Combination therapy of a PRMT5 inhibitor and daraxonrasib for use in the treatment of MTAP-null cancer

Abstract

Provided herein is a therapy of Compound G, or pharmaceutically acceptable salt thereof, and Compound A, or pharmaceutically acceptable salt thereof, for treating an MTAP-null cancer in a subject in need of treatment.

Description

Docket No. 32328 / 5536311017-W001-SECCOMBINATION THERAPIES TO TREAT CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 718,295, filed November s, 2025.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.

[0004] It has been well-established in literature that RAS proteins (K-RAS, H-RAS and N-RAS) play an important role in various human cancers and are therefore appropriate targets for anticancer therapy. Indeed, mutations in RAS proteins account for approximately 30% of all human cancers in the United States, many ofDocket No. 32328 / 5536311017-WC01-SEC which are fatal. Dysregulation of RAS proteins by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in RAS are frequently found in human cancer. For example, activating mutations at codon 12 in RAS proteins function by inhibiting both GTPase-activating protein (GAP)- dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of RAS mutant proteins to the "on” (GTP-bound) state (RAS(ON)), leading to oncogenic MAPK signaling. Notably, RAS exhibits a picomolar affinity for GTP, enabling RAS to be activated even in the presence of low concentrations of this nucleotide. Inhibitors that target RAS(ON) (e.g., selectively over the inactive (GDP-bound) state of RAS) can induce a new binding pocket in RAS by driving formation of a high affinity tri-complex between RAS protein and the cytosolic chaperon cyclophilin A (CYPA). The formation of this tri-complex can sterically occlude the interaction site between RAS and downstream effector molecules, such as RAF and PI3K, which are required for propagating the oncogenic signal.SUMMARY

[0005] Provided herein are methods of treating an MTAP-null cancer in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of Compound G, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound G and A have structures of:

[0006] Certain aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description.DETAILED DESCRIPTION

[0007] The disclosure provides methods of treating a subject suffering from an MTAP-null cancer comprising administering to the subject a therapeutically effective amount of Compound G, or pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Compound A, or pharmaceutically acceptable salt thereof.

[0008] The term "therapeutically effective amount” as used herein refers to that amount of a compound disclosed herein that elicits a desired biological or medical response in a cell, a tissue, a system, or a subject. In the present disclosure the desired biological response is to treat the MTAP-null cancer of the subject, such as slowing progression of the cancer, or reducing cancer presence in the patient.Docket No. 32328 / 5536311017-WC01-SEC

[0009] In some cases, the subject with the MTAP-null cancer being treated in the disclosed methods has not been treated with direct RAS-target therapy (e.g., degraders and / or inhibitors) prior to administration of the combination therapy disclosed herein. In some cases, the subject has no known history of central nervous system metastatic disease prior to administration of the combination therapy disclosed herein.Compound G - a PRMT5 Inhibitor

[0010] Compound G is a PRMT5 inhibitor, that is, it inhibits protein arginine methyltransferase 5. It has a structurecan be synthesized as described in InternationalPublication No. WO 2022132914.

[0011] In the methods disclosed herein, Compound G can be administered as its free base form. In some cases, Compound G can be administered as a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt” refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid). Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound either is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or associates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine). Additionally, the salts of the compounds described herein, can exist in either hydrated or anhydrous form or as solvates with other solvent molecules. In various embodiments, Compound G or salt thereof is administered orally.Docket No. 32328 / 5536311017-WC01-SECCompound A - a RAS Inhibitor

[0012] Compound A is a RAS inhibitor and has a structure ofcan be prepared as described in InternationalPublication No. WO 2022 / 060836 or in International Publication No. WO 2024 / 216017. Polymorph forms of Compound A are described in International Publication No. WO 2024 / 216048. Compound A targets, that is, selectively binds to or inhibits, RAS(ON) (e.g., selective over the GDP-bound, inactive state of RAS (RAS(OFF)), and forms a high affinity three-component complex between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., RAS), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A). Compound A induces a new binding pocket in RAS by driving formation of a high affinity tri-complex between the RAS protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA).

