Ras and PD-1 or PD-l1 inhibitors combination therapy

Abstract

The present invention relates to the use of a KRAS inhibitor (ERAS-4001) in combination with a PD-1 or PD-L1 inhibitor for treating cancer, specifically solid tumours.

Description

Attorney Docket No. 055745-562001WORAS AND PD-1 or PD-L1 INHIBITORS COMBINATION THERAPYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present disclosure claims the benefit of priority from US patent application No.63 / 721,078 filed on November 15, 2024, the contents of which are incorporated herein by reference in their entirety.BACKGROUND

[0002] The RAS-RAF-MEK-ERK signal transduction pathway, which is sometimes denoted as the mitogen-acti vated 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. Programmed cell death protein-1 (PD-1, Pdcdl), an inhibitory receptor in the immune response phase, was first identified in the early 1990s as a member of the CD28 / CTLA-4 family of immunoglobulin (1g) superfamily. PD-1 is a type I transmembrane protein with a size of SO-55 kDa, induced in a variety of hematopoietic cells in the peripheral blood and widely expressed in immune cells (T cells, B cells, macrophages, and certain types of dendritic cells, etc.) and tumor cells by antigen receptor signaling and cytokines.

[0003] PD-1 and PD-L1 inhibitors are important immune checkpoint inhibitors (ICIs) for the treatment of cancer after the discovery of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4).

[0004] Under normal circumstances, the immune system produces an anti-cancer immune response by executing cancer immunity cycle that kills cancer cells. And yet, the PD-1 / PD-L1 pathway is an adaptive immune resistance mechanism of tumor cells to endogenous immune anti-tumor activity. PD-l / PD-ligand interaction down-regulates the immune response during the regression of infection or tumor or the development of self-tolerance. PD-L1 is usually overexpressed in tumor cells or untransformed cells in tumor microenvironment and inhibits cytotoxic T cells by binding to PD-1 receptor on activated T cells, resulting in immune escape. The inhibitors of PD-1 and PD-L1 inhibit the interaction between PD-L1 and PD-1 receptor, preventing cancer cells from evading the immune system in this way and acting as ICIs by reactivating the T-cell-mediated tumor cell death process.SUMMARY

[0005] The present embodiments disclosed herein generally relate to compositions and methods related to combination therapies to treat cancer utilizing either a KRAS selective inhibitor or a Pan-Attorney Docket No. 055745-562001WORAS inhibitor in conjunction with a PD-1 or PD-L1 inhibitor while providing an unexpected degree of synergy.

[0006] 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 of(i)pharmaceutically acceptable salt thereof; and(ii) a PD-1 or a PD-L1 inhibitor.

[0007] Also 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 of(ii) a PD-1 or a PD-L1 inhibitor.

[0008] Also 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 ofAttorney Docket No. 055745-562001WG(i)pharmaceutically acceptable salt thereof;pharmaceutically acceptable salt thereof; and(iii) a PD-1 or a PD-L1 inhibitor.INCORPORATION BY REFERENCE

[0009] 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings of which:

[0011] FIG. 1 shows tumor growth inhibition following administration of Compound 1, an anti-PD-1, and Compound 1 + an anti-PD-1 in a pancreatic cancer model (KRAS G12D CDX).

[0012] FIG. 2 shows tumor growth inhibition (TGI) following administration of Compound 2, an anti-PD- 1 , and Compound 2 + an anti-PD- 1 in the KPC pancreatic cancer model (KRAS G12D CDX).Attorney Docket No. 055745-562001WG

[0013] FIG. 3 shows tumor growth inhibition following administration of Compound 2, an anti-PD-1, Compound 2 + an anti-PD-1, MRTX1133, and MRTX1133 + an anti-PD- 1 in the KPC pancreatic cancer model (KRAS G12D CDX).

[0014] FIG. 4 shows the % body change following administration of Compound 2, an anti-PD-1, Compound 2 + an anti-PD-1, MRTX1133, and MRTX1133 + an anti-PD-1 in the KPC pancreatic cancer model (KRAS G12D CDX).

[0015] FIG. 5 shows tumor growth inhibition (TGI) after re-challenge of KPC tumor cells following administration of Compound 2.

[0016] FIG. 6 shows tumor growth inhibition following administration of Compound 1, an anti-PD-1, and Compound 1 + an anti-PD-1 in a pancreatic cancer model (KRAS G12D CDX).

[0017] FIG. 7 shows the survival curves following administration of Compound 1 and Compound 1 + an anti-PD-1 in a pancreatic cancer model (KRAS G12D CDX).

[0018] FIG. 8 shows the in vivo anti-tumor efficacy of Compound 1 in a CT26 model.DETAILED DESCRIPTION

[0019] 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 related terms 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.

[0020] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0021] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a patient. In some embodiments, a therapeutic agent such as a compound 1 is directed to the treatment and / or the amelioration of cancers.

[0022] “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.Attorney Docket No. 055745-562001WOThus, 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 padent 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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, condition 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) .Attorney Docket No. 055745-562001WO

[0027] 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.Compound 1

[0028] 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.

[0029] 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 wildtype-mediated resistance relative to mutant-selective approaches.Compound 2

[0030] Disclosed herein is the pan-RAS molecular glue Compound 2:Attorney Docket No. 055745-562001WOpharmaceutically acceptable salt thereof, In some embodiments, Compound 2 is not a salt. In some embodiments, Compound 2 is provided as a pharmaceutically acceptable salt.PD-1 orPD-Ll Inhibitor

[0031] In some embodiments, the PD-1 inhibitor is an anti-PD-1. In some embodiments, the PD-1 inhibitor is acrixolimab, AMP-224, camrelizumab, cemiplimab, dostarlimab, MEDI0680, nivolumab, pembrolizumab, retifanlimab, sintilimab, spartalizumab, tislelizumab, toripalimab, or vopratelimab.

