[0159] 53A. The method of any one of embodiments 44A-51 A, wherein Compound G is administered orally.

[0160] 54A. The method of any one of embodiments 44A-53A, wherein Compound G is administered as a tablet formulation.

[0161] 55A. The method of any one of embodiments 44A-54A, comprising administering Compound G to the patient as a monotherapy.

EXAMPLES

Example 1

[0162] This is a phase 1b multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of Compound G in combination with carboplatin, pemetrexed, and pembrolizumab; or in combination with carboplatin, paclitaxel and pembrolizumab; or in combination with pembrolizumab in patients with NSCLC and homozygous MTAP-deletion (“MTAP-null”).

[0163] The study consists of 3 arms. Arm A assesses the safety of Compound G in combination with carboplatin, paclitaxel and pembrolizumab. Arm B assesses the safety of Compound G in combination with carboplatin, pemetrexed and pembrolizumab. Arm C assesses the safety of Compound G in combination with pembrolizumab.

[0164] The following dose levels of Compound G are explored:

[0165] Dose level 2: 1200 mg QD daily

[0166] Dose level 1 : 800 mg QD daily

[0167] Dose level -1 500 mg QD daily

[0168] Arms A and B will begin with dose level 1. Arm C will begin at dose level 2.

[0169] Summary of Subject Eligibility Criteria:

[0170] Adult subjects (> 18 years old) with advanced NSCLC with homozygous MTAP-deletion (i.e., MTAP- null) as assessed by local or central NGS testing or MTAP protein loss determined by IHC are eligible to participate in the study. Subjects participating in arm C are also required to have a tumor PD-L1 expression at levels approved as per local label for pembrolizumab monotherapy (e.g., TPS > 1% in the US, or TPS>50% in the EU) as determined by local or central immunohistochemistry (IHC) assay. MTAP-deletion may be determined via local test results, central prescreening Next Generation Sequencing (NGS). Once consented to the study, subjects will provide a medical history and undergo screening safety tests to confirm all eligibility requirements of the study have been met. Subjects must have adequate hematological, renal and hepatic function. Subjects must provide archived tumor tissue samples (formalin fixed paraffin embedded [FFPE] sample) collected within the past 5 years. If archived tumor tissue is not available, subjects must be willing to undergo a pre-treatment tumor biopsy if deemed safe per investigator judgment.

[0171] Treatments

[0172] Compound G is administered once daily continuously for 21 days. Compound G is administered regardless of food intake.

[0173] Carboplatin, pembrolizumab, paclitaxel (or pemetrexed) are administered intravenously [IV] on day 1 of every 21 -day cycle (all arms):

[0174] Arm A: carboplatin in combination with paclitaxel: AUG 5 or 6 (up to 4 cycles); paclitaxel: 200 mg/m² (up to 4 cycles only); and pembrolizumab: 200 mg (administered prior to chemotherapy)

[0175] Arm B: carboplatin in combination with pemetrexed: AUG 5 (up to 4 cycles); pemetrexed: 500 mg/m2 (with vitamin supplementation); pembrolizumab: 200 mg (administered prior to chemotherapy)

[0176] Arm C: pembrolizumab: 200 mg

[0177] Exemplary Inclusion Criteria

[0178] Age > 18 years of age

[0179] Histologically or cytologically confirmed diagnosis of NSCLC without prior systemic therapy for metastatic or unresectable disease with the exception of 28 days of first line of therapy outlined in the exclusion criteria below.

[0180] Arm A: predominantly squamous histology.

[0181] Arm B: predominantly non-squamous histology.

[0182] Arm C: PD-L1 positive per approved label for pembrolizumab monotherapy (e.g., TPS> 1% in the US or TPS> 50% in the EU) tumor regardless of histology.

[0183] Exemplary Exclusion Criteria

[0184] Prior/Concomitant Therapy:

[0185] -Prior systemic therapy for metastatic NSCLC. In order to enable local or central prescreening NGS testing and analysis, subjects that have started treatment with the standard of care first line therapy, i.e. , platinum chemoimmunotherapy, chemotherapy, or immunotherapy, and have received their first dose within 28 days at time of signing main consent are eligible. [0186] -Major surgery within 28 days of first dose of Compound G.

