Ras inhibitors combination therapy

Abstract

The present invention relates to the use of a KRAS inhibitor (ERAS-4001) in combination with a RAS(ON) inhibitor of the presently -defined Compound 2, for treating cancer, specifically solid tumours.

Description

WSGR Docket No. 59457-766.601RAS INHIBITORS COMBINATION THERAPYCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 721,094 filed November 15, 2024; which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] The RAS-RAF-MEK-ERK signal transduction pathway, which is sometimes denoted as the mitogen-activated protein kinase (MAPK) pathway is thought to play a central role in regulating a number of fundamental cellular processes including one or more of cell proliferation, survival, adhesion, cycle progression, migration, differentiation, metabolism, and transcription. The activation of the MAPK pathway has been reported in numerous tumor types including lung, colon, pancreatic, renal, and ovarian cancers. Accordingly, substances that could reduce activation could be of interest for possible treatments.SUMMARY

[0003] The present embodiments disclosed herein generally relate to compositions and methods related to combination therapies to treat cancer utilizing a KRAS selective inhibitor in conjunction with a Pan-RAS inhibitor while providing an unexpected degree of synergy.

[0004] In a first aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount ofacceptable salt thereof.

[0005] In a second aspect, the present disclosure provides a compound that is Compound 1 or its pharmaceutically acceptable salt:WSGR Docket No. 59457-766.601for use in a method of treating a subject having cancer, the method comprising administering to said subject a therapeutically effective amount of said Compound 1 or salt thereof in combination withits pharmaceutically acceptable salt.

[0006] In a third aspect, the present disclosure provides a compound that is Compound 2 or its pharmaceutically acceptable salt:for use in a method of treating a subject having cancer,the method comprising administering to said subject a therapeutically effective amount of said Compound 2 or salt thereof in combination with Compound 1 :

[0007] In some embodiments, the cancer is a RAS-dependent cancer. In some embodiments, the cancer comprises a RAS mutation. In some embodiments, the RAS mutation is a KRAS, aNRAS, and / or a HRAS mutation. In some embodiments, the RAS mutation is a mutation at the G12, G13, and / or Q61WSGR Docket No. 59457-766.601position of the RAS protein. In some embodiments, the RAS mutation is a G12C mutation of the RAS protein. In some embodiments, the RAS mutation is a G12D mutation of the RAS protein. In some embodiments, the RAS mutation is a G12S mutation of the RAS protein. In some embodiments, the RAS mutation is a G12V mutation of the RAS protein. In some embodiments, the RAS mutation is a G12A mutation of the RAS protein. In some embodiments, the RAS mutation is a G13D mutation of the RAS protein. In some embodiments, the RAS mutation is a Q61H mutation of the RAS protein. In some embodiments, the RAS mutation is a Q6 IK mutation of the RAS protein. In some embodiments, the RAS mutation is a Q61R mutation of the RAS protein.

[0008] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, gastrointestinal cancer, head and neck cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, salivary gland tumor, thyroid cancer, or uterine cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the gastrointestinal cancer is anal cancer, appendiceal cancer, bile duct cancer, cholangiocar cinoma cancer, colon cancer, colorectal cancer (CRC), gallbladder cancer, rectal cancer, small intestine cancer, or stomach cancer (gastric cancer).

[0009] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 100 mg and 500 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 200 mg and 500 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 300 mg and 500 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 400 mg and 500 mg per day.

[0010] In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 500 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 400 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 300 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 200 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 100 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 80 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 60 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 40 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 20 mg per day.

[0011] In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:250 to 500:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, toWSGR Docket No. 59457-766.601Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:10 to 30:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 3:1. In some embodiments, the molar ratio of Compound 1, or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 1:3. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:3 to 500:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:3 to 80:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 9:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 1:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:25 to 300:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 90:1.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 shows the mean tumor volume following administration of Compound 1, Compound 2, and Compound 1 + Compound 2 in the KRAS-G12V mutant NCI-H441 xenograft model.INCORPORATION BY REFERENCE

[0013] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTIONI. DEFINITIONS

[0014] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and relatedWSGR Docket No. 59457-766.601terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0015] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0016] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, or improve an unwanted condition or disease of a patient.

[0017] “Administering,” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering,” when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

[0018] The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “patient,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is under the age of 12 years. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.

[0019] By “pharmaceutically acceptable,” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0020] The term “pharmaceutical composition” shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0021] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease,WSGR Docket No. 59457-766.601condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0022] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.IL COMPOUNDSCompound 1

[0023] Disclosed herein is compoundpharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is not a salt. In some embodiments, Compound 1 is provided as a pharmaceutically acceptable salt. In some embodiments, the salt of Compound 1 is the dihydrochloride salt.

[0024] In some embodiments, Compound 1 is a potent and selective inhibitor of KRAS that has the potential to provide an improved therapeutic window relative to RAS inhibitors and prevent KRAS wild type-mediated resistance relative to mutant-selective approaches.Compound 2

[0025] Disclosed herein is Compound 2:WSGR Docket No. 59457-766.601embodiments, Compound 2 is not a salt. In some embodiments, Compound 2 is provided as a pharmaceutically acceptable salt.III. COMBINATIONS

[0026] Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount ofpharmaceutically acceptable salt thereof; and(ii)acceptable salt thereof.

[0027] Disclosed herein is a compound that is Compound 1 or its pharmaceutically acceptable salt:WSGR Docket No. 59457-766.601for use in a method of treating a subject having cancer,the method comprising administering to said subject a therapeutically effective amount of said Compound 1 or salt thereof in combination with Compound 2:

[0028] Also disclosed herein is a compound that is Compound 2 or its pharmaceutically acceptable salt:for use in a method of treating a subject having cancer,the method comprising administering to said subject a therapeutically effective amount of said Compound 2 or salt thereof, in combination with Compound 1 :IV. FURTHER COMBINATIONS

[0029] Disclosed herein is a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount ofWSGR Docket No. 59457-766.601acceptable salt thereof; and(iii) an additional therapeutic agent.