[0013] In the methods disclosed herein, Compound A can be administered as its free base form. In some cases, Compound A can be administered as a pharmaceutically acceptable salt. In various embodiments, Compound A or salt thereof is administered orally.MTAP-Null Cancers

[0014] The cancers of the methods disclosed are MTAP-null cancers and can optionally include a RAS mutation. These cancers are discussed in detail, below.

[0015] The disclosed methods can treat a cancer that is a MTAP-deleted cancer. A MTAP-deleted (or "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. MTAP-null cancers include MTAP-deficiency in at least 1% of disease cells.

[0016] Cancers with MTAP-null prevalence include (in decreasing levels of prevalence): glioblastoma (GBM), mesothelioma, bladder cancer, pancreatic cancer, esophageal cancer, squamous non-small cell lung cancer, melanoma, diffuse large B cell lymphoma (DLBCL), head and neck cancer, cholangiocarcinoma, adenocarcinoma (non-squamous) non-small lung cancer (NSCLC), sarcoma, stomach cancer, low grade glioma (LGG), adenoid cycstic carcinoma (ACC), and thymoma.Docket No. 32328 / 5536311017-WC01-SEC

[0017] In some cases, the cancer being treated does not exhibit a mutation in RAS, such that the cancer has wildtype RAS (such as wildtype KRAS, wildtype NRAS, wildtype HRAS). In some cases, the cancer being treated in the disclosed methods is a RAS mutated cancer. RAS mutations contemplated include those in KRAS, NRAS, HRAS, or combinations thereof. In some cases, the RAS mutation is a mutation in codon 12, 13, or 61 of RAS (G12, G13, or Q61). In some cases, the mutated RAS is G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, or G13V. In some cases, the mutated RAS is G12C, G12D, G13C, G12V, G13D, G12R, or G12S. In some cases, the mutated RAS is RAS G12. In some cases, the RAS mutation is Q61 K.

[0018] In some embodiments, the MTAP-null cancer is a solid tumor. In some embodiments, the tumor is malignant.

[0019] Exemplary MTAP-null solid tumors include, but are not limited to, MTAP-null brain cancer (e.g., MTAP- null glioma, MTAP-null oligodendroglioma, MTAP-null glioblastoma multiforme, MTAP-null astrocytoma, MTAP- null medulloblastoma, MTAP-null ependymoma, and MTAP-null meningioma), MTAP-null head and neck cancer (e.g., MTAP-null salivary gland (parotid) tumors, MTAP-null head and neck squamous cell carcinoma, and MTAP-null thyroid cancer), MTAP-null breast cancer (e.g., invasive ductal breast cancer, mixed mucinous breast cancer and lobular carcinoma), MTAP-null mesothelioma, MTAP-null gastrointestinal tract cancer (e.g., MTAP- null esophageal cancer (e.g., adenocarcinoma and squamous cell carcinoma), MTAP-null gastro-esophageal junction cancer, MTAP-null stomach cancer (e.g., adenocarcinoma and signet ring cell carcinoma), MTAP-null small bowel cancer, MTAP-null colon cancer, MTAP-null rectal cancer and MTAP-null gastrointestinal stromal tumor), MTAP-null neuroendocrine tumor, MTAP-null hepatobiliary cancer (e.g., MTAP-null biliary tract cancer, such as cholangiocarcinoma, gallbladder cancer and ampullary cancer; and MTAP-null hepatocellular carcinoma), MTAP-null pancreatic cancer (e.g., pancreatic adenocarcinoma, such as pancreatic ductal adenocarcinoma (PDAC), pancreatic neuroendocrine tumors, and acinar cell carcinoma), MTAP-null kidney cancer (e.g., MTAP-null renal cell carcinoma), MTAP-null adrenocortical carcinoma, MTAP-null bladder cancer (e.g., MTAP-null urothelial carcinoma), MTAP-null adrenocortical carcinoma, MTAP-null endometrial cancer, MTAP-null uterine cancer, MTAP-null testicular cancer, MTAP-null germ cell tumor, MTAP-null prostate cancer, MTAP-null sarcoma or MTAP-null bone cancer (e.g., MTAP-null osteosarcoma, MTAP-null chondrosarcoma, MTAP-null soft tissue sarcoma, MTAP-null Ewing sarcoma, MTAP-null liposarcoma, MTAP-null leiomyosarcoma, and MTAP-null myxofibrosarcoma), MTAP-null cutaneous tumors (e.g., MTAP-null cutaneous squamous cell carcinoma and MTAP-null melanoma), MTAP-null nerve sheath tumor, and MTAP-null cancer of unknown primary (CUP).

