WO2022271939A1

WO2022271939A1 - Erk1/2 and cdk4/6 inhibitors combination therapy

Info

Publication number: WO2022271939A1
Application number: PCT/US2022/034708
Authority: WO
Inventors: Robert Field SHOEMAKER; Wei Lin; Erin Denise LEW; Jingchuan Zhang; Joanne OH
Original assignee: Erasca Inc
Current assignee: Erasca Inc
Priority date: 2021-06-24
Filing date: 2022-06-23
Publication date: 2022-12-29
Anticipated expiration: 2023-12-24
Also published as: TW202317123A

Abstract

The present disclosure relates generally to the use of an ERK1/2 inhibitor in combination with a CDK4/6 inhibitor for treating cancer, specifically solid tumors.

Description

ERK1/2 AND CDK4/6 INHIBITORS COMBINATION THERAPY

CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63/214,768 filed June 24, 2021, U. S. Provisional Application Serial No. 63/236,636 filed August 24, 2021, U. S. Provisional Application Serial No. 63/279,880 filed November 16, 2021, U. S. Provisional Application Serial No. 63/314,832 filed February 28, 2022, U. S. Provisional Application Serial No. 63/321,610 filed March 18, 2022, which are hereby incorporated by reference in their entirety.

BACKGROUND

[0002] ERKl and ERK2 (collectively “ERKl/2”) are related protein-serine/threonine kinases that participate in, amongst others, the Ras-Raf-MEK-ERK signal transduction pathway, which is sometimes denoted as the mitogen-activated protein kinase (MAPK) pathway. This pathway is thought to play a central role in regulating a number of fundamental cellular processes including one or more of cell proliferation, survival, adhesion, cycle progression, migration, differentiation, metabolism, and transcription. The activation of the MAPK pathway has been reported in numerous tumor types including lung, colon, pancreatic, renal, and ovarian cancers. Accordingly, substances that could reduce activation could be of interest for possible treatments.

SUMMARY

[0003] ERK1/2 appear to be activated by MEK through phosphorylation of both a threonine and a tyrosine residue, namely at Tyr204/187 and Thr202/185. Once activated, ERK1/2 catalyze the phosphorylation of serine/threonine residues of more than 100 substrates and activate both cytosolic and nuclear proteins that are linked to cell growth, proliferation, survival, angiogenesis and differentiation, all hallmarks of the cancer phenotype. Thus it may be beneficial to target ERK 1 and ERK 2 to develop and use ERK 1/2 inhibitors as a way to inhibit tumor growth.

[0004] Furthermore, an ERK inhibitor may have utility in combination with other kinase, for example MAPK, inhibitors. Recently, researchers reported that dual inhibition of MEK and ERK by small molecule inhibitors was synergistic and acted to overcome acquired resistance to MEK inhibitors. See Hatzivassiliou et ah, ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition, Mol. Cancer Ther. 2012, 11, 1143-1154.

[0005] In addition to ERK 1/2, CDK4/6 plays a pivotal role in the regulation of cellular proliferation and transformation, as well as in the occurrence and progression of various malignant tumors. Inhibition of CDK4/6 has been shown to provide antitumor activity and manageable toxicity in HR+/HER2- breast cancer patients. Furthermore, it has been demonstrated that CDK4/6-related proteins have been co expressed with classical tumor signaling pathways, such as the RAS, PI3K, and MYC pathways.

[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) compound

, or a pharmaceutically acceptable salt thereof; and (ii) a CDK4/6 inhibitor.

[0007] In some embodiments, the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, FCN-437c, or alvociclib.

[0008] In some embodiments, the CDK4/6 inhibitor is palbociclib.

[0009] In some embodiments, palbociclib is administered in an amount that is between about 50 mg/day to about 500 mg/day.

[0010] In some embodiments, palbociclib is administered in an amount that is about 75 mg/day, 100 mg/day, 125 mg/day, or 150 mg/day.

[0011] In some embodiments, palbociclib is administered in an amount that is between about 50 mg once a week and about 650 mg once a week.

[0012] In some embodiments, palbociclib is administered in an amount that is about 200 mg once a week, 300 mg once a week, 400 mg once a week, 500 mg once a week, or 600 mg once a week.

[0013] 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) compound

, or a pharmaceutically acceptable salt thereof; and (ii) palbociclib.

[0014] In some embodiments, the pharmaceutically acceptable salt of compound 1 is the mandelic acid salt.

[0015] In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway driven cancer.

[0016] In some embodiments, the cancer is a BRAF -driven cancer, HRAS-driven cancer, or a NRAS- driven cancer.

[0017] In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK. [0018] In some embodiments, the cancer has at least one mutation in RAS. In some embodiments, the cancer has at least one mutation in RAF. In some embodiments, the cancer has at least one mutation in MEK.

[0019] In some embodiments, the cancer has a G12C KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a G12S KRAS mutation. In some embodiments, the cancer has a G12V KRAS mutation. In some embodiments, the cancer has a G13D KRAS mutation. In some embodiments, the cancer has a Q16H KRAS mutation. In some embodiments, the cancer has a Q 16K KRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation. [0020] In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

[0021] In some embodiments, the cancer is a MAPKm/MAPKi-naive pancreatic cancer or PDAC.

[0022] In some embodiments, the cancer comprises one or more EGFR mutation selected from the group consisting of EGFR gene copy gain, EGFR gene amplification, chromosome 7 polysomy, L858R, exon 19 deletions/insertions, L861Q, G719C, G719S, G719A, V765A, T783A, exon 20 insertions, EGFR splice variants (Viii, Vvi, and Vii), A289D, A289T, A289V, G598A, G598V, T790M, and C797S.

[0023] In some embodiments, the cancer comprises one or more EGFR mutation selected from the group consisting of L858R, exon 19 deletion, and T790M.

[0024] In some embodiments, the cancer is a solid tumor.

[0025] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

[0026] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is an EGFR mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G12C mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G12D mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G12S mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G12V mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G13D mutant NSCLC. In some embodiments, the NSCLC is a KRAS^Q61H mutant NSCLC. In some embodiments, the NSCLC is a KRAS^Q61K mutant NSCLC. In some embodiments, the NSCLC is a NRAS^Q61R mutant NSCLC. In some embodiments, the cancer is a MAPKm/MAPKi-naive NSCLC. In some embodiments, the cancer is a BRAFi-treated V600 NSCLC. In some embodiments, the cancer is a KRAS-treated G12C NSCLC. In some embodiments, the cancer is a KRAS-treated G12D NSCLC. In some embodiments, the cancer is a KRAS-treated G12S NSCLC. In some embodiments, the cancer is a KRAS-treated G12V NSCLC. In some embodiments, the cancer is a KRAS-treated G13D NSCLC. In some embodiments, the cancer is a KRAS-treated Q61H NSCLC. In some embodiments, the cancer is a KRAS-treated Q61K NSCLC. In some embodiments, the cancer is a NRAS-treated Q61RNSCLC.

[0027] In some embodiments, 1-28, the cancer is pancreatic cancer.

[0028] In some embodiments, the cancer is a MAPKm/MAPKi-naive pancreatic cancer or PDAC.

[0029] In some embodiments, the cancer is melanoma.

[0030] In some embodiments, the melanoma is a BRAF V600E or V600K mutant tumor. [0031] In some embodiments, the cancer is a BRAFi-treated V600 melanoma.

[0032] In some embodiments, the cancer is salivary gland tumor.

[0033] In some embodiments, the cancer is thyroid cancer.

[0034] In some embodiments, the cancer is colorectal cancer (CRC).

[0035] In some embodiments, the CRC is a BRAF V600E CRC.

[0036] In some embodiments, the CRC is a KRAS mutant CRC. In some embodiments, the CRC is a KRAS^G12C mutant CRC. In some embodiments, the CRC is a KRAS^G12D mutant CRC. In some embodiments, the CRC is a KRAS^G12S mutant CRC. In some embodiments, the CRC is a KRAS^G12V mutant CRC. In some embodiments, the CRC is a KRAS^G13D mutant CRC. In some embodiments, the CRC is a KRAS^Q61H mutant CRC. In some embodiments, the CRC is a KRAS^Q61K mutant CRC. In some embodiments, the CRC is a NRAS mutant CRC. In some embodiments, the CRC is a NRAS^Q61R mutant CRC.