[0030] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR Exon 19 deletion or an Exon 21 L858 R mutation and the additional therapeutic agent is afatinib, erlotinib, dacomitinib, gefitinib, or osimertinib.

[0031] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR Exon 19 deletion or an Exon 21 L858 R mutation and the additional therapeutic agent is osimertinib + pemetrexed.

[0032] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR Exon 19 deletion or an Exon 21 L858 R mutation, and the additional therapeutic agent is osimertinib + pemetrexed + cisplatin or carboplatin.

[0033] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR Exon 19 deletion or an Exon 21 L858 R mutation and the additional therapeutic agent is erlotinib + ramucirumab.

[0034] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR Exon 19 deletion or an Exon 21 L858 R mutation and the additional therapeutic agent is erlotinib + bevacizumab.

[0035] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR Exon 19 deletion or an Exon 21 L858 R mutation and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed.

[0036] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR S768I, L861Q and / or G719X mutation and additional therapeutic agent is afatinib, erlotinib, dacomitinib, gefitinib, or osimertinib.WSGR Docket No. 59457-766.601

[0037] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR S768I, L861Q and / or G719X mutation and additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed.

[0038] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR Exon 20 insertion mutation and the additional therapeutic agent is amivantamab-vmj w.

[0039] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR Exon 20 insertion mutation and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed.

[0040] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having a KRAS G12C mutation and the additional therapeutic agent is (adagrasib, divarasib, garsorasib, glecirasib, olomorasib, RMC-6291, or sotorasib) + / - anti-EGFR mab.

[0041] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having a BRAF V600E mutation and the additional therapeutic agent is (dabrafenib + trametinib, encorafenib + binimetinib, dabrafenib, or vemurafenib) + / - anti-EGFR mab.

[0042] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having a MET Exon 14 Skipping mutation or high-level MET amplification and the additional therapeutic agent is (capmatinib, crizotinib, or tepotinib) + / - anti-EGFR mab.

[0043] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having a HER2 mutation and the additional therapeutic agent is (fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine) + / - anti-EGFR mab.

[0044] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is (pembrolizumab or cemiplimab-rwlc) + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0045] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is pembrolizumab + pemetrexed + / - anti-EGFR mab.

[0046] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is atezolizumab + bevacizumab + carboplatin + paclitaxel + / - anti-EGFR mab.

[0047] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is atezolizumab + bevacizumab + / - anti-EGFR mab.

[0048] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is atezolizumab + carboplatin + albumin-bound paclitaxel + / - anti-EGFR mab.WSGR Docket No. 59457-766.601

[0049] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is nivolumab + ipilimumab + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0050] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is cemiplimab-rwlc + pemetrexed + (carboplatin / cisplatin) + / - anti-EGFR mab.

[0051] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is cemiplimab-rwlc + pemetrexed + / - anti-EGFR mab.

[0052] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is tremelimumab-actl + durvalumab + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0053] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is durvalumab + pemetrexed + / - anti-EGFR mab.

[0054] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is carboplatin + pemetrexed + / - anti-EGFR mab.

[0055] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is cisplatin + pemetrexed) + / - anti-EGFR mab.

[0056] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is bevacizumab + carboplatin + (paclitaxel or pemetrexed) + / - anti-EGFR mab.

[0057] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is bevacizumab + cisplatin + pemetrexed + / - anti-EGFR mab.

[0058] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is bevacizumab + / - anti-EGFR mab.

[0059] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is bevacizumab + pemetrexed + / - anti-EGFR mab.

[0060] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a non-squamous histology and the additional therapeutic agent is pemetrexed + / - anti-EGFR mab.WSGR Docket No. 59457-766.601

[0061] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a squamous histology and the additional therapeutic agent is pembrolizumab + carboplatin + (paclitaxel or albumin-bound paclitaxel) + / - anti-EGFR mab.

[0062] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a squamous histology and the additional therapeutic agent is nivolumab + ipilimumab + paclitaxel + carboplatin + / - anti-EGFR mab.

[0063] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the subject in need thereof has been determined to have a squamous histology and the additional therapeutic agent is tremelimumab-actl + durvalumab + gemcitabine + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0064] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is (pembrolizumab or atezolizumab or cemiplimab-rwlc or nivolumab or durvalumab or nivolumab + ipilimumab or tremelimumab-actl + durvalumab) + / - anti-EGFR mab.

[0065] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is fam-trastuzumab deruxtecan-nxki + / - anti-EGFR mab.

[0066] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is ramucirumab + docetaxel + / - anti-EGFR mab.

[0067] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is gemcitabine + docetaxel + / - anti-EGFR mab.

[0068] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is gemcitabine + vinorelbine + / - anti-EGFR mab.

[0069] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is (albumin-bound paclitaxel or docetaxel or gemcitabine or paclitaxel) + / -anti-EGFR mab.

[0070] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is cemiplimab-rwlc + paclitaxel + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0071] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is tremelimumab-actl + durvalumab + carboplatin + albumin-bound paclitaxel + / - anti-EGFR mab.

[0072] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is carboplatin + (albumin-bound paclitaxel or docetaxel or etoposide or gemcitabine or paclitaxel) + / - anti-EGFR mab.

[0073] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is cisplatin + (docetaxel or etoposide or gemcitabine or paclitaxel) + / - anti-EGFR mab.

[0074] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the anti-EGFR mab is cetuximab or panitumumab.WSGR Docket No. 59457-766.601

[0075] Disclosed herein is a method of treating colorectal cancer (CRC) in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount ofacceptable salt thereof; and(iii) an additional therapeutic agent.