[0032] In some embodiments, the PD-L1 inhibitor is an anti-PD-Ll antibody, such as an anti-PD-Ll monoclonal antibody (mab). In some embodiments, the PD-L1 inhibitor is atezolizumab, AUNP12, avelumab, BMS-986189, CA-170, cosibelimab (CK-301), durvalumab, or KN035.Combinations

[0033] 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 of(i)pharmaceutically acceptable salt thereof; and(ii) a PD-1 or a PD-L1 inhibitor.

[0034] Also 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 ofAttorney Docket No. 055745-562001WOpharmaceutically acceptable salt thereof; and(ii) a PD-1 or a PD-L1 inhibitor.

[0035] Also 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 of(i)pharmaceutically acceptable salt thereof;pharmaceutically acceptable salt thereof; and(iii) a PD-1 or a PD-L1 inhibitor.

[0036] Disclosed herein is a compound that is Compound 1 or its pharmaceutically acceptable salt:Attorney Docket No. 055745-562001WOfor 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 a PD-1 or a PD-L1 inhibitor.

[0037] 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 a PD-1 or a PD-L1 inhibitor.

[0038] Also disclosed herein is a compound that is Compound 1 or its pharmaceutically acceptable salt:for use in a method of treating a subject having cancer,Attorney Docket No. 055745-562001WOthe method comprising administering to said subject a therapeutically effective amount of said Compound 1 or salt thereof in combination with Compound 2:its pharmaceutically acceptable salt and in combination with a PD-1 or a PD-L1 inhibitor.

[0039] 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 :its pharmaceutically acceptable salt and in combination with a PD-1 or a PD-L1 inhibitor.Attorney Docket No. 055745-562001WO

[0040] Also disclosed herein is a use of a compound that is Compound 1wherein the compound is for use in combination with a PD-1 or a PD-L1 inhibitor.

[0041] Also disclosed herein is a use of a compound that is Compound 1its pharmaceutically acceptable salt in the manufacture of a medicament for treating cancer, wherein the compound is for use in combination with a PD-1 or a PD-L1 inhibitor.

[0042] In some embodiments, the cancer is as defined herein. In some embodiments, the PD-1 or a PD-L1 inhibitor is as defined herein.Further Combinations

[0043] 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 ofAttorney Docket No. 055745-562001WO(i)pharmaceutically acceptable salt thereof;(ii) a PD-1 or a PD-L1 inhibitor, andoptionally (iii) an additional therapeutic agent.

[0044] Also disclosed herein is a compound for use in treating non-small cell lung cancer (NSCLC) in a subject in need thereof, the compound being Compound 1compound is for use in combination with a PD-1 or a PD-L1 inhibitor.

[0045] Also disclosed herein is a use of a compound that is Compound 1Attorney Docket No. 055745-562001WOnon-small cell lung cancer (NSCLC) in a subject in need thereof, wherein the compound is for use in combination with a PD-1 or a PD-L1 inhibitor.

[0046] Also disclosed herein is a use of a compound that is Compound 1manufacture of a medicament for treating non-small cell lung cancer (NSCLC) in a subject in need thereof, wherein the compound is for use in combination with a PD-1 or a PD-L1 inhibitor.

[0047] In some embodiments, the compound or the pharmaceutically acceptable salt thereof is for use in combination with another therapeutic agent, such as defined herein.

[0048] Also 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 of(ii) a PD-1 or a PD-L1 inhibitor; and(iii) an additional therapeutic agent.

[0049] Also 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 ofAttorney Docket No. 055745-562001WG(i)pharmaceutically acceptable salt thereof;pharmaceutically acceptable salt thereof;(iii) a PD-1 or a PD-L1 inhibitor; and(iv) an additional therapeutic agent.

[0050] 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 a Exon 21 L858 R mutation and the additional therapeutic agent is afatinib, erlotinib, dacomitinib, gefitinib, or osimertinib.

[0051] 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 a Exon 21 L858 R mutation and the additional therapeutic agent is osimertinib + pemetrexed.

[0052] 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 a Exon 21 L858 R mutation, and the additional therapeutic agent is osimertinib + pemetrexed + cisplatin or carboplatin.

[0053] 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 a Exon 21 L858 R mutation and the additional therapeutic agent is erlotinib + ramucirumab.

[0054] 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 a Exon 21 L858 R mutation and the additional therapeutic agent is erlotinib + bevacizumab.Attorney Docket No. 055745-562001WG

[0055] 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 a Exon 21 L858 R mutation and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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) + / - and -EGFR mab.

[0061] 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.

[0062] 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.

[0063] 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 (famtrastuzumab deruxtecan-nxki or ado-trastuzumab emtansine) + / - anti-EGFR mab.

[0064] 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.

[0065] 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.Attorney Docket No. 055745-562001WO

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.Attorney Docket No. 055745-562001WO

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is ramucirumab + docetaxel + / - anti-EGFR mab.

[0087] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is gemcitabine + docetaxel + / - anti-EGFR mab.

[0088] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is gemcitabine + vinorelbine + / - anti-EGFR mab.

[0089] 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.Attorney Docket No. 055745-562001WG

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] In some embodiments of a method of treating non-small cell lung cancer (NSCLC), the anti-EGFR mab is cetixumab, or panitumuab.

[0095] 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 of(i)pharmaceutically acceptable salt thereof;(ii) a PD-1 or a PD-L1 inhibitor.(iii) an additional therapeutic agent.

[0096] Also 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 ofAttorney Docket No. 055745-562001WOpharmaceutically acceptable salt thereof;(ii) a PD-1 or a PD-L1 inhibitor; and(iii) an additional therapeutic agent.