[0037] In some embodiments, the cancer is esophageal cancer.

[0038] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg/day and about 300 mg/day.

[0039] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between 25 mg/day and 150 mg/day.

[0040] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

[0041] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

[0042] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 250 mg/day.

[0043] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day (QD). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day (BID). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered three times a day (TID).

[0044] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a week.

[0045] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 300 mg twice a day, once a week (BID-QW).

[0046] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 250 mg twice a day, once a week (BID-QW). [0047] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 150 mg twice a day, once a week (BID-QW).

[0048] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

[0049] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, once a week (BID-QW).

[0050] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 125 mg twice a day, once a week (BID-QW).

[0051] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

[0052] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered on day 1, day 8, day 15, and day 22 of a 28 -day cycle.

[0053] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered on day 1, day 8, day 15 of a 28-day cycle.

[0054] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0055] In some embodiments, the method further comprises administering an additional MAPK pathway inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAFl inhibitor, MEK1 inhibitor, MEK2 inhibitor, c-Mycv, CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a BRAF inhibitor. In some embodiments, the additional MAPK pathway inhibitor is an EGFR inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a CDK4/6. In some embodiments, the additional MAPK pathway inhibitor is a FLT3 inhibitor. In some embodiments, the additional MAPK pathway inhibitor is adagrasib, afatinib, ASTX029, binimetinib, cetuximab, cobimetinib, dabrafenib, dacomitinib, encorafenib, erlotinib, gefitinib, gilteritinib, lapatinib, LTT462, LY3214996, necitumumab, neratinib, nimotuzumab, osimertinib, panitumumab, selumetinib, sotorasib, trametinib, ulixertinib, vandetanib, or vemurafenib. In some embodiments, the additional MAPK pathway inhibitor is adagrasib. In some embodiments, the additional MAPK pathway inhibitor is cetuximab. In some embodiments, the additional MAPK pathway inhibitor is dabrafenib. In some embodiments, the additional MAPK pathway inhibitor is encorafenib. In some embodiments, the additional MAPK pathway inhibitor is gilteritinib. In some embodiments, the additional MAPK pathway inhibitor is panitumumab. In some embodiments, the additional MAPK pathway inhibitor is sotorasib. INCORPORATION BY REFERENCE

[0056] 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

[0057] 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:

[0058] FIG. 1A shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in LSI 80 cells.

[0059] FIG. IB shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in NCI-H727 cells.

[0060] FIG. 1C shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in A549 cells.

[0061] FIG. ID shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in SW-620 cells.

[0062] FIG. IE shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in HCT-116 cells.

[0063] FIG. IF shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in LoVo cells.

[0064] FIG. 1G shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in HCT-15 cells.

[0065] FIG. 1H shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in NCI-H1944 cells.

[0066] FIG. II shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in NCI-H460 cells.

[0067] FIG. 1J shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in SK-MEL-2 cells.

[0068] FIG. IK shows the results of a clonogenic assay performed with compound 1 alone, palbociclib alone, and compound 1 + palbociclib in Calu-6 cells.

[0069] FIG. 2A shows the in-vivo data for compound 1 alone, palbociclib alone, and compound 1 + palbociclib in LoVo KRAS^G13D CDX model.

[0070] FIG. 2B shows the in-vivo data for compound 1 alone, palbociclib alone, and compound 1 + palbociclib in SW-620 KRAS^G12V CDX model. [0071] FIG. 3A shows the in-vivo tumor growth inhibition (TGI) for palbociclib alone, compound 1 alone, and compound 1 + palbociclib in KRAS^G12D mutant PDAC PDX model PAN092.

[0072] FIG. 3B shows the in-vivo tumor growth inhibition (TGI) for palbociclib alone, compound 1 alone, and compound 1 + palbociclib in KRAS^G12D mutant PDAC PDX model PAN026.

[0073] FIG. 4 shows the in-vitro data of compound 1 alone, palbociclib alone, and compound 1 + palbocicilb in mutant KRAS^G12V cellular model SW-480.

[0074] FIG. 5 shows the in-vitro data of compound 1 alone, palbociclib alone, and compound 1 + palbocicilb in mutant NRAS^Q61K cellular model WM3268.

[0075] FIG. 6 shows the in-vitro data of compound 1 alone, palbociclib alone, and compound 1 + palbocicilb in mutant NRAS^Q61K cellular model WM3456.

DETAILED DESCRIPTION

[0076] 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.

[0077] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0078] 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.

[0079] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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).

[0084] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, 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. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments.

[0085] The term “substantially the same as” as used herein, refers to a powder x-ray diffraction pattern or differential scanning calorimetry pattern that is non-identical to those depicted herein, but that falls within the limits of experimental error, when considered by one of ordinary skill in the art.

Compound 1

[0086] Disclosed herein is (S)-N-(2-amino-l-(3-chloro-5-fluorophenyl)ethyl)-l-(5-methyl-2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-lH-imidazole-4-carboxamide:

[0087] In some embodiments, the salt of compound 1 is the mandelic acid salt. In some embodiments, the salt of compound 1 is the benzene sulfonic acid salt. In some embodiments, the salt of compound 1 is the hydrochloride salt. In some embodiments, the salt of compound 1 is the p-toluenesulfonic acid salt.

CDK4/6 Inhibitors

[0088] CDK4/6 inhibitors act at the Gi-to-S cell cycle checkpoint, which is tightly controlled by the D- type cyclins, CDK4 and CDK6. When CDK4 and CDK6 are activated by D-type cyclins, they phosphorylate the retinoblastoma-associated protein (pRb), which releases pRb’s suppression of E2F transcription factor family and allow the cell to proceed through cell cycle. In HR+ cancer, cyclin D overexpression is common and loss of pRb is rare, making the Gi-to-S checkpoint an ideal therapeutic agent.

[0089] In some embodiments, the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, FCN-437c, or alvociclib.

[0090] In some embodiments, the CDK4/6 inhibitor palbociclib. Palbociclib

[0091] Palbociclib

kinase inhibitor used for the treatment of

HR+/HER2- advanced or metastatic breast cancer. Palbociclib is sold as Ibrance® by Pfizer.

Combinations

[0092] 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) compound

, or a pharmaceutically acceptable salt thereof; and (ii) a CDK4/6 inhibitor.

[0093] In some embodiments, the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, FCN-437c, or alvociclib.

[0094] In some embodiments, the CDK4/6 inhibitor is palbociclib.

[0095] 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) compound

, or a pharmaceutically acceptable salt thereof; and (ii) palbociclib.

Further Combination

In some embodiments, the method comprises administering an additional MAPK pathway inhibitor. Without being bound by theory, suppression of MAPK signaling in cancer cells can result in downregulation of PD-L1 expression and increase the likelihood that the cancer cells are detected by the immune system. Such third MAPK pathway inhibitors may be based on other mutations of proteins in the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor inhibits a protein in the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor inhibits a protein outside the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAFl inhibitor, MEK1 inhibitor, MEK2 inhibitor, c-Mycv, CDK4/6, inhibitor CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor. Exemplary MAPK pathway inhibitors include, without limitation, adagrasib, afatinib, ASTX029, binimetinib, cetuximab, cobimetinib, dabrafenib, dacomitinib, encorafenib, erlotinib, gefitinib, gilteritinib, lapatinib, LTT462, LY3214996, necitumumab, neratinib, nimotuzumab, osimertinib, panitumumab, selumetinib, sotorasib, trametinib, ulixertinib, vandetanib, and vemurafenib.