[0076] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having a dMMR / MSI-H mutation and the additional therapeutic agent is anti-EGFR mab + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0077] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having a POLE / POLD1 mutation and the additional therapeutic agent is anti-EGFR mab + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0078] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having a BRAF WT mutation and the additional therapeutic agent is anti-EGFR mab + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0079] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having any RAS mutation and the additional therapeutic agent is anti-EGFR mab + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0080] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having any KRAS mutation and the additional therapeutic agent is anti-EGFR mab + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0081] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having any HER2 mutation and the additional therapeutic agent is anti-EGFR mab + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).WSGR Docket No. 59457-766.601

[0082] In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is anti-EGFR mab + chemotherapy.

[0083] In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is anti-VEGFR mab + anti-EGFR mab + chemotherapy.

[0084] In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is anti-EGFR mab + (fruquintinib or regorafenib).

[0085] In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is anti-EGFR mab.

[0086] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having a BRAF V600E mutation and the additional therapeutic agent is encorafenib + / - anti-EGFR mab.

[0087] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having a BRAF V600E mutation and the additional therapeutic agent is naporafenib + / - anti-EGFR mab.

[0088] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having a HER2 amplification or is IHC 3+ and the additional therapeutic agent is trastuzumab + (pertuzumab or lapatinib, or tucatinib) + / - anti-EGFR mab.

[0089] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having a HER2 amplification or is IHC 3+ and the additional therapeutic agent famtrastuzumab deruxtecan-nxki + / - anti-EGFR mab.

[0090] In some embodiments of a method of treating colorectal cancer (CRC), the cancer has been identified as having a KRAS G12C mutation and the additional therapeutic agent is anti-EGFR mab + (adagrasib or sotorasib or olomorasib or divarasib or glecirasib or garsorasib or RMC-6291).

[0091] In some embodiments of a method of treating colorectal cancer (CRC), the anti-EGFR mab is cetuximab or panitumumab.

[0092] In some embodiments of a method of treating colorectal cancer (CRC), the anti-VEGFR mab is bevacizumab, raucirumab, or zivaflibercept.

[0093] In some embodiments of a method of treating colorectal cancer (CRC), the chemotherapy is (5FU or capecitabine), (5FU or capecitabine) + oxaliplatin, (5FU or capecitabine) + irinotecan, (5FU or capecitabine) + oxaliplatin + irinotecan, irinotecan, or trifl uridine + tiparacil. In some embodiments, 5FU combinations also include leucovorin.

[0094] Disclosed herein is a method of treating pancreatic ductal adenocarcinoma (PDAC) in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount ofWSGR Docket No. 59457-766.601acceptable salt thereof; and(iii) an additional therapeutic agent.

[0095] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a dMMR / MSI-H mutation and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0096] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRAF WT mutation and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0097] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having any RAS mutation and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0098] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having any HER2 mutation and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0099] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having any BRCA1 / 2 mutation and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0100] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a PALB2 mutation and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0101] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the additional therapeutic agent is chemotherapy + / - anti-EGFR mab.WSGR Docket No. 59457-766.601

[0102] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the additional therapeutic agent is anti-EGFR mab.

[0103] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRAF V600E mutation and the additional therapeutic agent is dabrafenib + (trametinib or binimetinib) + / - anti-EGFR mab.

[0104] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRAF V600E mutation and the additional therapeutic agent is naporafenib + (trametinib or binimetinib) + / - anti-EGFR mab.

[0105] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a HER2 positive mutation or is IHC 3+ and the additional therapeutic agent is fam-trastuzumab deruxtecan-nxki + / - anti-EGFR mab.

[0106] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a KRAS G12C mutation and the additional therapeutic agent is (adagrasib or sotorasib or olomorasib or divarasib or glecirasib or garsorasib or RMC-6291) + / - anti-EGFR mab.

[0107] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRCA1 / 2 mutation and the additional therapeutic agent is gemcitabine + cisplatin + / - anti-EGFR mab.

[0108] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRCA1 / 2 mutation and the additional therapeutic agent is rucaparib + / - anti-EGFR mab.

[0109] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRCA1 / 2 mutation and the additional therapeutic agent is olaparib (BRCA1 / 2 only) + / - anti-EGFR mab.

[0110] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a PALB2 mutation and the additional therapeutic agent is gemcitabine + cisplatin + / - anti-EGFR mab.

[0111] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a PALB2 mutation and the additional therapeutic agent is rucaparib + / - anti-EGFR mab.

[0112] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a PALB2 mutation and the additional therapeutic agent is olaparib (BRCA1 / 2 only) + / - anti-EGFR mab.

[0113] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the anti-EGFR mab is cetuximab, or panitumumab.

[0114] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the anti-VEGFR mab is bevacizumab, raucirumab, zivaflibercept.WSGR Docket No. 59457-766.601

[0115] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the chemotherapy is (5FU or capecitabine), (5FU or capecitabine) + oxaliplatin, (5FU or capecitabine) + irinotecan, (5FU or capecitabine) + oxaliplatin + irinotecan, gemcitabine, gemcitabine + albumin-bound paclitaxel, gemcitabine + capecitabine, (5FU or capecitabine) + liposomal irinotecan + oxaliplatin, (5FU or capecitabine) + liposomal irinotecan, gemcitabine + albumin-bound paclitaxel + cisplatin, gemcitabine + docetaxel + capecitabine, or gemcitabine + erlotinib. In some embodiments, 5FU combinations also include leucovorin.V. CANCERS

[0116] Disclosed herein are methods of treating cancer using a combination disclosed herein.

[0117] “Cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including, without limitation, leukemias, lymphomas, myelomas, carcinomas, and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer (such as pancreatic adenocarcinoma, PDAC), medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, cancer of the head, Hodgkin's Disease, and Non-Hodgkin's Lymphomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the blood, thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0118] In some embodiments the cancer is a solid tumor.