[0097] Also 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 of(i)pharmaceutically acceptable salt thereof;pharmaceutically acceptable salt thereof;(iii) a PD-1 or a PD-L1 inhibitor; and(iv) an additional therapeutic agent.

[0098] 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).Attorney Docket No. 055745-562001WG

[0099] 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).

[0100] 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).

[0101] 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).

[0102] 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).

[0103] 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).

[0104] In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is anti-EGFR mab + chemotherapy.

[0105] In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is anti- VEGFR mab + anti-EGFR mab + chemotherapy.

[0106] In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is anti-EGFR mab + (fruquintinib or regorafenib).

[0107] In some embodiments of a method of treating colorectal cancer (CRC), the additional therapeutic agent is anti-EGFR mab.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.Attorney Docket No. 055745-562001WO

[0112] 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).

[0113] In some embodiments of a method of treating colorectal cancer (CRC), the anti-EGFR mab is cetixumab, or panitumuab.

[0114] In some embodiments of a method of treating colorectal cancer (CRC), the anti-VEGFR mab is bevacizumab, raucirumab, zivaflibercept.

[0115] 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 trifluridine + tiparacil. In some embodiments, 5FU combinations also include leucovorin.

[0116] 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 of(i)pharmaceutically acceptable salt thereof;(ii) a PD-1 or a PD-L1 inhibitor, andoptionally (iii) an additional therapeutic agent.

[0117] Also disclosed herein is a compound for use in treating pancreatic ductal adenocarcinoma (PDAC) in a subject in need thereof, the compound being Compound 1Attorney Docket No. 055745-562001WOcompound is for use in combination with a PD-1 or a PD-L1 inhibitor.

[0118] Also disclosed herein is a use of a compound that is Compound 1pancreatic ductal adenocarcinoma (PDAC) in a subject in need thereof, wherein the compound is for use in combination with a PD-1 or a PD-L1 inhibitor.

[0119] Also disclosed herein is a use of a compound that is Compound 1manufacture of a medicament for treating pancreatic ductal adenocarcinoma (PDAC) in a subject in need thereof, wherein the compound is for use in combination with a PD-1 or a PD-L1 inhibitor.Attorney Docket No. 055745-562001WO

[0120] In some embodiments, the compound or the pharmaceutically acceptable salt thereof is for use in combination with another therapeutic agent, such as defined herein.

[0121] Also 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 of(ii) a PD-1 or a PD-L1 inhibitor; and(iii) an additional therapeutic agent.

[0122] Also 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 of(i)pharmaceutically acceptable salt thereof;(ii)pharmaceutically acceptable salt thereof;Attorney Docket No. 055745-562001WG(iii) a PD-1 or a PD-L1 inhibitor; and(iv) an additional therapeutic agent.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the additional therapeutic agent is chemotherapy + / - anti-EGFR mab.

[0130] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the additional therapeutic agent is anti-EGFR mab.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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 agentAttorney Docket No. 055745-562001WGis (adagrasib or sotorasib or olomorasib or divarasib or glecirasib or garsorasib or RMC-6291) + / -anti-EGFR mab.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the anti-EGFR mab is cetixumab, or panitumuab.

[0142] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), the anti-VEGFR mab is bevacizumab, raucirumab, zivaflibercept.

[0143] 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 + albuminbound 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.Cancers

[0144] Disclosed herein are methods of treating cancer using a combination disclosed herein.

[0145] “ “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 brainAttorney Docket No. 055745-562001WGcancer, 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.

[0146] In some embodiments, the cancer harbors at least one of a KRAS, NRAS, or HRAS mutations.

[0147] In some embodiments, the cancer is a KRAS-driven cancer, HRAS-driven cancer, or a NRAS-driven cancer.

[0148] In some embodiments, the cancer has at least one RAS mutation.

[0149] In some embodiments, the RAS mutation is a mutation at the G12, G13, and / or Q61 position of the RAS protein.

[0150] In some embodiments, the cancer has a G12C RAS mutation. In some embodiments, the cancer has a G12D RAS mutation. In some embodiments, the cancer has a G12R RAS mutation. In some embodiments, the cancer has a G12S RAS mutation. 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 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 Q61K RAS mutation. In some embodiments, the cancer has a Q61R RAS mutation. In some embodiments, the cancer has a R68S RAS mutation.

[0151] In some embodiments, the cancer has been identified as having a BRCA1 / 2 mutation.

[0152] In some embodiments, the cancer has been identified as having a PALB2 mutation.

[0153] In some embodiments, the cancer has been identified as having a BRAF mutation.

[0154] In some embodiments, the cancer has been identified as having a BRAF V600E mutation.Attorney Docket No. 055745-562001WG

[0155] In some embodiments, the cancer has been identified as having a HER2 mutation.

[0156] In some embodiments, the cancer has been identified as having a MSI mutation.

[0157] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a BRAF V600E mutation.

[0158] In some embodiments, the cancer has been identified as having a HER2 mutation.

[0159] In some embodiments, the cancer has been identified as having a high level MET amplification.

[0160] In some embodiments, the cancer has been identified as having a MET Exon 14 Skipping mutation.

[0161] In some embodiments, the cancer has been identified as having an EGFR exon 19 deletion or exon 21 L858R mutation.

[0162] In some embodiments, the cancer has been identified as having an EGFR S768I, L861Q and / or G719X mutation.

[0163] In some embodiments, the cancer has been identified as having an EGFR Exon 20 insertion mutation.

[0164] In some embodiments, the cancer has been identified as having a MET amplification.

[0165] In some embodiments, the cancer has been identified as having a MET exon 14 skipping mutation.

[0166] In some embodiments, the cancer has been identified as having a NTRK 1 / 2 / 3 gene fusion.

[0167] In some embodiments, the cancer has been identified as having an Anaplastic lymphoma kinase (ALK) gene rearrangement.