[0020] In some embodiments, the MTAP-null cancer is a hematologic tumor. Exemplary hematologic tumors include, but are not limited to, MTAP-null leukemia (e.g., MTAP-null acute lymphocytic leukemia, MTAP-null acute myeloid leukemia), MTAP-null lymphoma (e.g., MTAP-null mantle cell lymphoma, MTAP-null follicular lymphoma, MTAP-null diffuse large B cell lymphoma, and MTAP-null mycosis fungoides).Docket No. 32328 / 5536311017-WC01-SEC

[0021] In some cases, the MTAP-null cancer is gastrointestinal cancer. In some cases, the MTAP-null gastrointestinal cancer is biliary tract cancer (e.g., cholangiocarcinoma, gallbladder cancer, ampullary carcinoma, and hepatocellular carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, such as pancreatic ductal adenocarcinoma (PDAC), pancreatic neuroendocrine tumors, and acinar cell carcinoma), esophageal cancer (e.g., adenocarcinoma and squamous cell carcinoma), gastro-esophageal junction (GEJ) cancer (e.g., adenocarcinoma of the GEJ), stomach cancer (e.g., adenocarcinoma, gastrointestinal stromal tumor, lymphoma, neuroendocrine tumors of the stomach, and signet ring cell carcinoma), small bowel cancer, colon cancer, anal cancer (e.g., squamous cell carcinoma, adenocarsinoma, basaloid carcinoma, melanoma), small intestinal cancer (e.g., adenocarcinoma, gastrointestinal stromal tumors, neuroendocrine tumor, lymphoma), and colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, gastrointestinal stromal tumors, carcinoid tumors, and lymphoma). In some cases, the MTAP-null gastrointestinal cancer is biliary tract cancer (e.g., cholangiocarcinoma, gallbladder cancer, ampullary carcinoma, and hepatocellular carcinoma). In some cases, the MTAP-null gastrointestinal cancer is pancreatic cancer (e.g., pancreatic adenocarcinoma, such as pancreatic ductal adenocarcinoma (PDAC), pancreatic neuroendocrine tumors, and acinar cell carcinoma). In some cases, the MTAP-null gastrointestinal cancer is esophageal cancer (e.g., adenocarcinoma and squamous cell carcinoma). In some cases, the MTAP-null gastrointestinal cancer is gastro-esophageal junction (GEJ) cancer (e.g., adenocarcinoma of the GEJ). In some cases, the MTAP-null gastrointestinal cancer is stomach cancer (e.g., adenocarcinoma, gastrointestinal stromal tumor, lymphoma, neuroendocrine tumors of the stomach, and signet ring cell carcinoma). In some cases, the MTAP-null gastrointestinal cancer is small bowel cancer. In some cases, the MTAP-null gastrointestinal cancer is colon cancer. In some cases, the MTAP-null gastrointestinal cancer is anal cancer (e.g., squamous cell carcinoma, adenocarsinoma, basaloid carcinoma, and melanoma). In some cases, the MTAP-null gastrointestinal cancer is small intestinal cancer (e.g., adenocarcinoma, gastrointestinal stromal tumors, neuroendocrine tumor, and lymphoma). In some cases, the MTAP-null gastrointestinal cancer is colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, gastrointestinal stromal tumors, carcinoid tumors, and lymphoma).