[0187] -Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.

[0188] -Toxicities from prior anti-tumor therapy not having improved to at least Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, with the exception of alopecia or toxicities that are stable and well controlled.

[0189] -Subjects who experienced grade 2 or higher immune-mediated adverse events (IrAEs) including those that lead to permanent discontinuation with immune oncology agents. Exceptions: Hypothyroidism

[0190] -Prior irradiation to > 25% of the bone marrow.

[0191] -Radiation therapy within 28 days of first dose (or local or focal radiotherapy with palliative intent within 14 days of first dose). All radiotherapy related toxicity must have improved to < grade 1 before first dose of study treatment.

[0192] -Live vaccine therapy within 4 weeks before study drug administration.

[0193] -Use of therapeutic anti-coagulation for treatment of active thromboembolic events. Note: Subjects receiving a stable dose of anti-coagulation therapy for thromboembolic events for a duration > 1 month may be eligible upon approval of principal investigator after consultation with medical monitor.

[0194] -Use of prescription medications that are known strong inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives (whichever is longer) before study day 1 that was not reviewed and approved.

[0195] Disease Related:

[0196] -Presence of actionable mutations for which approved targeted therapies for first line treatment of metastatic NSCLC are available, for example EGFR mutations or ALK rearrangements.

[0197] -Untreated symptomatic CNS metastatic disease regardless of size or asymptomatic brain metastases > 2 cm per lesion. Note: Subjects with treated CNS metastases that are radiographically and neurologically stable for > 14 days and have not required corticosteroid for at least 7 days before first dose of study treatment are eligible. Subjects with untreated asymptomatic brain metastases smaller or equal to 2 cm in size per lesion (if more than one) and not requiring corticosteroid treatment are eligible.

[0198] -Subjects with leptomeningeal disease are excluded regardless of presence or absence of symptoms even if treated.

[0199] -Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures at a frequency greater than one time per month. Subjects with PleurX catheters in place may be considered for the study with approval.

[0200] Other Medical Conditions: [0201] -History of other malignancy within the past 3 years, with the following exceptions: Malignancy treated with curative intent and with no known active disease present for > 2 years before enrollment and felt to be at low risk for recurrence by the treating physician. Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated cervical carcinoma in situ without evidence of disease.

Adequately treated breast ductal carcinoma in situ without evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer. Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ. Any evidence of current interstitial lung disease or pneumonitis or a prior history of interstitial lung disease or non-infectious pneumonitis. Active infection requiring systemic therapy. History of arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months of first dose of Compound G.

[0202] -Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or history of cardiac arrest, ventricular tachycardia, known Wolf-Parkinson White Syndrome, or a genetic syndrome with increased risk of sudden cardiac death, e.g., Long QT syndrome, short QT syndrome, hereditary hypertrophic cardiomyopathy, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, or catecholaminergic polymorphic ventricular tachycardia.

[0203] -Gastrointestinal tract disease causing the inability to take PC medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis).

[0204] -History of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of study entry unless approved or history of gastrointestinal procedure(s) that result in malabsorption.

[0205] -History of solid organ transplant.

[0206] Prior/Concurrent Clinical Study Experience: Currently receiving treatment in another investigational device or drug study, or less than 21 days or 5 half-lives, whichever is shorter, since ending treatment on another investigational device or drug study(ies). Other investigational procedures and participation in observational research studies while participating in this study are excluded.

[0207] Diagnostic Assessments:

[0208] -Known positive test for Human Immunodeficiency Virus. Note: Subjects with HIV, without detectable viral load, with adequate CD4 T cell counts and without history of AIDS-defining opportunistic infections are eligible.