[0168] In some embodiments, the cancer has been identified as having a Rearranged during transfection (RET) rearrangement.

[0169] In some embodiments, the cancer has been identified as having a ROS1 rearrangement.

[0170] In some embodiments, the cancer has a level of PD-L1 >= 50%.

[0171] In some embodiments, the cancer has alevel of PD-L1 >= l%-49%.

[0172] In some embodiments, the cancer has been identified as being a non-squamous cell carcinoma.

[0173] In some embodiments, the cancer has been identified as being a squamous cell carcinoma.

[0174] In some embodiments, the cancer has been identified as having a dMMR mutation.

[0175] In some embodiments, the cancer has been identified as having a dMMR / MSI-H mutation.

[0176] In some embodiments, the cancer has been identified as having a POLE / POLD1 mutation.

[0177] In some embodiments, the cancer is a liquid tumor. In some embodiments, the liquid tumor is leukemia. In some embodiments, the cancer is the leukemia is acute myeloid leukemia (AML).

[0178] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced or a metastatic solid tumor.Attorney Docket No. 055745-562001WG

[0179] 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.

[0180] In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

[0181] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a RAS mutation.

[0182] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a BRCA1 / 2 mutation.

[0183] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a PALB2 mutation.

[0184] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a BRAF mutation.

[0185] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a HER2 mutation.

[0186] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a MSI mutation.

[0187] In some embodiments, the pancreatic ductal adenocarcinoma (PDAC) has been identified as having a dMMR mutation.

[0188] 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).

[0189] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0190] some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a having a RAS mutation.

[0191] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a BRAF V600E mutation.

[0192] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a HER2 mutation.

[0193] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a high level MET amplification.

[0194] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a MET Exon 14 Skipping mutation.

[0195] 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.

[0196] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having an EGFR S768I, L861Q and / or G719X mutation.Attorney Docket No. 055745-562001WO

[0197] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having an EGFR Exon 20 insertion mutation.

[0198] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a BRAF V600E mutation.

[0199] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a HER2 mutation.

[0200] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a MET amplification.

[0201] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a MET exon 14 skipping mutation.

[0202] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a NTRK 1 / 2 / 3 gene fusion.

[0203] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having an Anaplastic lymphoma kinase (ALK) gene rearrangement.

[0204] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a Rearranged during transfection (RET) rearrangement.

[0205] In some embodiments, the non-small cell lung cancer (NSCLC) has been identified as having a ROS1 rearrangement.

[0206] In some embodiments, the non-small cell lung cancer (NSCLC) has a level of PD-L1 >= 50%.

[0207] In some embodiments, the non-small cell lung cancer (NSCLC) has a level of PD-L1 >= 1%-49%.

[0208] 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.

[0209] In some embodiments, the gastrointestinal cancer is colorectal cancer (CRC).

[0210] In some embodiments, the colorectal cancer (CRC) has been identified as having a RAS mutation.

[0211] In some embodiments, the colorectal cancer (CRC) has been identified as having a BRAF mutation.

[0212] In some embodiments, the colorectal cancer (CRC) has been identified as having a HER2 amplification.

[0213] In some embodiments, the colorectal cancer (CRC) has been identified as having a dMMR / MSI-H mutation.

[0214] In some embodiments, the colorectal cancer (CRC) has been identified as having a POLE / POLD1 mutation.Attorney Docket No. 055745-562001WODosing

[0215] In some embodiments, the compounds of the present disclosure (e.g. Compound 1 and / or Compound 2) are administered in a pharmaceutical composition as described herein. 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.

[0216] 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 pharmaceutical I y 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.

[0217] 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.Attorney Docket No. 055745-562001WO

[0218] 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.

[0219] 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.

[0220] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 500 mg per day.

[0221] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 400 mg per day.

[0222] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 300 mg per day.

[0223] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 200 mg per day.

[0224] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 100 mg per day.

[0225] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 100 mg and 500 mg per day.

[0226] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 200 mg and 500 mg per day.

[0227] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 300 mg and 500 mg per day.

[0228] In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 400 mg and 500 mg per day.

[0229] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered orally.

[0230] 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.

[0231] In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 100 mg per day.

[0232] In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 80 mg per day.

[0233] In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 60 mg per day.Attorney Docket No. 055745-562001WO

[0234] In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 40 mg per day.

[0235] In some embodiments, the amount of Compound 2, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 20 mg per day.Administration

[0236] 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 pharmaceutical ly 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 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. 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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 describedAttorney Docket No. 055745-562001WGherein 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.

[0241] 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.

[0242] 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 subject who is in a fasted state for at least 10 hours. In yet other 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 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.

[0243] 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 subject in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes postmeal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, 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 subject 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.

[0244] 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, andAttorney Docket No. 055745-562001WOcombination 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.

[0245] 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 subject in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes postmeal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, 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 subject 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.

[0246] 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 cycle ranges 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 treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, four, or five 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: Evaluation of the Anti-tumor Efficacy of Compound 1 in the Subcutaneous KPC Xenograft Model

[0247] The objective of this study was to evaluate the anti-tumor activity of Compound 1 in KPC mouse pancreatic tumor cells subcutaneously (s.c.) implanted in female C57 mice.