[0096] In some embodiment the additional MAPK pathway inhibitor is adagrasib. In some embodiment the additional MAPK pathway inhibitor is afatinib. In some embodiment the additional MAPK pathway inhibitors is binimetinib. In some embodiment the additional MAPK pathway inhibitor is cetuximab. In some embodiment the additional MAPK pathway inhibitor is cobimetinib. In some embodiment the additional MAPK pathway inhibitor is dabrafenib. In some embodiment the additional MAPK pathway inhibitor is dacomitinib. In some embodiment the additional MAPK pathway inhibitor is encorafenib. In some embodiment the additional MAPK pathway inhibitor is erlotinib. In some embodiment the additional MAPK pathway inhibitor is gefitinib. In some embodiment the additional MAPK pathway inhibitor is gilteritinib. In some embodiment the additional MAPK pathway inhibitor is lapatinib. In some embodiment the additional MAPK pathway inhibitor is LTT462. In some embodiment the additional MAPK pathway inhibitor is LY3214996. In some embodiment the additional MAPK pathway inhibitor is necitumumab. In some embodiment the additional MAPK pathway inhibitor is neratinib. In some embodiment the additional MAPK pathway inhibitor is nimotuzumab. In some embodiment the additional MAPK pathway inhibitor is osimertinib. In some embodiment the additional MAPK pathway inhibitor is panitumumab. In some embodiment the additional MAPK pathway inhibitor is selumetinib. In some embodiment the additional MAPK pathway inhibitor is sotorasib. In some embodiment the additional MAPK pathway inhibitor is trametinib. In some embodiment the additional MAPK pathway inhibitor is ulixertinib. In some embodiment the additional MAPK pathway inhibitor is vandetanib.

Cancers

[0097] Disclosed herein are methods of treating cancer using a combination disclosed herein.

[0098] “Cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including, without limitation, leukemias, lymphomas, myelomas, carcinomas, and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer (such as pancreatic adenocarcinoma, PDAC), medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, cancer of the head, Hodgkin's Disease, and Non-Hodgkin's Lymphomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the blood, thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0099] In some embodiments, the cancer has a class 1 B-Raf mutation.

[00100] In some embodiments, the cancer harbors at least one of a EGFR, KRAS, BRAF (e.g., BRAF class III) and/or NF1 (e.g., loss of function) mutations.

[00101] In some embodiments, the mutant B-Raf comprises a V600 mutation. In some embodiments, the mutant of B-Raf comprises the mutation V600E. In some embodiments, the mutation is V600K. In some embodiments, the mutation is V600D. In some embodiments, the mutation is V600F. In some embodiments, the mutation is V600R. In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

[00102] In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway driven cancer.

[00103] In some embodiments, the cancer is a BRAF-driven cancer, HRAS-driven cancer, or a NRAS- driven cancer.

[00104] In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK. [00105] In some embodiments, the cancer has at least one mutation in RAS. In some embodiments, the cancer has at least one mutation in RAF. In some embodiments, the cancer has at least one mutation in MEK.

[00106] In some embodiments, the cancer has a G12C KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a G12S KRAS mutation. In some embodiments, the cancer has a G12V KRAS mutation. In some embodiments, the cancer has a G13D KRAS mutation. In some embodiments, the cancer has a Q16H KRAS mutation. In some embodiments, the cancer has a Q16K KRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation. [00107] In some embodiments, the cancer is a MAPKm/MAPKi-naive pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the PDAC is indicated by a KRAS G12V mutation.

[00108] In some embodiments, the cancer comprises one or more EGFR mutation selected from the group consisting of EGFR gene copy gain, EGFR gene amplification, chromosome 7 polysomy, L858R, exon 19 deletions/insertions, L861Q, G719C, G719S, G719A, V765A, T783A, exon 20 insertions, EGFR splice variants (Viii, Vvi, and Vii), A289D, A289T, A289V, G598A, G598V, T790M, and C797S. In some embodiments, the cancer comprises one or more EGFR mutation selected from the group consisting of L858R, exon 19 deletion, and T790M.

[00109] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced or a metastatic solid tumor.

[00110] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

[00111] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is an EGFR mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G12C mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G12D mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G12S mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G12V mutant NSCLC. In some embodiments, the NSCLC is a KRAS^G13D mutant NSCLC. In some embodiments, the NSCLC is a KRAS^Q61H mutant NSCLC. In some embodiments, the NSCLC is a KRAS^Q61K mutant NSCLC.

[00112] In some embodiments, the NSCLC is a NRAS^Q61R mutant NSCLC. In some embodiments, the cancer is a MAPKm/MAPKi-naive NSCLC. In some embodiments, the cancer is a BRAFi-treated V600 NSCLC. In some embodiments, the cancer is a KRAS-treated G12C NSCLC. In some embodiments, the cancer is a KRAS-treated G12D NSCLC. In some embodiments, the cancer is a KRAS-treated G12S NSCLC. In some embodiments, the cancer is a KRAS-treated G12V NSCLC. In some embodiments, the cancer is a KRAS-treated G13D NSCLC. In some embodiments, the cancer is a KRAS-treated Q61H NSCLC. In some embodiments, the cancer is a KRAS-treated Q61K NSCLC. In some embodiments, the cancer is a NRAS-treated Q61RNSCLC.

[00113] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a MAPKm/MAPKi-naive pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the PDAC is indicated by a KRAS G12V mutation.

[00114] In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is a BRAF V600E or V600K mutant tumor. In some embodiments, the cancer is a BRAFi-treated V600 melanoma.

[00115] In some embodiments, the cancer is salivary gland tumor.

[00116] In some embodiments, the cancer is thyroid cancer. [00117] In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is a BRAF V600E CRC. In some embodiments, the CRC is a KRAS mutant CRC.

[00118] In some embodiments, the CRC is a KRAS^G12C mutant CRC. In some embodiments, the CRC is a KRAS^G12D mutant CRC. In some embodiments, the CRC is a KRAS^G12S mutant CRC. In some embodiments, the CRC is a KRAS^G12V mutant CRC. In some embodiments, the CRC is a KRAS^G13D mutant CRC. In some embodiments, the CRC is a KRAS^Q61H mutant CRC. In some embodiments, the CRC is a KRAS^Q61K mutant CRC. In some embodiments, the CRC is a NRAS mutant CRC. In some embodiments, the CRC is aNRAS^Q61R mutant CRC.

[00119] In some embodiments, the cancer is esophageal cancer.

[00120] In some embodiments, the cancer is colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma cancer, appendiceal cancer, gastric cancer, esophageal cancer, non-small cell lung cancer (NSCLC), head and neck cancer, ovarian cancer, uterine cancer, acute myeloid leukemia (AML), or melanoma.

[00121] In some embodiments, the cancer is a gastrointestinal cancer. In some embodiments, the gastrointestinal is anal cancer, bile duct cancer, colon cancer, rectal cancer, esophageal cancer, gallbladder cancer, liver cancer, pancreatic cancer, small intestine cancer, or stomach cancer (gastric cancer).

Dosing

[00122] 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.

[00123] 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). 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.

[00124] 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.

[00125] In some embodiments, palbociclib is administered in an amount that is between about 50 mg/day and about 500 mg/day. In some embodiments, palbociclib is administered in an amount that is about 75 mg/day. In some embodiments, palbociclib is administered in an amount that is about 100 mg/day. In some embodiments, palbociclib is administered in an amount that is about 125 mg/day. In some embodiments, palbociclib is administered in an amount that is about 150 mg/day.

[00126] In some embodiments, palbociclib is administered in an amount that is between about 50 mg once weekly and about 650 mg once a week. In some embodiments, palbociclib is administered in an amount that is about 200 mg once a week. In some embodiments, palbociclib is administered in an amount that is about 300 mg once a week. In some embodiments, palbociclib is administered in an amount that is about 400 mg once a week. In some embodiments, palbociclib is administered in an amount that is about 500 mg once a week. In some embodiments, palbociclib is administered in an amount that is about 600 mg once a week.

[00127] 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.

[00128] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[00129] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg/day and about 300 mg/day.

[00130] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between 25 mg/day and 150 mg/day.

[00131] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

[00132] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

[00133] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 25 mg to about 300 mg twice a day, once a week (BID-QW). [00134] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 250 mg twice a day, once a week (BID- QW). [00135] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 200 twice a day, once a week (BID- QW).

[00136] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 150 mg twice a day, once a week (BID- QW).

[00137] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 100 mg twice a day, once a week (BID- QW).

[00138] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 50 mg twice a day, once a week (BID- QW).

[00139] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 50 mg to about 300 mg twice a day, once a week (BID- QW).

[00140] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 50 mg and about 250 twice a day, once a week (BID- QW).

[00141] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 50 mg and about 200 mg twice a day, once a week (BID- QW).