[0209] -Viral hepatitis infection based on the following results and/or criteria: Positive for hepatitis B surface antigen (HBsAg). If negative HBsAg and positive for hepatitis B core antibody, then testing of Hepatitis B virus DNA by polymerase chain reaction is required. Subjects with detectable hepatitis B virus DNA are ineligible. If positive Hepatitis C virus antibody (HCVAb), then testing of Hepatitis C virus RNA by PGR is required. Subjects with detectable hepatitis C virus RNA are ineligible. [0210] Other Exclusions: Current treatment or within 14 days of study day 1 with immunosuppressive corticosteroid defined as 10 mg prednisone daily or equivalent. Steroids with minimal systemic effect (such as topical or inhalation) are permitted.

[0211] Data as of February 9, 2025 (data cut off)

*defined as at least 6 weeks of treatment with scan

**not confirmed, subsequent scan showed PD

***includes one patient with PD during cycle 1

Example 2

[0212] 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-deletion (“MTAP-null") NSCLC with active, previously untreated brain metastases.

[0213] Compound G is administered orally CD continuously in 21-day cycles. Compound G is administered regardless of food intake. The following dose levels of Compound G are explored:

[0214] Dose level 2: 1200 mg CD daily

[0215] Dose level 1 : 800 mg CD daily

[0216] Dose level -1 : 500 mg CD daily

[0217] Summary of Subject Eligibility Criteria:

[0218] Adult subjects (> 18 years old) with advanced NSCLC and active brain metastases (at least one newly detected brain lesion) and homozygous MTAP-deletion, as assessed by local or central NGS testing or MTAP protein loss as determined by local immunohistochemistry are eligible to participate in the study. MTAP-deletion may be determined via local test results or central prescreening Next Generation Sequencing (NGS). Once consented to the study, subjects provide a medical history and undergo screening safety tests to confirm all eligibility requirements of the study have been met. Subjects must have adequate hematological, renal and hepatic function. Subjects must provide archived tumor tissue samples (formalin fixed paraffin embedded [FFPE] sample) collected within the past 5 years. If archived tumor tissue is not available, subjects must be willing to undergo a pre-treatment tumor biopsy if deemed safe per investigator judgment.

[0219] Exemplary Inclusion criteria

[0220] Histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC with brain metastases, if the treating physician determines that immediate CNS specific treatment (e.g., radiation therapy or surgery) is unlikely to be required. Note: If small cell elements are present, the subject is ineligible.

[0221] At least 1 newly diagnosed and previously untreated, i.e., surgery or radiotherapy, brain lesion meeting RANO-BM criteria for measurable disease by MRI. Subjects are eligible if they meet all of the following criteria: a) neurological symptoms grade < 2; and b) on stable or decreasing doses of dexamethasone, if applicable. Note: Subjects requiring antiepileptic therapy or prophylaxis are not eligible unless approved by the Medical Monitor.

[0222] Subjects will have received and progressed or experienced disease recurrence on or after receiving at least 1 prior systemic therapy for locally advanced or metastatic disease. Prior treatment must include a platinum-based doublet chemotherapy and checkpoint inhibitor, (if locally approved and considered standard of care), either given as one line of therapy or as individual lines of therapy unless the subject has a medical contraindication to one of the required therapies. Subjects with actionable mutations must have received at least 1 approved targeted therapy for the treatment of these mutations, e.g., EGFR, ALK, KRASG12C, etc.

[0223] -Adjuvant therapy will count as a line of therapy if the subject progressed on or within 6 months of adjuvant therapy administration.

[0224] -If chemoradiation is followed by planned systemic therapy without documented progression between chemoradiation and systemic therapy, the entire treatment course counts as one line of therapy.

[0225] -Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate line of therapy. Note: Bisphosphonate or denosumab for skeletal related events per institution guideline is permitted.

[0226] Either (1) Homozygous MTAP deletion as assessed by local or central NGS testing, or (2) MTAP protein loss as determined by local IHC testing.

[0227] Exemplary Exclusion Criteria

[0228] Prior/Concomitant Therapy:

[0229] -Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, hormonal therapy, or investigational agent) within 28 days of study day 1, unless antitumor therapy is a therapy with 5 times the half life being shorter than 28 days (in this case, enrollment may be allowed with washout from prior therapy of < 28 days after appropriate consultation). Note: bisphosphonate or denosumab for skeletal related events per institution guideline is permitted.