[0248] The Anti-PD-1 was obtained from Amyjet Scientific Inc, Lot No: BP0146, Specs: 54.8 mg / 5.6 mL.Attorney Docket No. 055745-562001WOCell line

[0249] The KPC tumor cell line was purchased from ATCC and maintained in the WuXi AppTec laboratory. Cells were maintained in vitro in DMEM supplemented with 10% heat inactivated fetal calf serum at 37°C in an atmosphere of 5% CO2. The subculture ratio was 1:4 and subculture occurred 3 ~ 4 times per week.Experimental design

[0250] The test article administration and the animal numbers in each study group were shown in the following experimental design table.Dosing formulation of test articlesVehicle preparation (10% research grade Captisol (CyDex Pharmaceuticals, KS) in 50 mM citrate solution pH 5.0)

[0251] 300 mL of sterile water was added to the bottle containing 6.5 g of citrate and vortexed to form a uniform system. Sterile water was added to adjust to a final volume of 500 mL. 50g of captisol was added to get a clear solution, adjust the pH to about 5. The final soludon was marked as solution B and stored at 4°C.Vehicle preparation (10% HP- -CD preparation)

[0252] 300 mL of sterile water was added to the bottle containing 60 g of HP- -CD and vortexed to form a uniform system. Sterile water was added to adjust to a final volume of 600 mL. The final solution was marked as solution A and stored at 4°C.Anti PD-1 preparation (10 mg / kg)

[0253] 0.894 mL of anti-PD-1 was added to 7.853 mL of DPBS.Anti PD-1 preparation (5 mg / kg)

[0254] 0.477 mL of anti-PD-1 was added to 8.3 mL of DPBS.Compound 1 preparation (100 mg / kg)Attorney Docket No. 055745-562001WG

[0255] 2.45 mL of DMSO was added to a vial containing 533.14 mg of Compound 1 and vortexed to form a clear solution. 14.7 mL of PEG400 was then added and vortexed well to form a homogenous solution. Finally, 31.85 mL of solution A was added and vortexed well unhl a clear soludon formed. The final soludon was divided into 7 tubes . They were prepared once a week and stored at 4°C.Tumor cell inoculation and animal grouping for efficacy evaluation

[0256] The KPC tumor model was established in female C57 mice by subcutaneous injection into the right flank with cell suspension (3xl06 / 0.2 mL / site / animal, 1:1 mixed with BD Matrigel). When tumor volume reached 94.46±2.71 mm3, the mice were randomized into 6 groups according to experimental design (7 animals / group) based on animal body weights and tumor volume. The mice were then administated treatments as indicated in study design (defined as Day 1).Tumor cell inoculation for rechallenge study

[0257] Rechallenge of KPC tumor model was established in female C57 mice by subcutaneous injection in the left flank with cell suspension (3xl06 / 0.2 mL / site / animal, 1:1 mixed with BD Matrigel) (defined as Day 1 in rechallenge study).Experimental indicatorsTumor volume

[0258] Tumor volume was measured by caliper and expressed in mm3using the formula: Tumor volume (mm3) = length x width2 / 2, where length and width refer to the larger and smaller perpendicular dimensions collected at each measurement.Tumor growth inhibition was calculated as TGITV = [1 - (Ti - Ti) / (Ci - C i)] x 100%.Ti: tumor volume of the treated groups on day i; Tp tumor volume at the day of the start of treatment; Ci: tumor volume of the vehicle group on day i; Cp tumor volume at the day of the start of treatment. The relative tumor volume was calculated as RTV = TVi / TVi x 100%Among them, TVi means the tumor volume on the day of the start of treatment, and TVi means the tumor volume on day i.Relative tumor growth rate (T / C%) = RTVt / RTVCx 100%RTVt means the mean relative tumor volume in the treatment group and RTVCmeans the mean relative tumor volume in the vehicle group.Body weight

[0259] The body weight of each mouse was weighed twice per week along with the tumor volume measurement.Body weight change was calculated as BWC = (BWi - BWi) / BWixl00%(BW : body weight of the groups on day i, BWp body weight at the day of the start of treatment).Attorney Docket No. 055745-562001WGStatistical analysis

[0260] Data was analyzed using ANOVA techniques with PRISM software. One-way ANOVA was used for analyses implicating five-group comparisons. Data were presented as the (Mean + SEM). Statistical significance was defined as p<0.05.ResultsTumor volume

[0261] The anti-tumor efficacy of Compound 1 in the KPC model was evaluated in this study. On day 26, the mean tumor volume of vehicle group reached 1,160.20 ± 146.93 mm3. Treatment with anti-PD-1 at 10 mg / kg BIW inhibited the tumor growth insignificantly relative to vehicle group (p>0.05) with the TGI value of 12.66% and the mean tumor volume of 1,025.13 ± 172.09 mm3. Treatment with Compound 1 at 100 mg / kg BID significantly inhibited the tumor growth with the TGI value of 95.25% (p<0.0001), and the mean tumor volume of 145.05 ± 56.44 mm3. Treatment with the combination of Compound 1 at 100 mg / kg BID and anti-PD-1 at 10 mg / kg BIW significantly inhibited the tumor growth with the TGI value of 108.53% (p<0.0001), and the mean tumor volume of 3.64 ± 2.46 mm3. The data is shown in FIG. 1.Meanwhile, the treatment was stopped for Group 3 (treated with Compound 1 at 100 mg / kg BID) on Day 26, and 2 out of 7 mice of the group achieved the complete response (Tumor volume of 0) on day 75. The treatment was stopped for Group 4 (treated with anti-PD-1 at 10 mg / kg BIW and Compound 1 at 100 mg / kg BID) on Day 38 and 7 out of 7 mice of the group achieved the complete response on day 75.