[00142] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 50 mg and about 150 mg twice a day, once a week (BID- QW).

[00143] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 50 mg and about 100 mg twice a day, once a week (BID- QW).

[00144] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 100 mg and about 300 mg twice a day, once a week (BID-QW).

[00145] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 100 mg and about 250 mg twice a day, once a week (BID-QW).

[00146] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 100 mg and about 200 mg twice a day, once a week (BID-QW). [00147] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 100 mg and about 150 mg twice a day, once a week (BID-QW).

[00148] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 150 mg and about 300 mg twice a day, once a week (BID-QW).

[00149] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 150 mg and about 250 mg twice a day, once a week (BID-QW).

[00150] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 150 mg and about 200 mg twice a day, once a week (BID-QW).

[00151] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 175 mg and about 300 mg twice a day, once a week (BID-QW).

[00152] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 175 mg and about 250 mg twice a day, once a week (BID-QW).

[00153] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 175 mg and about 200 mg twice a day, once a week (BID-QW).

[00154] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 200 mg and about 300 mg twice a day, once a week (BID-QW).

[00155] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 200 mg and about 250 mg twice a day, once a week (BID-QW).

[00156] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 225 mg and about 300 mg twice a day, once a week (BID-QW).

[00157] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 225 mg and about 250 mg twice a day, once a week (BID-QW).

[00158] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 300 mg once a week (QW).

[00159] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 50 mg and about 250 mg once a week (QW). [00160] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 100 mg and about 300 mg once a week (QW).

[00161] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 100 mg and about 250 mg once a week (QW).

[00162] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 150 mg and about 300 mg once a week (QW).

[00163] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 150 mg and about 250 mg once a week (QW).

[00164] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 100 mg once a week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 150 mg once a week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 200 mg once a week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 250 mg once a week (QW).

[00165] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 300 mg twice a day, once a week (BID-QW).

[00166] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 250 mg twice a day, once a week (BID-QW).

[00167] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 150 mg twice a day, once a week (BID-QW).

[00168] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

[00169] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, once a week (BID-QW).

[00170] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 125 mg twice a day, once a week (BID-QW).

[00171] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 250 mg once a day, once a week.

[00172] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, 30 mg, 40 mg, 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg.

[00173] In some embodiments, each of the above-recited amounts may be administered QD, QW, BID, BID-QD, or BID-QW.

Administration

[00174] 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 embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for prophylactic and/or therapeutic treatments. 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. 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.

[00175] In prophylactic applications, the compositions described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, e.g., cancer. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's age, state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the risk or susceptibility of developing the particular disease, previous therapy, the patient's health status and response to the compositions, and the judgment of the treating physician.

[00176] 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.

[00177] In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered once a day. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered twice a day. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered three times a day.

[00178] In some embodiments, palbociclib is administered once daily. In some embodiments, palbociclib is administered twice daily. In some embodiments, palbocicilib is administered three times daily.

[00179] In some embodiments, palbociclib is administered once per week. In some embodiments, palbociclib is administered twice per week. In some embodiments, palbocicilib is administered three times per week. [00180] In some embodiments, palbociclib is administered once daily for 21 days followed by 7 days off treatment.

[00181] 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.

[00182] 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 post-meal,

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.

[00183] 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.

[00184] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered in 28-day cycles. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered for multiple 28-day cycles. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered for at least one 28-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered for at least two 28-day cycles. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered for at least three 28-day cycles. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered for at least four 28-day cycles. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered for at least five 28-day cycles. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein, are administered for at least six 28-day cycles.

[00185] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.

[00186] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 1 of a 28-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 8 of a 28-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 15 of a 28-day cycle.

In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 22 of a 28-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is not administered twice a day on day 22 of a 28 -day cycle.

[00187] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 1, day 8, and day 15 of a 28-day cycle.

[00188] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, days 9-14, days 16-21, days 23-28 of a 28-day cycle.

[00189] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered in 35-day cycles. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered for multiple 35-day cycles. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered for at least one 35-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered for at least two 35-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered for at least three 35-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered for at least four 35-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered for at least five 35-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, and combination partners described herein are administered for at least six 35-day cycle.

[00190] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 35-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 35 -day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 35 -day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 35 -day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-35 of each 35 -day cycle.

[00191] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 1 of a 35 -day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 8 of a 35-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 15 of a 35 -day cycle.

In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 22 of a 35 -day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 29 of a 35-day cycle. In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is not administered twice a day on day 29 of a 35 -day cycle. [00192] In some embodiments of a method of treating a cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on day 1, day 8, day 15, and day 22 of a 35-day cycle. [00193] In some embodiments of a method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, days 9-14, days 16-21, days 23-28, and days 30- 35 of a 28 -day cycle. Patient selection

[00194] In some embodiments of a method of treating cancer, the subject is 18 years of age. In another embodiment, the subject is 18 years of age or older. In another embodiment, the subject is no more than 99 years of age.

[00195] In some embodiments of a method of treating cancer, the subject is willing and able to give written informed consent.

[00196] In some embodiments of a method of treating cancer, the subject has histologically or cytologically confirmed metastatic CRC harboring applicable mutations based on an analytically validated assay performed on tumor tissue in a certified testing laboratory. In some embodiments, the subject has a BRAFm V600E mutations. In some embodiments, the subject has a KRAS mutation. In some embodiments, the subject has a NRAS mutation.

[00197] In some embodiments of a method of treating cancer, the subject has adequate bone marrow and organ function.

[00198] In some embodiments of a method of treating cancer, the subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[00199] In some embodiments of a method of treating cancer, the subject is willing to comply with all protocol-required visits, assessments, and procedures.

[00200] In some embodiments of a method of treating cancer, the subject is able to swallow oral medication.

[00201] In some embodiments of a method of treating cancer, the subject has not received prior therapy with a RAS, MEK, or ERK inhibitor.

[00202] In some embodiments of a method of treating cancer, the subject has not received anti -cancer therapy < 21 days prior to first dose of the study drug or a drug combination.

[00203] In some embodiments of a method of treating cancer, the subject has not received anti -cancer therapy 4 half-lives prior to first dose of the study drug or a drug combination.

[00204] In some embodiments of a method of treating cancer, the subject has not received palliative radiation < 7 days prior to first dose of study drug or a drug combination.

[00205] In some embodiments of a method of treating cancer, the subject does not have or has not been diagnosed with symptomatic brain metastasis or a leptomeningeal disease.

[00206] In some embodiments of a method of treating cancer, the subject does not have or has not been diagnosed with gastrointestinal conditions that may affect absorption of oral medications.

[00207] In some embodiments of a method of treating cancer, the subject does not have or has not been diagnosed with active infection requiring systemic therapy, or a history of HIV infection, hepatitis B virus, or hepatitis C virus.

[00208] In some embodiments of a method of treating cancer, the subject does not have a history of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention, such as immunomodulatory, immunosuppressive medications or surgery, < 12 months prior to first dose of study drug or a drug combination.

[00209] In some embodiments of a method of treating cancer, the subject does not have an active and clinically significant interstitial lung disease or pneumonitis.

[00210] In some embodiments of a method of treating cancer, the subject does not have an impaired cardiovascular function or clinically significant cardiovascular disease.

[00211] In some embodiments of a method of treating cancer, the subject does not have a history of thromboembolic or cerebrovascular events < 6 months prior to first dose of study drug or a drug combination.

[00212] In some embodiments of a method of treating cancer, the subject has not had major surgery within 28 days of enrollment of the study or anticipate of major surgery during study treatment.

[00213] In some embodiments of a method of treating cancer, the subject does not have known intolerance or contraindication to encorafenib, cetuximab, or palcociclib.

[00214] In some embodiments of a method of treating cancer, the subject is not pregnant or is not breastfeeding.

[00215] In some embodiments of a method of treating cancer, the subject does not have any evidence of severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding that renders the patient inappropriate to participate in the study.