[0119] In some embodiments, the cancer harbors at least one of a KRAS, NRAS, or HRAS mutations.

[0120] In some embodiments, the cancer is a KRAS-driven cancer, HRAS-driven cancer, or a NRAS-driven cancer.

[0121] In some embodiments, the cancer has at least one RAS mutation.

[0122] In some embodiments, the RAS mutation is a mutation at the G12, G13, and / or Q61 position of the RAS protein.

[0123] In some embodiments, the cancer has a G12C RAS mutation. In some embodiments, the cancer has a G13C RAS mutation. In some embodiments, the cancer has a G12D RAS mutation. In some embodiments, the cancer has a G12RRAS mutation. In some embodiments, the cancer has a G12S RASWSGR Docket No. 59457-766.601mutation. In some embodiments, the cancer has a G12V RAS mutation. In some embodiments, the cancer has G12W RAS mutation. In some embodiments, the cancer has G12A RAS mutation. In some embodiments, the cancer has a G13D RAS mutation. In some embodiments, the cancer has a H95D RAS mutation. In some embodiments, the cancer has a H95Q RAS mutation. In some embodiments, the cancer has a H95R RAS mutation. In some embodiments, the cancer has a Q61H RAS mutation. In some embodiments, the cancer has a Q61KRAS mutation. In some embodiments, the cancer has a Q61R RAS mutation. In some embodiments, the cancer has a R68S RAS mutation.

[0124] In some embodiments, the cancer has been identified as having a BRCA1 / 2 mutation.

[0125] In some embodiments, the cancer has been identified as having a PALB2 mutation.

[0126] In some embodiments, the cancer has been identified as having a BRAF mutation.

[0127] In some embodiments, the cancer has been identified as having a BRAF V600E mutation.

[0128] In some embodiments, the cancer has been identified as having a HER2 mutation.

[0129] In some embodiments, the cancer has been identified as having a MSI mutation.

[0130] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a BRAF V600E mutation.

[0131] In some embodiments, the cancer has been identified as having a HER2 mutation.

[0132] In some embodiments, the cancer has been identified as having a high-level MET amplification.

[0133] In some embodiments, the cancer has been identified as having a MET Exon 14 Skipping mutation.

[0134] In some embodiments, the cancer has been identified as having an EGFR exon 19 deletion or exon 21 L858R mutation.

[0135] In some embodiments, the cancer has been identified as having an EGFR S768I, L861Q and / or G719X mutation.

[0136] In some embodiments, the cancer has been identified as having an EGFR Exon 20 insertion mutation.

[0137] In some embodiments, the cancer has been identified as having a MET amplification.

[0138] In some embodiments, the cancer has been identified as having a MET exon 14 skipping mutation.

[0139] In some embodiments, the cancer has been identified as having aNTRK 1 / 2 / 3 gene fusion.

[0140] In some embodiments, the cancer has been identified as having an Anaplastic lymphoma kinase (ALK) gene rearrangement.

[0141] In some embodiments, the cancer has been identified as having a Rearranged during transfection (RET) rearrangement.

[0142] In some embodiments, the cancer has been identified as having a ROS1 rearrangement.

[0143] In some embodiments, the cancer has a level of PD-L1 >= 50%.

[0144] In some embodiments, the cancer has a level of PD-L1 >= l%-49%.

[0145] In some embodiments, the cancer has been identified as being a non-squamous cell carcinoma.

[0146] In some embodiments, the cancer has been identified as being a squamous cell carcinoma.WSGR Docket No. 59457-766.601

[0147] In some embodiments, the cancer has been identified as having a dMMR mutation.

[0148] In some embodiments, the cancer has been identified as having a dMMR / MSI-H mutation.

[0149] In some embodiments, the cancer has been identified as having a POLE / POLD1 mutation.

[0150] In some embodiments, the cancer is the cancer is a liquid tumor. In some embodiments, the cancer is the liquid tumor is leukemia. In some embodiments, the cancer is the leukemia is acute myeloid leukemia (AML).

[0151] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced or a metastatic solid tumor.

[0152] In some embodiments, the cancer is breast cancer, esophageal cancer, gastrointestinal cancer, head and neck cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, salivary gland tumor, thyroid cancer, or uterine cancer.

[0153] In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

[0154] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a RAS mutation.

[0155] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a BRCA1 / 2 mutation.

[0156] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a PALB2 mutation.

[0157] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a BRAF mutation.

[0158] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a HER2 mutation.

[0159] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a MSI mutation.

[0160] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a dMMR mutation.

[0161] In some embodiments, the gastrointestinal cancer is anal cancer, appendiceal cancer, bile duct cancer, cholangiocarcinoma cancer, colon cancer, colorectal cancer (CRC), gallbladder cancer, rectal cancer, small intestine cancer, or stomach cancer (gastric cancer).

[0162] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0163] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a having a RAS mutation.

[0164] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a BRAF V600E mutation.

[0165] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a HER2 mutation.

[0166] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a high-level MET amplification.WSGR Docket No. 59457-766.601

[0167] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a MET Exon 14 Skipping mutation.

[0168] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having an EGFR exon 19 deletion or exon 21 L858R mutation.

[0169] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having an EGFR S768I, L861Q and / or G719X mutation.

[0170] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having an EGFR Exon 20 insertion mutation.

[0171] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a BRAF V600E mutation.

[0172] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a HER2 mutation.

[0173] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a MET amplification.

[0174] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a MET exon 14 skipping mutation.

[0175] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a NTRK 1 / 2 / 3 gene fusion.

[0176] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having an Anaplastic lymphoma kinase (ALK) gene rearrangement.

[0177] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a Rearranged during transfection (RET) rearrangement.