[0230] -Prior treatment with an MAT2A inhibitor or a PRMT5 inhibitor.

[0231] -Major surgery within 28 days of first dose of Compound G.

[0232] -Prior irradiation to > 25% of the bone marrow.

[0233] -Radiation therapy within 28 days of first dose (or local or focal radiotherapy with palliative intend within 14 days of first dose). All radiotherapy related toxicity must have improved to < grade 1 before first dose of study treatment.

[0234] -Live vaccine therapy within 4 weeks before study drug administration.

[0235] -Use of therapeutic anti-coagulation for treatment of active thromboembolic events. Note: Subjects receiving a stable dose of anti-coagulation therapy for thromboembolic events for a duration > 1 month may be eligible upon approval. Note: For subjects receiving anti-coagulation and undergoing biopsies, safety precautions such as a drug holiday may be considered if deemed necessary and safe.

[0236] -Use of prescription medications that are known strong inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives (whichever is longer) before study day 1 that was not reviewed and approved.

[0237] -Unresolved toxicity from prior anti-cancer therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria, with the exception of alopecia. Grade 2 or 3 toxicities from prior anti-cancer therapy that are considered irreversible (defined as having been present and stable for > 5 months), such as endocrinopathies controlled with hormone replacement therapy may be allowed if they are not otherwise described in the exclusion criteria and there is agreement to allow.

[0238] Disease Related: Spinal cord compression.

[0239] Other Medical Conditions:

[0240] -History of other malignancy within the past 3 years, with the following exceptions: Malignancy treated with curative intent and with no known active disease present for > 2 years before enrollment and felt to be at low risk for recurrence by the treating physician. Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated cervical carcinoma in situ without evidence of disease.

Adequately treated breast ductal carcinoma in situ without evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer. Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ.

[0241] -Any evidence of current interstitial lung disease or pneumonitis or a prior history of interstitial lung disease or non-infectious pneumonitis.

[0242] -Active infection requiring systemic therapy. [0243] -History of arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months of first dose of Compound G.

[0244] -Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication within 12 months of first dose of Compound G.

[0245] -Gastrointestinal tract disease causing the inability to take PC medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis).

[0246] -History of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of study entry unless approved or history of gastrointestinal procedure(s) that result in malabsorption.

[0247] -History of solid organ transplant.

[0248] -Diagnosis of Congenital Short QT Syndrome.

[0249] Prior/Concurrent Clinical Study Experience: Currently receiving treatment in another investigational device or drug study, or less than 21 days or 5 half-lives since ending treatment on another investigational device or drug study(ies). Other investigational procedures and participation in observational research studies while participating in this study are excluded.

[0250] Diagnostic Assessments

[0251] -Known positive test for Human Immunodeficiency Virus. Note: Subjects with HIV, without detectable viral load, with adequate CD4 T cell counts and without history of AIDS-defining opportunistic infections are eligible.

[0252] -Viral hepatitis infection based on the following results and/or criteria:

[0253] • positive hepatitis B surface antigen (HepBsAg)

[0254] • negative HepBsAg and positive for hepatitis B core antibody (HepBcAb)

[0255] -hepatitis B virus DNA by polymerase chain reaction (PCR) is required. Subjects with detectable hepatitis B virus DNA are ineligible.

[0256] • positive hepatitis C virus antibody (HCVAb): Hepatitis C virus RNA by PCR is required. Subjects with detectable hepatitis C virus RNA are ineligible.

References:

[0257] ABRAXANE® U.S. Prescribing Information, Bristol-Myers Squibb Company, New Jersey, 08543 (revision 8/2020).

[0258] ALIMTA® U.S. Prescribing Information, Lilly USA, LLC, Indianapolis, Indiana 46285 (revision 03/2023). [0259] CARBOplatin Injection, U.S. Prescribing Information, Fresenius KABI, Lake Zurich, Illinois, 60047 (revision 5/2021).