EXAMPLES

Example 1: In-Vitro Clonogenic Assays

[00216] Cells were plated at indicated density in a 12-well plate and allowed to adhere overnight (see table below). The following day, vehicle or compounds were added to the well in lmL of media. After 7- day incubation, medium was replaced with fresh medium containing vehicle or compounds. After 14-day incubation, cells were washed two times in lxPBS, fixed for 30 minutes in 4% formaldehyde, and then washed twice with lxPBS. Cells were stained with 0.1% crystal violet for 60 minutes and then washed five times with lxPBS. Plates were dried for 2 hours at room temperature and imaged. Subsequently, cells were de-stained with 10% acetic acid, and absorbance measured using BCA protocol or absorbance at 560nm.

Results

[00217] Compound 1 and palbociclib demonstrate combination benefit in vitro in mutant RAS cellular models. Clonogenic assays were performed with compound 1 alone, palbociclib alone, or in combination in cell lines harboring RAS mutations in tumor types as indicated (FIG. 1A to FIG. IK).

Example 2: Phase lb/2 Study of Compound 1 and Palbociclib Combination Targeting the MAPK Pathway in Patient with Advanced Gastrointestinal Malignancies Study Design

[00218] This phase lb/2 study will evaluate the safety, clinical pharmacology, and preliminary efficacy of compound 1 administered once weekly (QW) in combination with palbociclib on either a once daily (QD) or once weekly (QW) schedule in patients with previously treated KRASm or NRASm colorectal cancer.

[00219] Part 1 will determine the recommended dose (RD) for compound 1 QW plus palbocicilib QD, and Part 3 will determine the recommended dose (RD) for compound 1 QW plus palbociclib QW. Only the RD from Part 1 and Part 3 will be selected for expansion in Part 2 or Part 4, respectively, in a larger cohort of patients. The RD selection will be based on a comparison of safety, tolerability, PK, PD, and preliminary efficacy. The expansion is designed to test the hypothesis that the combination of compound 1 and palbociclib has superior anti-tumor activity than the current standard of care in patients with previously treated KRASm or NRASm CRC.

[00220] Up to approximately 252 patients will be enrolled in this study, with up to approximately 58 and 82 safety-evaluable patients enrolled in Part 1 and Part 3 respectively. Patients who withdraw from the study during the 28-day DLT evaluation period due to reasons not related to treatment-emergent toxicities will be replaced. After RD and schedule selection, assuming 10% of patients who receive at least 1 dose of compound 1 withdraw from the study prior to the first post-dose tumor assessment, up to approximately 112 patients will be enrolled in Part 2 or Part 4 with a target of 100 efficacy-evaluable patients.

Part 1

[00221] Part 1 will determine the recommended dose (RD) for compound 1 QW plus palbocicilib QD. Part 1 will evaluate compound 1 QW plus palbociclib QD on a 28 -day cycle with 21 days on palbociclib and 7 days off (or QD [3/1]), at multiple dose levels, using a Bayesian optimal interval (BOIN) design. [00222] The first dose cohort in Part 1 will be compound 1 100 mg QW plus palbociclib 75 mg QD (3/1). The Safety Review Committee (SRC) will use the safety, PK, and PD data from this QD Sentinel Cohort to inform the decision on 1) further evaluation of this combination schedule at higher dose levels in the QD Dose-Escalation Matrix, and 2) the initial evaluation of compound 1 100 mg QW plus palbociclib 200 mg QW in the QW Sentinel Cohort. QD Dose Escalation

[00223] A total of 9 possible dose levels may be explored in the compound 1 QW plus palbociclib QD (3/1) schedule, with compound 1 at 100, 150, 200, or 250 mg QW and palbociclib at 75, 100, or 125 mg QD.

Part 3

[00224] P The first dose cohort in Part 3 (QW Sentinel Cohort) will be compound 1 at 100 mg QW plus palbociclib 200 mg QW. The decision to open this cohort will be based on an assessment of the safety data and available PK and PD data from the QD Sentinel Cohort in Part 1, or, if the SRC deems necessary, data from additional cohorts in the QD Dose-Escalation Matrix.

QW Dose Escalation

[00225] A total of 15 possible dose levels may be explored in the compound 1 QW plus palbociclib QW schedule, with compound 1 at 100 mg 150, 200, or 250 mg QW and palbociclib at 200, 300, 400, 500, or 600 mg QW.

Study Objectives Part 1

[00226] The primary objectives of Part 1 are to evaluate the safety and tolerability of escalating doses of compound 1 QW plus palbociclib QD in patients with previously treated KRASm/NRASm CRC, and to determine the Maximum Tolerated Dose (MTD) and/or Recommended Dose (RD) for compound 1 (QW) plus palbociclib (QD).

[00227] The second objectives of Part 1 are to evaluate the antitumor activity of compound 1 QW plus palbociclib QD in patients with previously treated KRASm/NRASm CRC, and to evaluate the PK profiles of compound 1 and palbociclib administered in combination.

Part 2

[00228] The primary objectives of Part 2 are to evaluate the antitumor activity of compound 1 QW plus palbociclib QD at the RD established in Part 1 in patients with previously treated KRASm/NRASm CRC. [00229] The secondary objectives of Part 2 are to evaluate the durability of antitumor activity of compound 1 QW plus palbociclib QD at the RD established in Part 1 in previously treated KRASm/NRASm CRC patients, to evaluate the safety and tolerability of compound 1 QW plus palbociclib QD, and to evaluate the PK profiles of compound 1 QW and palbociclib QD administered in combination.

Part 3

[00230] The primary objectives of Part 3 are to evaluate the safety and tolerability of escalating doses of palbociclib monotherapy and compound 1 QW plus palbociclib QW in patients with previously treated KRASm/NRASm CRC, and to determine the MTD and/or RD for compound 1 (QW) plus palbociclib (QW).

[00231] The secondary objectives of Part 3 are to evaluate the antitumor activity of compound 1 QW plus palbociclib QW in patients with previously treated KRASm/NRASm CRC, and to evaluate the PK profiles of palbociclib monotherapy and compound 1 QW and palbociclib QW administered in combination.

Part 4

[00232] The primary objective of Part 4 is to evaluate the antitumor activity of compound 1 QW plus palbociclib QW at the RD established in Part 3 in patients with previously treated KRASm/NRASm CRC. [00233] The secondary objectives of Part 4 are to evaluate the durability of antitumor activity of compound 1 QW plus palbociclib QW at the RD established in Part 4 in previously treated KRASm/ NRASm CRC patients, to evaluate the safety and tolerability of compound 1 QW plus palbociclib QW, and to evaluate the PK profiles of compound 1 QW and palbociclib QW administered in combination.

Dosing Schedule

^a Compound 1 QW - Compound 1 oral once a week ^b Palbociclib QD - Palbociclib oral daily for 21 consecutive days followed by 7 days off in 28 -day cycle ^c Palbociclib QW - Palbociclib oral once a week ^d Compound 1 BID-QW: Compound 1 oral twice a day on a single day each week

Inclusion Criteria:

[00234] Age > 18 years. [00235] Willing and able to give written informed consent.

[00236] Have histologically or cytologically confirmed metastatic CRC harboring applicable mutation(s) (e.g., BRAFm V600E; KRAS or NRAS mutations) based on an analytically validated assay performed on tumor tissue in a certified testing laboratory.

[00237] Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) vl .1.

[00238] Adequate bone marrow and organ function.

[00239] Have ECOG performance status of 0 or 1.

[00240] Willing to comply with all protocol-required visits, assessments, and procedures.

[00241] Able to swallow oral medication.

Exclusion Criteria:

[00242] Prior therapy with a RAS, MEK, or ERK inhibitor. Depending on which treatment arm the patient is assigned, other therapies could also be prohibitive.

[00243] Anti -cancer therapy < 21 days or 4 half-lives prior to first dose of study drug, whichever is shorter.

[00244] Palliative radiation < 7 days prior to first dose of study drug.

[00245] Symptomatic brain metastasis or leptomeningeal disease.

[00246] Gastrointestinal conditions that may affect absorption of oral medications.

[00247] Active infection requiring systemic therapy, or history of HIV infection, hepatitis B virus, or hepatitis C virus.

[00248] History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) < 12 months prior to first study drug dose.

[00249] Active, clinically significant interstitial lung disease or pneumonitis.

[00250] Impaired cardiovascular function or clinically significant cardiovascular disease.

[00251] History of thromboembolic or cerebrovascular events < 6 months prior to first dose.