[0262] Compound 1 showed combination benefit with an anti-PD-1 in the syngeneic subcutaneous KPC xenograft model.Example 2: In Vivo Anti-tumor Efficacy of Compound 2 in Subcutaneous KPC Xenograft Model

[0263] The objective of this study was to evaluate the anti-tumor activity of Compound 2 alone against pancreatic cell line derived xenograft model KPC subcutaneously (s.c.) implanted in female C57 mice. KRAS G12D inhibitor MRTX1133 was used as reference compound.The Anti-PD-1 was obtained from Amyjet Scientific Inc, Lot No: BP0146, Specs: 54.8 mg / 5.6 mL Cell line

[0264] The KPC tumor cell line was purchased from ATCC and maintained in WuXi AppTec laboratory. Cell line pathogen testing was performed to confirm pathogen-free status. Cells were maintained in vitro in DMEM supplemented with 10% heat inactivated fetal calf serum at 37°C in an atmosphere of 5% CO2. The subculture ratio was 1:4 and 3~4 times per week.Attorney Docket No. 055745-562001WOExperimental design and methods

[0265] The test article administration and the animal numbers in each study group were shown in the following experimental design table.*Vehicle group was treated with 5% DMSO+30% PEG400+65% (lO%HP- -CD in water)Dosing formulation of test articlesVehicle preparation

[0266] 10% research grade Captisol (CyDex Pharmaceuticals, KS) in 50 mM citrate solution pH 5.0 300 mL sterile water was added to the bottle containing 6.5 g citrate and vortexed to form a uniform system. Sterile water was added to adjust to a final volume of 500 mL. 50g captisol was added to get a clear solution and the pH was adjusted to about 5. The final solution was marked as solution B and stored at 4°C.MRTX1133 preparation (10 mg / kg)

[0267] 7 mL solution B was added to a vial containing 7.35 mg of MRTX1133 and vortexed to form a clear solution. The final solution was stored at 4°C.Anti PD-1 preparation (10 mg / kg)

[0268] 0.894 mL anti-PD-1 was added to 7.853 mL DPBS.Anti PD-1 preparation (5 mg / kg)

[0269] 0.477 mL anti-PD-1 was added to 8.3 mL DPBS.Compound 2 preparation (5 mg / kg)

[0270] 12.25 mg of compound was added to 1.225 mL DMSO and vortexed to obtain a clarified solution. 2.45 mL of solutol was added and further vortexed to achieve a homogeneous solution. Finally, 20.825 mL of DD water was added and vortexed to achieve a homogeneous solution.Solution was divided into 7 tubes for once weekly preparation. Solution was stored at 4°C.Attorney Docket No. 055745-562001WOCompound 2 preparation (2 mg / kg)

[0271] 4.9 mg of compound 2 was added to 1.225 mL DMSO and vortexed to obtain a clear solution. 2.45 mL of solutol was added and further vortexed to achieve a homogeneous solution. Finally, 20.825 mL of DD water was added and vortexed to achieve a homogeneous solution.Soludon was divided into 7 tubes to prepare once a week. Solution was stored at 4°C.Tumor cell inoculation and animal grouping for efficacy evaluation

[0272] KPC tumor model was established in female C57 mice by subcutaneous injection in the right flank with cell suspension (3xl06 / 0.2 mL / site / animal, 1:1 mixed with BD Matrigel). When tumor volume reached 94.43+2.69 mm3, the mice were randomized into 6 groups according to experimental design (7 animals / group) based on animal body weights and tumor volume. The mice were then administrated treatments as indicated in study design (defined as Day 1).Tumor cell inoculation for rechallenge study

[0273] Rechallenge of KPC tumor model was established in female C57 mice by subcutaneous injection in the left armpit with cell suspension (3xl06 / 0.2 mL / site / animal, 1:1 mixed with BD Matrigel) (defined as Day 1 in rechallenge study).Experimental indicatorsTumor volume

[0274] Tumor volume was measured by caliper and expressed in mm3using the formula: Tumor volume (mm3) = lengthxwidth2 / 2, where length and width refer to the larger and smaller perpendicular dimensions collected at each measurement.Tumor growth inhibition was calculated as TGlTv=[l-(Ti-Ti) / (Ci-Ci)] xl00%.Ti: means tumor volume of the treated groups at day i; Ti: means tumor volume at the day of the start of treatment; Ci: means tumor volume of the vehicle group at day i; Ci: means tumor volume at the day of the start of treatment.The relative tumor volume was calculated as RTV=TVi / TVixl00%Among them, TVi was the tumor volume at the day of the start of treatment, and TVi was the tumor volume at day i.Relative tumor growth rate (T / C%) =RTVt / RTVcxl00%RTVt was the mean relative tumor volume in the treatment group and RTVCwas the mean relative tumor volume in the vehicle group.Body weight

[0275] Body weight of each mouse was weighed twice per week along with the tumor volume measurement.

[0276] Body weight change was calculated as BWC = (BWi- BWi) / BWixl00%(BWi: means body weight of the groups at day i, BWi: means body weight at the day of the start of treatment).Attorney Docket No. 055745-562001WGStatistical analysis

[0277] Data were analyzed using ANOVA techniques with PRISM software. One-way ANOVA was used for analyses implicating five-group comparisons. Data were presented as the (Mean + SEM). Statistical significance was defined as p<0.05.ResultsTumor volume

[0278] The efficacy of Compound 2 in KPC xenograft model was evaluated in this study. At Day 26, the mean tumor volume of vehicle group reached 1160.20+146.93 mm3. Treatment with anti-PD-1 at 10 mg / kg showed no significant tumor growth inhibition relative to vehicle group (p>0.05), with a TGI value of 12.66% and the mean tumor volume on day 26 of 1,025.13+172.09 mm3. Treatment with MRTX1133 at 10 mg / kg significantly inhibited tumor growth, with a TGI value of 93.45% (p<0.0001 and mean tumor volume on day 26 of 164.27+70.33 mm3. Treatment with Compound 2 significantly inhibited tumor growth, with a TGI value of 96.57% (p= 0.0018) and mean tumor volume on day 26 of 130.98+70.42 mm3. Treatment with the combination of MRTX1133 and anti-PD-1 significantly inhibited tumor growth, with a TGI value of 103.85% (p<0.0001) and a mean tumor volume on day 26 of 53.41+47.32 mm3(p<0.0001). Treatment with the combination of Compound 2 and anti-PD-1 significantly inhibited the tumor growth, with a TGI value of 108.27% and a mean tumor volume of 6.21+3.4 mm3(p 0.0024). The data is shown in FIG. 2, FIG. 3, and FIG.5

[0279] Mice in group 5 (treated with Compound 2) stopped receiving treatment after Day 26 (one mouse achieved CR, no signs of CR in other mice). Mice in group 4 (treated with anti-PD-1 and MRTX1133) stopped receiving treatment after Day 38 (5 mice achieved stable CR), and 5 mice achieved complete response at Day 75. Mice in group 6 (treated with anti-PD-1 and Compound 2) stopped receiving drug on Day 38 (7 mice achieved stable CR) and 7 mice achieved complete response at Day 75.