[0178] In some embodiments, thenon-small cell lung cancer (NSCLC) has been identified as having a RO SI rearrangement.

[0179] In some embodiments, thenon-small cell lung cancer (NSCLC) has a level of PD-L1 >= 50%.

[0180] In some embodiments, the non-small cell lung cancer (NSCLC) has a level of PD-L1 >= 1%-49%.

[0181] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as being a non-squamous cell carcinoma. In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as being a squamous cell carcinoma.

[0182] In some embodiments, the gastrointestinal cancer is colorectal cancer (CRC).

[0183] In some embodiments, the colorectal cancer (CRC) has been identified as having a RAS mutation.

[0184] In some embodiments, the colorectal cancer (CRC) has been identified as having a BRAF mutation.

[0185] In some embodiments, the colorectal cancer (CRC) has been identified as having aHER2 amplification.WSGR Docket No. 59457-766.601

[0186] In some embodiments, the colorectal cancer (CRC) has been identified as having a dMMR / MSI-H mutation.

[0187] In some embodiments, the colorectal cancer (CRC) has been identified as having a POLE / POLD1 mutation.VI. DOSING

[0188] In one aspect, the compositions described herein are used for the treatment of diseases and conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of compositions in therapeutically effective amounts to said subject.

[0189] Dosages of compositions described herein can be determined by any suitable method.Maximum tolerated doses (MTD) and maximum response doses (MRD) for Compound 1, or a pharmaceutically acceptable salt thereof can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of Compound 1, or a pharmaceutically acceptable salt thereof, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). Dosages of compositions described herein can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for Compound 2, or a pharmaceutically acceptable salt thereof can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of Compound 2, or a pharmaceutically acceptable salt thereof, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.

[0190] In some embodiments, the amount of a given formulation comprising compound 1, or a pharmaceutically acceptable salt thereof that corresponds to such an amount varies depending upon factors such as the molecular weight of a particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.WSGR Docket No. 59457-766.601

[0191] In some embodiments, the amount of a given formulation comprising compound 2, or a pharmaceutically acceptable salt thereof that corresponds to such an amount varies depending upon factors such as the molecular weight of a particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.

[0192] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, as described herein is relative to the free-base equivalent of Compound 1.

[0193] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0194] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered per day may be about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, or 550 mg, or any value therebetween.

[0195] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 500 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 400 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 300 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 200 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 100 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 100 mg and 500 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 200 mg and 500 mg per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 300 mg and 500 mgWSGR Docket No. 59457-766.601per day. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 400 mg and 500 mg per day.

[0196] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, as described herein is relative to the free-base equivalent of Compound 2.

[0197] In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered per day may be about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, or 550 mg, or any value therebetween.

[0198] In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 500 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 400 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 300 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 200 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 100 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 80 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 60 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 40 mg per day. In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 20 mg per day.

[0199] In some embodiments, the molar ratio of Compound 1, or a pharmaceutically acceptable salt thereof, to Compound 2, or a pharmaceutically acceptable salt thereof, is about 500:1, 490:1, 480:1, 470:1, 460:1, 450:1, 440:1, 430:1, 420:1, 410:1, 400:1, 390:1, 380:1, 370:1, 360:1, 350:1, 340:1, 330:1, 320:1, 310:1, 300:1, 290:1, 280:1, 270:1, 260:1, 250:1, 240:1, 230:1, 220:1, 210:1, 200:1, 190:1, 180:1,WSGR Docket No. 59457-766.601170:1, 160:1, 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 100:1, 99:1, 98:1, 97:1, 96:1, 95:1, 94:1, 93:1, 92:1, 91:1, 90:1, 89:1, 88:1, 87:1, 86:1, 85:1, 84:1, 83:1, 82:1, 81:1, 80:1, 79:1, 78:1, 77:1, 76:1, 75:1, 74:1, 73:1, 72:1, 71:1, 70:1, 69:1, 68:1, 67:1, 66:1, 65:1, 64:1, 63:1, 62:1, 61:1, 60:1, 59:1, 58:1, 57:1, 56:1, 55:1, 54:1, 53:1, 52:1, 51:1, 50:1, 49:1, 48:1, 47:1, 46:1, 45:1, 44:1, 43:1, 42:1, 41:1, 40:1, 39:1, 38:1, 37:1, 36:1, 35:1, 34:1, 33:1, 32:1, 31:1, 30:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50, 1:51, 1:52, 1:53, 1:54, 1:55, 1:56, 1:57, 1:58, 1:59, 1:60, 1:61, 1:62, 1:63, 1:64, 1:65, 1:66, 1:67, 1:68, 1:69, 1:70, 1:71, 1:72, 1:73, 1:74, 1:75, 1:76, 1:77, 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84, 1:85, 1:86, 1:87, 1:88, 1:89, 1:90, 1:91, 1:92, 1:93, 1:94, 1:95, 1:96, 1:97, 1:98, 1:99, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:310, 1:320, 1:330, 1:340, 1:350, 1:360, 1:370, 1:380, 1:390, 1:400, 1:410, 1:420, 1:430, 1:440, 1:450, 1:460, 1:470, 1:480, 1:490, or 1:500, or any range of values therebetween.

[0200] In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:250 to 500:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:25 to 300:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:10 to 30:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 90:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 10:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 9:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 8:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 7:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 6: 1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 5:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 4:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 3:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, toWSGR Docket No. 59457-766.601Compound 2 or a pharmaceutically acceptable salt thereof, is about 2:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 1:3. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 1:2. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 1:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:3 to 500:1. In some embodiments, the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2, or a pharmaceutically acceptable salt thereof, ranges from 1:3 to 80:1.