[0022] In some cases, the MTAP-null cancer is lung cancer. In some cases, the MTAP-null cancer is nonsmall cell lung cancer (e.g., squamous or non-squamous) pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), biliary tract cancer (BTC), head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, mesothelioma, gastric or gastroesophageal junction (GEJ) cancer, glioblastoma, glioma, or an MTAP-null solid tumor. In some cases, the MTAP-null cancer is non-small cell lung cancer (e.g., squamous or non- squamous) pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), biliary tract cancer (BTC), head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, mesothelioma, or gastric or gastroesophageal junction (GEJ) cancer. In some cases, MTAP-null cancer is non-small cell lung cancer (NSCLC). In some cases, the NSCLC is squamous. In some cases, the NSCLC is non-squamous. In some cases, the MTAP-null cancer is pancreatic cancer. In some cases, the pancreatic cancer is pancreatic adenocarcinoma (PDAC). In some cases, the MTAP-null cancer is biliary tract cancer (BTC). In some cases, the MTAP-null cancer is head and neckDocket No. 32328 / 5536311017-WC01-SEC squamous cell carcinoma (HNSCC). In some cases, the MTAP-null cancer is gallbladder cancer. In some cases, the MTAP-null cancer is mesothelioma. In some cases, the MTAP-null cancer is gastric or gastroesophageal junction (GEJ) cancer. In some cases, the MTAP-null cancer is glioblastoma. In some cases, the MTAP-null cancer is glioma. In some cases, the MTAP-null cancer is a MTAP-null solid tumor. In some cases, the MTAP- null cancer is not a primary brain tumor or lymphoma.Pharmaceutical formulations and routes of administration

[0023] Compound G or Compound A may be administered by any suitable route in the form of a pharmaceutical formulation adapted to such a route and in a dose effective for the treatment intended. The formulation may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients. The pharmaceutical formulation of Compound G or Compound A may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. In some cases, the pharmaceutical formulation is made in the form of a dosage unit containing a particular amount of Compound G or Compound A.

[0024] Pharmaceutical formulations containing Compound G or Compound A can be manufactured, e.g., by mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. In some cases, Compound G is administered as an oral dosage form. In some cases, Compound G is administered as an oral dosage form once daily. In some cases, Compound G is administered as an oral dosage form twice daily. In some cases, Compound G is administered as an oral tablet. In some cases, Compound G is administered as a free base in the form of an oral tablet. In some cases, Compound A is administered as an oral dosage form. In some cases, Compound A is administered as an oral dosage form once daily. In some cases, Compound A is administered as an oral tablet. In some cases, Compound A is administered as a free base in the form of an oral tablet. In some cases, Compound A is administered as a salt in the form of an oral tablet.Monitoring Efficacy of Treatment

[0025] 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 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.Docket No. 32328 / 5536311017-WC01-SECCombination Therapy Efficacy