[0260] Eisenhauer, et al., Eur. J. Cancer 2009 45:228-247.

[0261] KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ 07033 (revision 3/2023).

[0262] LIBTAYO® US Prescribing Information, Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 (revision 11/2022).

[0263] National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute.

[0264] National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Version 3.2022, available at https://www.nccn.org/.

[0265] OPDIVO® US Prescribing Information, Bristol-Myers Squibb Co., Princeton, NJ 08543 (revision 02.2023).

[0266] Singh et al., Cancer, 125:2203-2212, 2019.

[0267] TAXOL® (paclitaxel) INJECTION U.S. Prescribing Information, Bristol-Myers Squibb Company, Princeton, New Jersey, 08543 (revision 4/2011).

Claims

What is claimed is:

1 . A method of treating a MTAP-null lung cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of

(a) Compound pharmaceutically acceptable salt thereof; and

(b) an anti-PD1 antibody.

2. The method of claim 1 , wherein Compound G is administered as a free base.

3. The method of claim 1 or 2, comprising administering to the patient a total daily dose of 500 mg Compound G, based upon free base weight of Compound G.

4. The method of claim 1 or 2, comprising administering to the patient a total daily dose of 600 mg Compound G, based upon free base weight of Compound G.

5. The method of claim 1 or 2, comprising administering to the patient a total daily dose of 800 mg Compound G, based upon free base weight of Compound G.

6. The method of claim 1 or 2, comprising administering to the patient a total daily dose of 900 mg Compound G, based upon free base weight of Compound G.

7. The method of claim 1 or 2, comprising administering to the patient a total daily dose of 1200 mg Compound G, based upon free base weight of Compound G.

8. The method of claim 1 or 2, comprising administering to the patient a total daily dose of 1600 mg Compound G, based upon 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 squamous.

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

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

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

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, comprising administering to the patient 200 mg pembrolizumab via IV every three weeks.

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

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

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

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

25. The method of claim 19, comprising administering to the patient (a) 1200 mg Compound G once daily, based upon free base weight of Compound G, and (b) 200 mg pembrolizumab, wherein the pembrolizumab is administered via IV 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, comprising administering to the patient AUC5 or AUC6 carboplatin 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, comprising administering to the patient 200 mg/m² paclitaxel via IV every three weeks.

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

31 . The method of claim 30, comprising administering to the patient 500 mg/m² pemetrexed via IV every three weeks.

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

33. The method of claim 32, comprising administering to the patient (a) 500 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

34. The method of claim 32, comprising administering to the patient (a) 600 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

35. The method of claim 32, comprising administering to the patient (a) 800 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

36. The method of claim 32, comprising administering to the patient (a) 900 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

37. The method of claim 32, comprising administering to the patient (a) 1200 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² paclitaxel, and (d) 200 mg pembrolizumab, wherein the carboplatin, paclitaxel, and pembrolizumab are administered via IV every three weeks.

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

39. The method of claim 38, comprising administering to the patient (a) 500 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

40. The method of claim 38, comprising administering to the patient (a) 600 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

41 . The method of claim 38, comprising administering to the patient (a) 800 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

42. The method of claim 38, comprising administering to the patient (a) 900 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed, and pembrolizumab are administered via IV every three weeks.

43. The method of claim 38, comprising administering to the patient (a) 1200 mg Compound G once daily, based upon free base weight of Compound G, (b) AUC5 or AUC6 carboplatin, (c) 200 mg/m² pemetrexed, and (d) 200 mg pembrolizumab, wherein the carboplatin, pemetrexed and pembrolizumab via IV every three weeks.

44. A method of treating a patient suffering from a MTAP-null cancer and having brain metastases comprising administering to the patient a therapeutically effective amount of Compound G: pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein the MTAP-null 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 squamous.

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

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

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

51 . The method of any one of claims 44-50, wherein the brain metastases are active, previously untreated brain metastases.

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, comprising administering Compound G to the patient as a monotherapy.