[0201] In some embodiments, the combination of Compound 1 and Compound 2 provide a synergistic effect. In some embodiments, the combination of Compound 1 and Compound 2 provide a therapeutic response greater than the additive effects of each compound used alone. In some embodiments, the synergistic effect comprises a synergistic inhibitory effect. In some embodiments a determination of a synergistic interaction between Compound 1 and Compound 2 can be based on the results obtained from the assays described herein. In some embodiments, the combination effects can be evaluated using the BLISS independence model. In some embodiments, the BLISS score is determined using an in-vitro cellbased proliferation assay in LSI 80 cell line. In some embodiments, the BLISS score is determined using an in-vitro cell-based proliferation assay in SU86.86 cell line. In some embodiments, the BLISS score is determined using an in-vitro cell-based proliferation assay in KP-4 cell line. In some embodiments, the BLISS score is determined using an in-vitro cell-based proliferation assay inNCI-H727 cell line. In some embodiments, BLISS scores quantify degree of potentiation from the combination of Compound 1 and Compound 2. In some embodiments, a BLISS score >0 suggests greater than simple additivity. In some embodiments, the synergistic inhibitory effect on a cancer cell of a mixture of Compound 1 or a pharmaceutically acceptable salt thereof, and Compound 2 or a pharmaceutically acceptable salt thereof, is determined by the molar ratio of Compound 1 and Compound 2 administered in said mixture. In some embodiments, the dosage of Compound 1 and Compound 2 in the combination therapy may be lower than the dosage required when each compound is administered individually.Vn. ADMINISTRATION

[0202] Administration of Compound 1 , or a pharmaceutically acceptable salt thereof, and combination partners described herein are at a dosage described herein or at other dose levels and compositions determined and contemplated by a medical practitioner. In certain therapeutic applications, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a patient already suffering from a disease in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms. Administration of Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein are at a dosage described herein or at other dose levels and compositions determined and contemplated by a medical practitioner. In certain therapeutic applications, Compound 2, or a pharmaceutically acceptable salt thereof, and combinationWSGR Docket No. 59457-766.601partners described herein, are administered to a patient already suffering from a disease in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms. Amounts effective for this use depend on the age of the patient, severity of the disease, previous therapy, the patient's health status, weight, and response to the compositions, and the judgment of the treating physician.Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

[0203] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of a composition described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease. In other embodiments, administration of a composition continues until complete or partial response of a disease.

[0204] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered three times daily.

[0205] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered three times daily.

[0206] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered once a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered twice a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered three times a day.

[0207] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered once a day. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered twice a day. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered three times a day.

[0208] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered to a subject who is in a fasted state. A fasted state refers to a subject who has gone without food or fasted for a certain period of time. General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject who is in a fasted state for at least 8 hours. In other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subj ect who is in a fasted state for at least 10 hours. In yet other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, andWSGR Docket No. 59457-766.601combination partners described herein, are administered to a subject who is in a fasted state for at least 12 hours. In other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subject who has fasted overnight.

[0209] In other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subject who is in a fed state. A fed state refers to a subject who has taken food or has had a meal. In certain embodiments, a composition is administered to a subj ect in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1-hour postmeal, or 2 hours post-meal. In certain instances, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fed state 30 minutes post-meal. In other instances, Compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subj ect in a fed state 1-hour post- meal. In yet further embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject with food.

[0210] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered to a subject who is in a fasted state. A fasted state refers to a subject who has gone without food or fasted for a certain period of time. General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered to a subject who is in a fasted state for at least 8 hours. In other embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subject who is in a fasted state for at least 10 hours. In yet other embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subject who is in a fasted state for at least 12 hours. In other embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subject who has fasted overnight.

[0211] In other embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subject who is in a fed state. A fed state refers to a subject who has taken food or has had a meal. In certain embodiments, a composition is administered to a subj ect in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1-hour postmeal, or 2 hours post-meal. In certain instances, Compound 2, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fed state 30 minutes post-meal. In other instances, Compound 2, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered to a subj ect in a fed state 1-hour post- meal. In yet further embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered to a subject with food.

[0212] The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycleWSGR Docket No. 59457-766.601ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is five weeks (35 days). In some embodiments, the length of a treatm e n t cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, four, orfive weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. In some embodiments, a treatment cycle lasts five weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.EXAMPLESExample 1: Combination cellular proliferation activity of Compound 1 and Compound 2 in-vitro, in the KRAS-G12D mutant LS180 cell line

[0213] This example analyzed the benefit of the combination of Compound 1 and Compound 2 in the LSI 80 colorectal adenocarcinoma cell line harboring KRAS G12D mutation.

[0214] Combination cellular proliferation assays: LSI 80 (5000 cells per well) were plated onto 96-well plates in 100 pl cell culture medium. Cells were treated with Compound 1 and Compound 2 at concentrations varying from 0.005 to 100 nM for Compound 1, and from 0.14 to 100 nM for Compound 2, by using the Tecan D300e Digital Dispenser combination matrix protocol. At day 5, 100 pl of CellTiter-Glo (CTG) reagent (Promega) was added and the plates were incubated for 60 minutes with gentle shaking. After 60 minutes of incubation, the luminescent signal was determined according to the provider’s instructions (Promega) and combination data was generated by the standard BLISS model. Table 1 summarizes the results of the synergy and antagonism of Compound 1 and Compound 2 in LSI 80 cell line. The combination synergy was represented by positive numbers. The negative numbers represent antagonism of the combination.

[0215] This example demonstrated the synergistic combination of Compound 1 with Compound 2 in the KRAS G12D CRC CDX LSI 80 cell line. The combination of Compound 1 at a concentration of 1.2 nM with Compound 2 at a concentration of 0.4 nM provided with the highest BLISS score of 18.79.Table 1. BLISS synergy and antagonism of Compound 1 and Compound 2 in LSI 80 cell lineWSGR Docket No. 59457-766.601Example!: Combination cellular proliferation activity of Compound 1 and Compound 2 in-vitro, in the KRAS-G12D mutant SU86.86 cell line

[0216] This example analyzed the benefit of the combination of Compound 1 and Compound 2 in the SU86.86 p an creatic cancer cell line harboring KRAS G12D mutation.