[0026] In some embodiments, the combination therapy described herein exhibits a combination benefit. The term "combination benefit” refers to an observed efficacy with a combination therapy that is higher than treatment with at least one individual therapy alone (i.e., a monotherapy). In some embodiments, the combination therapy described herein exhibits a combination benefit compared to Compound G monotherapy. In some embodiments, the combination therapy described herein exhibits a combination benefit compared to Compound A monotherapy. In some cases, the combination therapy described herein exhibits a combination benefit compared to Compound G monotherapy and Compound A monotherapy. In some cases, the combination benefit is a synergism between Compound A and Compound G, which can be measured as described in the below examples. In some cases, synergy is assessed using the CalcuSyn software to determine Combination Index (Cl) scores, based upon drug concentrations and a corresponding Fa score. In some cases, the synergy is exhibited by a Cl score as low as 0.2. In some cases, the synergy is exhibited by a Cl score as low as 0.5. In some cases, the synergy is exhibited by a Cl score as low as 0.7.EXEMPLARY EMBODIMENTS1 . A method of treating an MTAP-null cancer in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of Compound G, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound G and A have structures of:2. The method of embodiment 1 , wherein the cancer is a solid tumor.3. The method of embodiment 2, wherein the tumor is malignant.4. The method of any one of embodiments 1 to 3, wherein the cancer is a RAS-mutated cancer.5. The method of embodiment 4, wherein the RAS mutation is a mutation in KRAS, NRAS, orHRAS.6. The method of embodiment 5, wherein the KRAS mutation is at codon 12, 13, or 61 (G12, G13, or Q61).Docket No. 32328 / 5536311017-WC01-SEC7. The method of embodiment 5, wherein the NRAS mutation is at codon 12, 13, or 61 (G12, G13, or Q61).8. The method of embodiment 5, wherein the HRAS mutation is at codon 12, 13, or 61 (G12, G13, or Q61).9. The method of any one of embodiments 1 to 8, wherein the cancer is lung cancer.10. The method of embodiment 9, wherein the lung cancer is non-small cell lung cancer (NSCLC).11. The method of embodiment 10, wherein the NSCLC is squamous.12. The method of embodiment 10, wherein the NSCLC is non-squamous.13. The method of any one of embodiments 1 to 8, wherein the cancer is pancreatic cancer.14. The method of embodiment 13, wherein the cancer is pancreatic adenocarcinoma (PDAC).15. The method of any one of embodiments 1 to 8, wherein the cancer is biliary tract cancer(BTC).16. The method of any one of embodiments 1 to 8, wherein the cancer is head and neck squamous cell carcinoma.17. The method of any one of embodiments 1 to 8, wherein the cancer is gallbladder cancer.18. The method of any one of embodiments 1 to 8, wherein the cancer is mesothelioma.19. The method of any one of embodiments 1 to 8, wherein the cancer is gastroesophageal or gastroesophageal junction (GEJ) cancer.20. The method of any one of embodiments 1 to 19, wherein the cancer is not a primary brain tumor or lymphoma.21 . The method of any one of embodiments 1 to 20, wherein Compound G or salt thereof is administered orally.22. The method of any one of embodiments 1 to 21 , wherein Compound G or salt thereof is administered once daily.23. The method of any one of embodiments 1 to 22, wherein Compound G or salt thereof is administered twice daily.24. The method of any one of embodiments 1 to 23, wherein Compound G is administered as a free base.25. The method of any one of embodiments 1 to 24, wherein Compound A or salt thereof is administered orally.Docket No. 32328 / 55363 11017-WC01-SEC26. The method of any one of embodiments 1 to 25, wherein Compound A or salt thereof is administered once daily.27. The method of any one of embodiments 1 to 26, wherein Compound A is administered as a salt.28. The method of any one of embodiments 1 to 26, wherein Compound A is administered as a free base.29. The method of any one of embodiments 1 to 28, wherein the subject has not been treated with a direct RAS-target therapy prior to first administration of a combination therapy of Compound A and Compound G.30. The method of any one of embodiments 1 to 29, wherein the subject has no known history of central nervous system metastatic disease prior to first administration of a combination therapy of Compound A and Compound G.EXAMPLES

[0027] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art will appreciate readily that the present disclosure is well-adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends, and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.

[0028] Four MTAP-null cell lines - MIAPACA2 (a PDAC KRAS G12C cell line); SU86.86 (a PDAC KRAS G12D cell line); HuPT4 (a PDAC KRAS G12V cell line); and SK-LU-1 (a NSCLC KRAS G12D cell line) - were treated with the combination of Compound G and Compound A, for 6 days. Compound G was performed at a 1.9-fold dilution series and Compound A was performed at 1.7 to 2.5-fold dilution series to create an 8 x 10 dose matrix including DMSO-only controls. Cell viability was measured by the CellTiter-Glo Luminescence assay.Raw luminescent values were converted to Fraction Affected (Fa) with the following equation: Fa = 1- (Treatment I Average of DMSO-only wells). The tables below show representative Compound G and Compound A concentrations and their corresponding combination Fa and Cl scores. Synergy analysis was performed using CalcuSyn software to generate Combination Index (Cl) scores. Cl values indicate a strong synergism between 0.1 to 0.3; synergism between 0.3-0.7, moderate synergism between 0.7-0.85, slight synergism between 0.85- 0.9, and nearly additive activity between 0.9-1 .1 . Synergy or strong synergy was observed for the combination of Compound A and Compound G for each of the cell lines tested.Table 1-1 - MIAPACA2 - MTAP-null and KRAS G12C PDACDocket No. 32328 / 5536311017-WC01-SECTable 1-2 - SU86.86 - MTAP-null and KRAS G12D PDACTable 1-3 - HuPT4 - MTAP-null and KRAS G12V PDACDocket No. 32328 / 5536311017-WC01-SECTable 1-4 - SK-LU-1- MTAP-null and KRAS G12D NSCLC