[00252] Major surgery within 28 days of enrollment or anticipate of major surgery during study treatment.

[00253] Known intolerance or contraindication to encorafenib, cetuximab, or palcociclib.

[00254] Pregnant or breastfeeding women.

[00255] Any evidence of severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding that renders the patient inappropriate to participate in the study.

Example 3: In-vivo Studies of Compound 1 alone, Palbociclib alone, and Compound 1 + Palbociclib Combination in LoVo KRAS Mutant CRC Models

[00256] The vehicle/control article of Compound 1, 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 in deionized water, was prepared and stored under ambient conditions throughout the 28-day administration in mice. [00257] The test article Compound 1 was prepared in vehicle of 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 solution weekly and stored under ambient conditions. The combination agent palbociclib was prepared weekly in vehicle of 50 mM sodium lactate buffer, pH 3.8-4.0, and stored at 2-8 °C.

[00258] Female Balb/c nude mice were purchased from the Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were hosted in a special pathogen-free (SPF) environment of the vivarium facility and acclimated to their new environment for at least 3 days prior to initiation of any experiments. Mice were between 6-8 weeks of age at the time of implantation. All procedures related to animal handling, care, and treatment in this study were performed according to the protocols and guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of GenenDesign. Animal facility and program is operated under the standard of Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) and accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all portions of this study performed at GenenDesign adhered to the study protocols reviewed and approved by IACUC and applicable standard operating procedures (SOPs).

Preparation ofPDX

[00259] LoVo is a human CRC cell line harboring a KRAS^G13D mutation. The LoVo cell line was purchased from the American Type Culture Collection (ATCC® CCL-229™). LoVo cells were cultured in F12K medium containing 10% Fetal Bovine Serum (FBS) at 37°C in an atmosphere of 5% CO2 in air. The medium was renewed every 2 to 3 days and tumor cells were routinely sub-cultured at a confluency of 80-90%. The cells growing in an exponential growth phase were harvested using trypsin-EDTA, counted for inoculation, and subsequently implanted into mice subcutaneously. 200 pL cell suspensions containing 2 x 10⁶ tumor cells mixed with 50% Matrigel were subcutaneously implanted into the right flank of mouse using a syringe. Animal health and tumor growth were monitored daily. Tumor volume was measured twice a week by caliper when tumors were palpable and measurable. When tumor volumes reached a mean of 190 mm³ (range of 150-259 mm³), tumor-bearing mice were randomized into different groups with 8 mice in each group. The randomization date was denoted as treatment day 0.

Treatment

[00260] Treatment started on the day of randomization. The treatment start day was denoted as treatment day 0. Mice were dosed by oral administration of vehicle control solution, palbociclib at 25 mg/kg QD, or Compound 1 at 30 mg/kg QD monotherapy. One additional group received combination treatment of Compound 1 and palbociclib, dosing Compound 1 at 30 mg/kg QD with palbociclib at 25 mg/kg QD. In the combination treatment group, Compound 1 dose was reduced from its maximum efficacious monotherapy dose of 30 mg/kg/dose BID to 30 mg/kg QD based on a previously executed tolerability study. The dosing volume for each compound was 5 mL/kg and interval of BID regimen was 8 hours. Compound 1 was dosed at one hour after palbociclib in the combination group. The study was terminated on treatment day 28 as defined in the study protocol. [00261] As illustrated by FIG. 2A, Compound 1 and palbociclib demonstrate combination benefit in vivo in LoVo KRAS mutant CRC model.

Example 4: In-vivo Studies of Compound 1 alone, Palbociclib alone, and Compound 1 + Palbociclib Combination in SW-620 KRAS Mutant CRC Models

[00262] The vehicle/control article of Compound 1, 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 in deionized water, was prepared and stored under ambient conditions throughout the 28-day administration in mice.

[00263] The test article Compound 1 was prepared in vehicle of 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 solution weekly and stored under ambient conditions. The combination agent palbociclib was prepared weekly in vehicle of 50 mM sodium lactate buffer, pH 3.8-4.0, and stored at 2-8 °C.

[00264] Female Balb/c nude mice were purchased from the Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were hosted in a special pathogen-free (SPF) environment of the vivarium facility and acclimated to their new environment for at least 3 days prior to initiation of any experiments. Mice were between 6-8 weeks of age at the time of implantation. All procedures related to animal handling, care, and treatment in this study were performed according to the protocols and guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of GenenDesign. Animal facility and program is operated under the standard of Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) and accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all portions of this study performed at GenenDesign adhered to the study protocols reviewed and approved by IACUC and applicable standard operating procedures (SOPs).

Preparation ofPDX

[00265] SW-620 is a human CRC cell line harboring a KRAS^G12V mutation. The SW-620 cell line was purchased from the American Type Culture Collection (ATCC® CCL-227). SW-620 cells were cultured in L-15 medium plus 10% Fetal bovine serum (FBS) at 37°C in an atmosphere of 100% of air. The medium was renewed every 2 to 3 days and tumor cells were routinely sub-cultured at a confluency of 80- 90%. The cells growing in an exponential growth phase were harvested using trypsin-EDTA, counted for inoculation, and subsequently implanted into mice subcutaneously. 200 pL cell suspensions containing 5 x 10⁶ tumor cells mixed with 50% Matrigel were subcutaneously implanted into the right flank of mouse using a syringe. Animal health and tumor growth were monitored daily. Tumor volume was measured twice a week by caliper when tumors were palpable and measurable. When tumor volumes reached a mean of 210 mm³ (range of 150-271 mm³), tumor-bearing mice were randomized into different groups with 8 mice in each group. The randomization date was denoted as treatment day 0 Treatment

[00266] Treatment started on the day of randomization. The treatment start day was denoted as treatment day 0. Mice were dosed by oral administration of vehicle control solution, palbociclib at 25 mg/kg QD, or Compound 1 at 30 mg/kg QD monotherapy. One additional group received combination treatment of Compound 1 and palbociclib, dosing Compound 1 at 30 mg/kg QD with palbociclib at 25 mg/kg QD. In the combination treatment group, Compound 1 dose was reduced from its maximum efficacious monotherapy dose of 30 mg/kg/dose BID to 30 mg/kg QD based on a previously executed tolerability study. The dosing volume for each compound was 5 mL/kg and interval of BID regimen was 8 hours. Compound 1 was dosed at one hour after palbociclib in the combination group. The study was terminated on treatment day 28 as defined in the study protocol.

[00267] As illustrated by FIG. 2B, Compound 1 and palbociclib demonstrate combination benefit in vivo in SW-620 KRAS mutant CRC model.

Example 5 - In-vivo Studies of Palbociclib alone, Compound 1 alone, and Compound 1 + Palbociclib Combination in KRAS^G12D Mutant PDAC PDX Model PAN092 Vehicle/control Article

[00268] The vehicle/control article of Compound 1, 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 in deionized water, was prepared and stored under ambient conditions throughout the 28-day administration in mice.

Formulation of Test Article

[00269] The test article Compound 1 was freshly prepared in vehicle of 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 solution weekly and stored under ambient conditions. The combination agent palbociclib was freshly prepared weekly in vehicle of 50 mM sodium lactate buffer, pH 3.8-4.0, and stored at 2-8°C. Animals

[00270] Female Balb/c nude mice were purchased from the Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were between 6-8 weeks of age at the time of implantation. Mice were hosted in a special pathogen-free (SPF) environment of the vivarium facility and acclimated to their new environment for at least 3 days prior to initiation of any experiments according to IACUC protocol. [00271] All procedures related to animal handling, care, and treatment in this study were performed according to the protocols and guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of GenenDesign. Animal facility and program is operated under the standard of Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) and accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all portions of this study performed at GenenDesign adhered to the study protocols reviewed and approved by IACUC and applicable standard operating procedures (SOPs).