[0280] Compound 2 showed combination benefit with an anti-PD-1 in the syngeneic subcutaneous KPC xenograft model.

[0281] Compound 2 in combination with anti-PD-1 therapy resulted in complete response in 7 out of 7 treated mice on day 31.

[0282] Compound 2 as a monotherapy and in combination with an anti-PD-1 was well tolerated (FIG. 4).

[0283] Tumor formation was not observed up to 24 days after KPC rechallenge (FIG. 2 and FIG. 5).Example 3: In Vivo Anti-tumor Efficacy of Compound 1 in KRAS G12D CDX model

[0284] KPC pancreatic CDX model harboring a KRAS G12D mutation was tested in vivo to evaluate the combination activity of either Compound 1 or Compound 2 in combination with an antiAttorney Docket No. 055745-562001WGPD-1 inhibitor. The cell line was obtained from ATCC (Manassas, VA, USA) and maintained at low passage (<P5) and pathogen testing was performed periodically at IDEXX (Westbrook, Maine) to ensure pathogen-free status. Prior to implantation, cells were maintained in vitro in DMEM supplemented with 10% FBS and 1% Penicillin / Streptomycin at 37°C in an atmosphere of 5% CO2 in air. Cells were routinely sub-cultured at a confluence of 80-90% by trypsin-EDTA, and media renewed every 2-3 days.Female C57 mice were purchased from Beijing Vital River Laboratory Animal Technology Co. Ltd. The animals were housed in SPF room in individual ventilated cages (IVC), with constant temperature (21-25°C) and humidity (40-70%). Housing was provided a 12:12-h light-dark cycle. The bedding material was autoclaved corn-cob bedding that was changed once a week. Animals (3-5 animals per cage) were provided with autoclaved tap water and food ad libitum. All the procedures related to animal handling, care and the treatment in the study were performed according to the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Charles River Laboratories (P202206230001) and following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). At the time of routine monitoring, the animals were checked daily for any effects of tumor growth and treatments on normal behavior, such as mobility, food and water consumption (by looking only), body weight gain / loss (body weights were measured twice weekly), eye / hair matting and any other abnormal effect as stated in the protocol. Death and observed clinical signs were recorded.KPC tumor model was established in female C57 mice by subcutaneous injection in the right flank with cell suspension (3x106 / 0.2 mL / site / animal, 1:1 mixed with BD Matrigel). When tumor volume reached 94.43+2.69 mm3, the mice were randomized into 6 groups according to experimental design (7 animals / group) based on animal body weights and tumor volume. The mice were then administered treatments as indicated in study design (defined as Day 1). Rechallenge of KPC tumor model was established in female C57 mice by subcutaneous injection in the left armpit with cell suspension (3x106 / 0.2 mL / site / animal, 1:1 mixed with BD Matrigel) (defined as Day 1 in rechallenge study).

[0285] Treatment stopped at day 38. KPC rechallenge demonstrated immune memory effect by a contralateral inoculation of KPC cells in combination treatment groups that resulted in tumor formation. See FIG. 6 and FIG. 7.Attorney Docket No. 055745-562001WGExample 4: In Vivo Anti-tumor Efficacy of Compound 1 in CT26 model

[0286] CT26 is a mouse colorectal adenocarcinoma tumor cell line that harbors a KRAS G12D mutation. The CT26 cell line was purchased from ATCC, and cell line pathogen testing was performed to confirm pathogen-free status (IDEXX BioResearch, Columbia, MO). CT26 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% CO 2 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.

[0287] Female Balb / c mice were purchased from Envigo (n=200). Mice arrived on 6 February 2025 and were between 6-8 weeks of age at the time of implantation. Mice were hosted at a special pathogen-free (SPF) environment of the Charles River Spectrum III facility. Mice were acclimated to their new environment for at least 72 hours prior to initiation of experiments according to IACUC protocol.

[0288] All procedures related to animal handling, care, and treatment in this study were performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Erasca, Inc. and Charles River Laboratories, Inc. During the study, the care and use of animals were conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). In addition, all portions of this study were performed at the Charles River Spectrum III facility and adhered to the study protocols approved by the study director and applicable standard operating procedures (SOPs).

[0289] CT26 tumor cells were implanted into mice subcutaneously. 100 pL cell suspensions containing 2 x 106tumor cells mixed with 100% PBS 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 75.8 mm3 (range of 28.1-143.1 mm3), mice were randomized into different groups with 10 mice in each group. The randomization date was denoted as treatment day 0.