Claims

Docket No. 32328 / 5536311017-WC01-SECWhat is claimed is:1 . A method of treating an MTAP-null cancer in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of Compound G, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound G and A have structures of:

2. The method of claim 1 , wherein the MTAP-null cancer is a solid tumor.

3. The method of claim 2, wherein the tumor is malignant.

4. The method of any one of claims 1 to 3, wherein the MTAP-null cancer is a RAS-mutated cancer.

5. The method of claim 4, wherein the RAS mutation is a mutation in KRAS, NRAS, or HRAS.

6. The method of claim 5, wherein the KRAS mutation is at codon 12, 13, or 61 (G12, G13, orQ61).

7. The method of claim 5, wherein the NRAS mutation is at codon 12, 13, or 61 (G12, G13, or Q61).

8. The method of claim 5, wherein the HRAS mutation is at codon 12, 13, or 61 (G12, G13, or Q61).

9. The method of any one of claims 1 to 8, wherein the MTAP-null cancer is lung cancer.

10. The method of claim 9, wherein the lung cancer is non-small cell lung cancer (NSCLC).11 . The method of claim 10, wherein the NSCLC is squamous.

12. The method of claim 10, wherein the NSCLC is non-squamous.

13. The method of any one of claims 1 to 8, wherein the MTAP-null cancer is pancreatic cancer.

14. The method of claim 13, wherein the cancer is pancreatic adenocarcinoma (PDAC).Docket No. 32328 / 5536311017-WC01-SEC15. The method of any one of claims 1 to 8, wherein the MTAP-null cancer is biliary tract cancer (BTC).

16. The method of any one of claims 1 to 8, wherein the MTAP-null cancer is head and neck squamous cell carcinoma.

17. The method of any one of claims 1 to 8, wherein the MTAP-null cancer is gallbladder cancer.

18. The method of any one of claims 1 to 8, wherein the MTAP-null cancer is mesothelioma.

19. The method of any one of claims 1 to 8, wherein the MTAP-null cancer is gastroesophageal or gastroesophageal junction (GEJ) cancer.

20. The method of any one of claims 1 to 19, wherein the MTAP-null cancer is not a primary brain tumor or lymphoma.21 . The method of any one of claims 1 to 20, wherein Compound G or salt thereof is administered orally.

22. The method of any one of claims 1 to 21 , wherein Compound G or salt thereof is administered once daily.

23. The method of any one of claims 1 to 22, wherein Compound G or salt thereof is administered twice daily.

24. The method of any one of claims 1 to 23, wherein Compound G is administered as a free base.

25. The method of any one of claims 1 to 24, wherein Compound A or salt thereof is administered orally.

26. The method of any one of claims 1 to 25, wherein Compound A or salt thereof is administered once daily.

27. The method of any one of claims 1 to 26, wherein Compound A is administered as a salt.

28. The method of any one of claims 1 to 26, wherein Compound A is administered as a free base.

29. The method of any one of claims 1 to 28, wherein the subject has not been treated with a direct RAS-target therapy prior to first administration of a combination therapy of Compound A and Compound G.

30. The method of any one of claims 1 to 29, wherein the subject has no known history of central nervous system metastatic disease prior to first administration of a combination therapy of Compound A and Compound G.

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