Preparation of PDX

[00272] The PAN092 model was established for nonclinical efficacy studies at GenenDesign (Shanghai, China). The PDX model was derived from a 65 -year-old male Chinese PDAC patient that harbored a KRASG12D mutation. The KRASG12D mutation in the PDX model PAN092 was confirmed by whole exome sequencing and PCR sequencing. Tumor fragments harvested from the PDX model were implanted subcutaneously in the right flanks of female Balb/c nude mice. Mice were anesthetized with isoflurane, and anesthesia was maintained throughout the implantation procedure. The right flank of the mouse was sterilized with appropriate surgical scrub and alcohol, and aseptic surgical procedures were used. A small skin incision was made using the sharp end of the trocar and a 1.5 cm subcutaneous pocket along the right lateral chest wall was formed by blunt dissection with the stylet of a 10-12g trocar needle. Tumor fragments (15-30 mm3) were placed into the trocar needle and advanced into the subcutaneous pocket in the right flank. The trocar incision was closed with suture or a wound clip which was removed one week after closure. When tumor sizes reached a mean volume of 204 mm3 (range of 150-250 mm3), tumor-bearing mice were randomly divided into study groups with 8 mice in each group. The randomization date was denoted as treatment day 0.

Treatment

[00273] Treatment started on the day of randomization. The treatment start day was denoted as treatment day 0. Mice were dosed by oral administration of vehicle control solution, palbociclib at 25 mg/kg QD, Compound 1 at 30 mg/kg/dose BID, or Compound 1 at 30 mg/kg QD as monotherapy treatments. One additional group received combination treatment of Compound 1 and palbociclib, dosing Compound 1 at 30 mg/kg QD with palbociclib at 25 mg/kg QD. In the combination treatment group, Compound 1 dose was reduced from its maximum efficacious monotherapy dose of 30 mg/kg/dose BID to 30 mg/kg QD based on a previously executed tolerability study. The dosing volume for each compound was 5 mL/kg and interval of BID regimen was 8 hours. Compound 1 was dosed at one-hour post-palbociclib in the combination group. In addition to regular food and water supply, DietGel (ClearH20, US) was added in cages where at least two mice in a treatment group showed > 10% BWL as a regular practice. Per this practice, mice in the Compound 1 at 30 mg/kg/dose BID monotherapy treatment group and mice in the combination treatment group were supplied with DietGel food starting on treatment day 10 and 21, respectively, and continuing through the remaining study period. The study was terminated on treatment day 28 as defined in the study protocol.

[00274] Compound 1 and palbociclib demonstrate combination benefit in vivo in KRAS^G12D mutant PDAC PDX model PAN092.

Example 6 - In-vivo Studies of Palbociclib alone, Compound 1 alone, and Compound 1 + Palbociclib Combination in KRAS^G12D Mutant PDAC PDX Model PAN026

[00275] The vehicle/control article of Compound 1, 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 in deionized water, was prepared and stored under ambient conditions throughout the 28-day administration in mice.

Formulation of Test Article

[00276] The test article Compound 1 was freshly prepared in vehicle of 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 solution weekly and stored under ambient conditions. The combination agent palbociclib was freshly prepared weekly in vehicle of 50 mM sodium lactate buffer, pH 3.8-4.0, and stored at 2-8°C. Animals

[00277] Female Balb/c nude mice were purchased from the Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were between 6-8 weeks of age at the time of implantation. Mice were hosted in a special pathogen-free (SPF) environment of the vivarium facility and acclimated to their new environment for at least 3 days prior to initiation of any experiments according to IACUC protocol. [00278] All procedures related to animal handling, care, and treatment in this study were performed according to the protocols and guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of GenenDesign. Animal facility and program is operated under the standard of Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) and accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all portions of this study performed at GenenDesign adhered to the study protocols reviewed and approved by IACUC and applicable standard operating procedures (SOPs).

Preparation ofPDX

[00279] The PAN026 model was established for nonclinical efficacy studies at GenenDesign (Shanghai, China). The PDX model was derived from a 58-year-old male Chinese PDAC patient that harbored a KRAS^G12D mutation. The KRAS^G12D mutation in the PDX model PAN026 was confirmed by whole exome sequencing and PCR sequencing. Tumor fragments harvested from the PDX model were implanted subcutaneously in the right flanks of female Balb/c nude mice. Mice were anesthetized with isoflurane, and anesthesia was maintained throughout the implantation procedure. The right flank of the mouse was sterilized with appropriate surgical scrub and alcohol, and aseptic surgical procedures were used. A small skin incision was made using the sharp end of the trocar and a 1.5 cm subcutaneous pocket along the right lateral chest wall was formed by blunt dissection with the stylet of a 10-12g trocar needle. Tumor fragments (15-30 mm3) were placed into the trocar needle and advanced into the subcutaneous pocket in the right flank. The trocar incision was closed with suture or a wound clip which was removed one week after closure. When tumor sizes reached a mean volume of 190 mm3 (range of 140-269 mm3), tumor-bearing mice were randomly divided into study groups with 8 mice in each group. The randomization date was denoted as treatment day 0.

Treatment

[00280] Treatment started on the day of randomization. The treatment start day was denoted as treatment day 0. Mice were dosed by oral administration of vehicle control solution, palbociclib at 25 mg/kg QD, Compound 1 at 30 mg/kg QD, or Compound 1 at 30 mg/kg/dose BID as monotherapy treatments. One additional group received combination treatment of Compound 1 and palbociclib, dosing Compound 1 at 30 mg/kg QD with palbociclib at 25 mg/kg QD. In the combination treatment group, Compound 1 dose was reduced from its maximally efficacious monotherapy dose of 30 mg/kg/dose BID to 30 mg/kg QD based on a previously executed tolerability study. The dosing volume for each compound was 5 mL/kg and interval of BID regimen was 8 hours. Compound lwas dosed at one-hour post palbociclib dose in the combination group. In addition to regular food and water supply, DietGel (ClearH20, US) was added in cages where at least two mice in a treatment group started showing > 10% BWL as a regular practice. Per this practice, mice in the Compound lat 30 mg/kg/dose BID monotherapy treatment group were supplied with DietGel food starting on treatment day 23 and continuing through the remaining study period. The study was terminated on treatment day 28 as defined in the study protocol.

[00281] Compound 1 and palbociclib demonstrate combination benefit in vivo in KRAS^G12D mutant PDAC PDX model PAN026.

Example 7 - In-vitro Studies of Compound 1 alone, Palbociclib alone, and Compound 1 + Palbociclib Combination in Mutant KRAS^G12V Cellular Model SW-480 Materials and Methods Cell Plating and Treatment

[00282] Cells were plated at 3,000 cells per well in a 12-well flat bottom cell culture plate. Cells were allowed to adhere overnight at 37°C, 0% or 5% C02, 95% air and 100% relative humidity overnight. [00283] The following day, compounds were dissolved to generate a lOmM stock in DMSO. To prepare the compound stock plate (lOOOx), the lOmM stock was serially diluted from highest to lowest in DMSO according to the plate map. To treat cells, compound was prepared as follows:

(1). 20X concentrate compound plate preparation: Add 196 pL of assay medium into each well of the V-bottom plate; then transfer 4 pL of the stock compound solution of each concentration from the stock plate. Add 4 pL of DMSO into the Control wells. Pipette up and down to mix well. This V-plate is designated as the 20X concentrate compound plate.

(2). Compound Treatment: Add 50 pL compound-A-medium and 50 pL compound-B -medium of each well from the 20X concentrate compound plate into the cells in 12-well assay plate according to the plate map. For Vehicle group, Add 100 pL of the DMSO-medium into the wells. The final DMSO concentration was 0.2%.

(3). Return the assay plates into incubator and incubate for 7 days.

[00284] After 7 days in culture, media was replaced with freshly prepared compound and incubated for another 7 days.

Cell Staining

[00285] At day 14, cells were washed with lmL of PBS and subsequently fixed by adding lmL of 100% methanol to each well for 10-15 minutes at room temperature. After methanol was removed, cells were stained with 0.1% crystal violet at room temperature for 60 minutes. Cells were then washed 4-6 times with water and dried for 2 hours at room temperature prior to imaging.

Crystal Violet Destaining and OD Measurement

[00286] Cells were destained by incubation with 10% acetic acid and absorbance was measured using regular BCA protocol. The absorbance of each well was tested in duplicate. [00287] As illustrated in FIG. 4, the combination of Compound 1 and palbociclib led to greater reduction of the relative colony number, and demonstrate combination benefit in vitro in KRAS^G12V mutant cellular model SW-480.