[0217] Combination cellular proliferation assays: SU86.86 (5000 cells per well) were plated onto 96-well plates in 100 pl cell culture medium. Cells were treated with Compound 1 and Compound 2, at concentrations varying from 0.14 to 100 nM for Compound 1 and 0.005 to 100 nM for Compound 2, by using the Tecan D300e Digital Dispenser combination matrix protocol. At day 5, 100 pl of CellTiter-Glo (CTG) reagent (Promega) was added and the plates were incubated for 60 minutes with gentle shaking. After 60 minutes of incubation, the luminescent signal was determined according to the provider’s instructions (Promega) and combination data was generated by the standard BLISS model. Table 2 summarizes the results of the synergy and antagonism of Compound 1 and Compound 2 in SU.86.86 cell line. The combination synergy was represented by positive numbers. The negative numbers represent antagonism of the combination.

[0218] This example demonstrated the synergistic combination of Compound 1 with Compound 2 in the KRAS G12D pancreatic cancer SU.86.86 cell line. The combination of Compound 1 at a concentration of 1.2 nM with Compound 2 at a concentration 0.14 nM, provided with the highest BLISS score of 27.58.Table 2. BLISS synergy and antagonism of Compound 1 and Compound 2 in SU.86.86 cell lineExample 3: Combination cellular proliferation activity of Compound 1 and Compound 2 in-vitro, in the KRAS-G12D mutant KP-4 cell line

[0219] This example analyzed the benefit of the combination of Compound 1 and Compound 2 in the KP-4 pancreatic cancer cell line harboring KRAS G12D mutation.

[0220] Combination cellular proliferation assays: KP-4 (5000 cells per well) were plated onto 96-well plates in 100 pl cell culture medium. Cells were treated with Compound 1 and Compound 2, at concentrations varying from 0.14 to 100 nM for Compound 1 and 0.005 to 100 nM for Compound 2, by using the Tecan D300e Digital Dispenser combination matrix protocol. At day 5, 100 pl of CellTiter-GloWSGR Docket No. 59457-766.601(CTG) reagent (Promega) was added and the plates were incubated for 60 minutes with gentle shaking. A f ter 60 minutes of incubation, the luminescent signal was determined according to the provider’s instructions (Promega) and combination data was generated by the standard BLISS model. Table 3 summariz esthe results of the synergy and antagonism of Compound 1 and Compound 2 in KP-4 cell line. The combination synergy was represented by positive numbers. The negative numbers represent antagonism of the combination.

[0221] This example demonstrated the synergistic combination of Compound 1 with Compound 2 in the KRAS G12D pancreatic cancer KP-4 cell line. The combination of Compound 1 at a concentration of 0.4 nM with Compound 2 at a concentration of 0.14 nM concentration, provided with the highest BLISS score of 13.09.Table 3. BLISS synergy and antagonism of Compound 1 and Compound 2 in KP-4 cell lineExample 4: Combination cellular-proliferation activity of Compound 1 and Compound 2 in-vitro, in the KRAS-G12V mutant NCI-H727 cell line

[0222] This example analyzed the benefit of the combination of Compound 1 and Compound 2 in the NCI-H727 lung cancer cell line harboring KRAS G12V mutation.

[0223] Combination cellular proliferation assays: NCI-H727 (5000 cells per well) were plated onto 96-well plates in 100 pl cell culture medium. Cells were treated with Compound 1 and Compound 2, at concentrations varying from 0.05 to 1000 nM for Compound 1 and 0. 1 to 100 nM for Compound 2, by using the Tecan D300e Digital Dispenser combination matrix protocol. At day 5, 100 pl of CellTiter-Glo (CTG) reagent (Promega) was added and the plates were incubated for 60 minutes with gentle shaking. After 60 minutes of incubation, the luminescent signal was determined according to the provider’s instructions (Promega) and combination data was generated by the standard BLISS model. Table 4 summarizes the results of the synergy and antagonism of Compound 1 and Compound 2 in NCI-H727 cell line. The combination synergy was represented by positive numbers. The negative numbers represent antagonism of the combination.WSGR Docket No. 59457-766.601

[0224] This example demonstrated the synergistic combination of Compound 1 with Compound 2 in the KRAS G12V lung cancer NCI-H727 cell line. The combination of Compound 1 at a concentration of 37.0 nM with Compound 2 ata concentration of 0.4nM, provided with the highest BLISS score of 14.37.Table 4. BLISS synergy and antagonism of Compound 1 and Compound 2 in NCI-H727 cell lineExample 5: In-Vivo Assay

[0225] NCI-H441 is a non-small cell lung tumor cell line that harbors a KRAS-G12V mutation. The NCI-H441 cell line was purchased from ATCC, and cell line pathogen testing was performed to confirm pathogen-free status (IDEXX BioResearch, Columbia, MO). NCI-H441 cells were cultured in Roswell Park Memorial Institute medium (RPMI) containing 10% Fetal Bovine Serum (FBS) and 1% penicillin / streptomycin at 37°C in an atmosphere of 5% CO2 in air. The medium was renewed every 2 to 5 days and tumor cells were routinely sub-cultured once to twice weekly at a confluence of 80-90%. The cells growing in an exponential growth phase were harvested and counted for inoculation.Female athymic nude mice were purchased from Envigo (n=148). Mice were 7 weeks of age at the time of implantation.