[0290] Mice were dosed twice daily with Compound 1, and significant dose dependent TGI was observed for both Compound 1 and anti-PD- 1 monotherapy groups as well as the groups treated with the combination relative to vehicle. On day 16, the mean tumor volume of the vehicle group was 1482 ± 312 mm3while Compound 1 at 50 mg / kg BID significantly inhibited tumor growth with a TGI value of 59% with mean tumor volumes of 648 ± 117 mm3. Similarly, treatment with anti-PD-1 at 10 mg / kg BIW demonstrated efficacy with a TGI value of 67% with mean tumor volumes of 541 ± 253 mm3. The combination of Compound 1 at 50 mg / kg BID and anti-PD-1 at lOmg / kg BIW resulted in greater efficacy with TGI values of 84% with mean tumor volumes of 303 ± 153 mm3. Both combinations were well tolerated with no significant body weight loss or clinical observations noted. The results of the study are shown in FIG. 8.Attorney Docket No. 055745-562001WO

[0291] The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the present disclosure. The description is made with the understanding that it is to be considered an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated.

Claims

Attorney Docket No. 055745-562001WOCLAIMS 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 of, or a pharmaceutical I y acceptable salt thereof; and(ii) a PD-1 or a PD-L1 inhibitor.A compound that is Compound 1 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 1 or salt thereof in combination with a PD-1 or a PD-L1 inhibitor.Attorney Docket No. 055745-562001WOpharmaceutically acceptable salt, for treating cancer in a subject need thereof, wherein the compound is for use in combination with a PD-1 or a PD-L1 inhibitor.pharmaceutically acceptable salt, for treating cancer in a subject need thereof, wherein the compound is for use in combination with a PD-1 or a PD-L1 inhibitor.

5. The method of any one of claims 1-7, wherein the PD-1 inhibitor is an anti-PD-1.

6. The method of claim 1, the compound for use of claim 2, or the use of claim 3 or 4, wherein the PD-1 inhibitor is acrixolimab, AMP-224, camrelizumab, cemiplimab, dostarlimab, MEDI0680, nivolumab, pembrolizumab, retifanlimab, sintilimab, spartalizumab, tislelizumab, toripalimab, or vopratelimab.

7. The method of claim 1, the compound for use of claim 2, or the use of claim 3 or 4, wherein the PD-L1 inhibitor is an anti-PD-Ll antibody, optionally an anti PD-L1 monoclonal antibody (mab).

8. The method of claim 1, the compound for use of claim 2, or the use of claim 3 or 4, wherein the PD-L1 inhibitor is atezolizumab, AUNP12, avelumab, BMS-986189, CA-170, cosibelimab (CK-301), durvalumab, or KN035.Attorney Docket No. 055745-562001WG9. The method of any one of claims 1 and 5 to 8, the compound for use of any one of claims 2 and 5 to 8, or the use of any one of claims 3 to 8, wherein the cancer is a RAS-dependent cancer.

10. The method of any one of claims 1 and 5 to 8, the compound for use of any one of claims 2 and 5 to 8, or the use of any one of claims 3 to 8, wherein the cancer comprises a RAS mutation.

11. The method, the compound for use or the use of claim 10, wherein the RAS mutation comprises a KRAS, a NRAS, and / or a HRAS mutation.

12. The method, the compound for use or the use of claim 10 or 11, wherein the RAS mutation comprises a mutation at the G12, G13, and / or Q61 position of the RAS protein.

13. The method, the compound for use or the use of any one of claims 10 to 12, wherein the RAS mutation comprises a G12C mutation of the RAS protein.

14. The method, the compound for use or the use of any one of claims 10 to 12, wherein the RAS mutation comprises a G12D mutation of the RAS protein.

15. The method, the compound for use or the use of any one of claims 10 to 12, wherein the RAS mutation comprises a G12S mutation of the RAS protein.

16. The method, the compound for use or the use of any one of claims 10 to 12, wherein the RAS mutation comprises a G12V mutation of the RAS protein.

17. The method, the compound for use or the use of any one of claims 10 to 12, wherein the RAS mutation comprises a G12A mutation of the RAS protein.

18. The method, the compound for use or the use of any one of claims 10 to 17, wherein the RAS mutation comprises a G13D mutation of the RAS protein.

19. The method, the compound for use or the use of any one of claims 10 to 18, wherein the RAS mutation comprises a Q61H mutation of the RAS protein.

20. The method, the compound for use or the use of any one of claims 10 to 18, wherein the RAS mutation comprises a Q61K mutation of the RAS protein.

21. The method, the compound for use or the use of any one of claims 10 to 18, wherein the RAS mutation comprises a Q61R mutation of the RAS protein.

22. The method of any one of claims 1 and 5 to 21, the compound for use of any one of claims 2 and 5 to 21, or the use of any one of claims 3 to 21, wherein the cancer is a solid tumor.

23. The method of any one of claims 1 and 5 to 22, the compound for use of any one of claims 2 and 5 to 22, or the use of any one of claims 3 to 22, 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.

24. The method, the compound for use, or the use of claim 23, wherein the lung cancer is nonsmall cell lung cancer (NSCLC).Attorney Docket No. 055745-562001WO25. The method, the compound for use, or the use of claim 23, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

26. The method, the compound for use, or the use of claim 23, 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).

27. The method of any one of claims 1 and 5 to 26, the compound for use of any one of claims 2 and 5 to 26, or the use of any one of claims 3 to 26, wherein the amount of Compound 1 , or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 500 mg per day.

28. The method, the compound for use, or the use of claim 27, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 400 mg per day.

29. The method, the compound for use, or the use of claim 27 or 28, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 300 mg per day.

30. The method, the compound for use, or the use of any one of claims 27 to 29, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 200 mg per day.

31. The method, the compound for use, or the use of any one of claims 27 to 30, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 1 mg and 100 mg per day.

32. The method, the compound for use, or the use of claim 27, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 100 mg and 500 mg per day.

33. The method, the compound for use, or the use of claim 27 or 32, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 200 mg and 500 mg per day.

34. The method, the compound for use, or the use of any one of claims 27, 32 and 33, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 300 mg and 500 mg per day.

35. The method, the compound for use, or the use of any one of claims 27, and 32 to 34, wherein the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered is between 400 mg and 500 mg per day.

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