[0226] NCI-H441 tumor cells were implanted into mice subcutaneously. 200 pL cell suspensions containing 50 x 106tumor cells mixed with Matrigel in a 50:50 ratio were subcutaneously implanted into the right flank of mouse using a syringe with 25 -gauge needle. Animal health was monitored daily. Tumor volumes were measured twice a week by caliper when tumors were palpable and measurable. When tumor volumes reached a mean of 150-300 mm3, mice were randomized into different groups with 8 mice in each group. The randomization date was denoted as treatment day 0.

[0227] Mice were dosed twice daily with Compound 1 or once daily with Compound 2. On day 27, the mean tumor volume of the vehicle group was 1511 ± 307 mm3and tumor growth inhibition (TGI) was observed with either Compound 1 or Compound 2 alone. At day 27, the mean tumor volume of Compound 1 at 50mg / kg BID was 592 ± 50 mm3with 73% TGI and the mean tumor volume of Compound 2at O.lmg / kg QD was 1360 ± 250 mm3with 12% TGI. Combination benefit was also observed between Compound 1 and Compound 2 (50mg / kg BID + 0. Img / kg QD) with mean tumor volume of the combination group 315 ± 31 mm3with TGI of 94%. Both monotherapy and combinationWSGR Docket No. 59457-766.601treatments were well tolerated with no significant body weight loss or clinical observations noted. See FIG. 1.

Claims

WSGR Docket No. 59457-766.601CLAIMS WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount ofpharmaceutically acceptable salt thereof; andpharmaceutically acceptable salt thereof.A compound that is Compound 1 or its pharmaceutically acceptable salt:for use in a method of treating a subject having cancer,WSGR Docket No. 59457-766.601the method comprising administering to said subject a therapeutically effective amount of said Compound 1 or salt thereof in combination with Compound 2:for use in a method of treating a subject having cancer,the method comprising administering to said subject a therapeutically effective amount of said Compound 2 or salt thereof in combination with Compound 1 :

4. The method or use of any one of claims 1-3, wherein the cancer is a RAS-dependent cancer.

5. The method or use of any one of claims 1-4, wherein the cancer comprises a RAS mutation.

6. The method or use of claim 5, wherein the RAS mutation is a KRAS, a NRAS, and / or a HRAS mutation.

7. The method or use of claim 5, wherein the RAS mutation is a mutation at the G12, G13, and / or Q61 position of the RAS protein.

8. The method or use of claim 5, wherein the RAS mutation is a G12C mutation of the RAS protein.WSGR Docket No. 59457-766.6019. The method or use of claim 5, wherein the RAS mutation is a G12D mutation of the RAS protein.

10. The method or use of claim 5, wherein the RAS mutation is a G12S mutation of the RAS protein.

11. The method or use of claim 5, wherein the RAS mutation is a G12V mutation of the RAS protein.

12. The method or use of claim 5, wherein the RAS mutation is a G12A mutation of the RAS protein.

13. The method or use of claim 5, wherein the RAS mutation is a G13D mutation of the RAS protein.

14. The method or use of claim 5, wherein the RAS mutation is a Q61H mutation of the RAS protein.

15. The method or use of claim 5, wherein the RAS mutation is a Q61K mutation of the RAS protein.

16. The method or use of claim 5, wherein the RAS mutation is a Q61R mutation of the RAS protein.

17. The method or use of any one of claims 1-16, wherein the cancer is a solid tumor.

18. The method or use of any one of claims 1-17, wherein the cancer is breast cancer, gastrointestinal cancer, head and neck cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, salivary gland tumor, thyroid cancer, or uterine cancer.

19. The method or use of claim 18, wherein the lung cancer is non-small cell lung cancer (NSCLC).

20. The method or use of claim 18, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

21. The method or use of claim 18, wherein the gastrointestinal cancer is anal cancer, appendiceal cancer, bile duct cancer, cholangiocarcinoma cancer, colon cancer, colorectal cancer (CRC), gallbladder cancer, rectal cancer, small intestine cancer, or stomach cancer (gastric cancer).

22. The method or use of any one of claims 1-21, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 100 mg and 500 mg per day.

23. The method or use of any one of claims 1-22, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 200 mg and 500 mg per day.

24. The method or use of any one of claims 1-23, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 300 mg and 500 mg per day.

25. The method or use of any one of claims 1-24, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 400 mg and 500 mg per day.

26. The method or use of any one of claims 1-25, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 500 mg per day.

27. The method or use of any one of claims 1-26, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 400 mg per day.WSGR Docket No. 59457-766.60128. The method or use of any one of claims 1-27, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 300 mg per day.

29. The method or use of any one of claims 1-28, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 200 mg per day.

30. The method or use of any one of claims 1-29, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 100 mg per day.

31. The method or use of any one of claims 1-30, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 80 mg per day.

32. The method or use of any one of claims 1-31, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 60 mg per day.

33. The method or use of any one of claims 1-32, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 40 mg per day.

34. The method or use of any one of claims 1-33, wherein the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 20 mg per day.

35. The method or use of any one of claims 1-7, 9, 17-19, or 21, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:250 to 500:1.

36. The method or use of claim 35, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:10 to 30:1.

37. The method or use of claim 36, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 3:1.

38. The method or use of claim 36, wherein the molar ratio of Compound 1, or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 1:3.

39. The method or use of claim 35, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:3 to 500:1.

40. The method or use of claim 39, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:3 to 80:1.

41. The method or use of claim 40, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 9:1.

42. The method or use of claim 40, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 1:1.WSGR Docket No. 59457-766.60143. The method or use of any one of claims 1-7, 11, or 18-20, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, ranges from 1:25 to 300:1.

44. The method or use of claim 43, wherein the molar ratio of Compound 1 or a pharmaceutically acceptable salt thereof, to Compound 2 or a pharmaceutically acceptable salt thereof, is about 90:1.

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