Example 8: In vivo in NRAS^Q61K mutant melanoma CDX model WM3268 assay [00288] The vehicle/control article of compound 1, 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 in deionized water, was prepared and stored under ambient conditions throughout the 36-day administration in mice.

[00289] The test article compound 1 was prepared in vehicle of 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 solution weekly and stored under ambient conditions. The combination agent palbociclib was prepared weekly in vehicle of 50 mM sodium lactate buffer, pH 3.8-4.0, and stored at 2-8°C.

Female Balb/c nude mice were were between 6-8 weeks of age at the time of implantation. Mice were hosted in a special pathogen-free (SPF) environment of the vivarium facility and acclimated to their new environment for at least 3 days prior to initiation of any experiments according to IACUC protocol. [00290] WM3268 is a human melanoma cell line that harbors a NRAS^Q61K mutation.

[00291] WM3268 cells were cultured in tumor specialized media (80% MCDB153, 20% Leibovitz’s L- 15, 1.68mM CaCL) + 2% FBS + Pen/Strep at 37°C in an atmosphere of 5% CO2 in air. The medium was renewed every 2 to 3 days and tumor cells were routinely sub-cultured at a confluence of 80-90% by trypsin-EDTA. Cells growing in an exponential growth phase were harvested and counted for inoculation. WM3268 tumor cells were implanted into mice subcutaneously. 200 pL cell suspensions containing 10 x 10⁶ tumor cells mixed with 50% Matrigel were subcutaneously implanted into the right flank of mouse using a syringe. 84 mice were implanted in this study. Animal health and tumor growth were monitored daily. Tumor volume was measured twice a week by caliper when tumors were palpable and measurable. When tumor volumes reached a mean of 144 mm³ (range of 117-198 mm³) at day 22 post subcutaneous implantation, tumor-bearing mice were randomized into different groups with 8 mice in each group. The randomization date was denoted as treatment day 0.

Treatment

[00292] Treatment started on the day after randomization. The treatment start day was denoted as treatment day 1. Mice were dosed by oral administration of vehicle control solution or monotherapy treatments of compound 1 at 30 mg/kg/dose QD or palbociclib at 25 mg/kg QD. An additional group received combination treatment of compound 1 at 30 mg/kg/dose QD or palbociclib at 25 mg/kg QD. In the combination group, palbociclib was dosed first and compound 1 was dosed one hour later. The study was terminated on treatment day 36 as defined in the study protocol. Results are shown in FIG. 5. Compound 1 and palbociclib demonstrated combination benefit in vivo in the NRAS^Q61K mutant melanoma CDX model WM3268. Tumor growth curves for WM3268 PDX model. Example 9: In vivo in NRAS^Q61K mutant melanoma CDX model WM3456 assay [00293] The vehicle/control article of compound 1, 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 in deionized water, was prepared and stored under ambient conditions throughout the 28-day administration in mice.

[00294] The test article compound 1 was prepared in vehicle of 0.5% Methyl Cellulose (MC) & 0.1% Tween 80 solution weekly and stored under ambient conditions. The combination agent palbociclib was prepared weekly in vehicle of 50 mM sodium lactate buffer, pH 3.8-4.0, and stored at 2-8°C.

[00295] Female Balb/c nude mice were were between 6-8 weeks of age at the time of implantation. Mice were hosted in a special pathogen-free (SPF) environment of the vivarium facility and acclimated to their new environment for at least 3 days prior to initiation of any experiments according to IACUC protocol. [00296] WM3456 is a human melanoma cell line that harbors a NRAS^Q61K mutation.

[00297] WM3456 cells were cultured in tumor specialized media (80% MCDB153, 20% Leibovitz’s L- 15, 1.68mM CaCL) + 2% FBS + Pen/Strep at 37°C in an atmosphere of 5% C02 in air. The medium was renewed every 2 to 3 days and tumor cells were routinely sub-cultured at a confluence of 80-90% by trypsin-EDTA. Cells growing in an exponential growth phase were harvested and counted for inoculation. WM3456 tumor cells were implanted into mice subcutaneously. 200 pL cell suspensions containing 10 x 10⁶ tumor cells mixed with 50% Matrigel were subcutaneously implanted into the right flank of mouse using a syringe. 84 mice were implanted in this study. Animal health and tumor growth were monitored daily. Tumor volume was measured twice a week by caliper when tumors were palpable and measurable. When tumor volumes reached a mean of 149 mm3 (range of 136-180 mm³) at day 16 post subcutaneous implantation, tumor-bearing mice were randomized into different groups with 8 mice in each group. The randomization date was denoted as treatment day 0.

Treatment

[00298] Treatment started on the day after randomization. The treatment start day was denoted as treatment day 1. Mice were dosed by oral administration of vehicle control solution or monotherapy treatments of compound 1 at 30 mg/kg/dose QD or palbociclib at 25 mg/kg QD. An additional group received combination treatment of compound 1 at 30 mg/kg/dose QD or palbociclib at 25 mg/kg QD. In the combination group, palbociclib was dosed first and compound 1 was dosed one hour later. The study was terminated on treatment day 36 as defined in the study protocol. Results are shown in FIG. 6. Compound 1 and palbociclib demonstrated combination benefit in vivo in NRAS^Q61K mutant melanoma CDX model WM3456. Tumor growth curves for WM3456 PDX model.

Claims

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

(i) compound

, or a pharmaceutically acceptable salt thereof; and

(ii) a CDK4/6 inhibitor.

2. The method of claim 1, wherein the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, FCN-437c, or alvociclib.

3. The method of claim 1 or 2, wherein the CDK4/6 inhibitor is palbociclib.

4. The method of claim 3, wherein palbociclib is administered in an amount that is between about 50 mg/day to about 500 mg/day.

5. The method of claim 4, wherein palbociclib is administered in an amount that is about 75 mg/day, 100 mg/day, 125 mg/day, or 150 mg/day.

6. The method of claim 3, wherein palbociclib is administered in an amount that is between about 50 mg once a week and about 650 mg once a week.

7. The method of claim 6, wherein palbociclib is administered in an amount that is about 200 mg once a week, 300 mg once a week, 400 mg once a week, 500 mg once a week, or 600 mg once a week.

8. 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) compound

, or a pharmaceutically acceptable salt thereof; and

(ii) palbociclib.

9. The method of any one of claims 1-8, wherein the pharmaceutically acceptable salt of compound 1 is the mandelic acid salt.

10. The method of any one of claims 1-9, wherein the cancer is a mitogen-activated protein kinase (MAPK) pathway driven cancer.

11. The method of any one of claims 1-9, wherein the cancer is a BRAF -driven cancer, HRAS-driven cancer, or a NRAS-driven cancer.

12. The method of any one of claims 1-9, wherein the cancer comprises at least one cancer cell driven by deregulated ERK.

13. The method of any one of claims 1-9, wherein the cancer has at least one mutation in RAS.

14. The method of any one of claims 1-9, wherein the cancer has at least one mutation in RAF.

15. The method of any one of claims 1-9, wherein the cancer has at least one mutation in MEK.

16. The method of any one of claims 1-9, wherein the cancer has a G12C KRAS mutation.

17. The method of any one of claims 1-9, wherein the cancer has a G12D KRAS mutation.

18. The method of any one of claims 1-9, wherein the cancer has a G12S KRAS mutation.

19. The method of any one of claims 1-9, wherein the cancer has a G12V KRAS mutation.

20. The method of any one of claims 1-9, wherein the cancer has a G13D KRAS mutation.

21. The method of any one of claims 1 -9, wherein the cancer has a Q 16H KRAS mutation.

22. The method of any one of claims 1-9, wherein the cancer has a Q16K KRAS mutation.

23. The method of any one of claims 1-9, wherein the cancer has a Q61RNRAS mutation.

24. The method of any one of claims 1-9, wherein the cancer is a BRAF V600E or V600K mutant tumor.

25. The method of any one of claims 1-9, wherein the cancer is a MAPKm/MAPKi -naive pancreatic cancer or PD AC.

26. The method of any one of claims 1-9, wherein the cancer comprises one or more EGFR mutation selected from the group consisting of EGFR gene copy gain, EGFR gene amplification, chromosome 7 polysomy, L858R, exon 19 deletions/insertions, L861Q, G719C, G719S, G719A, V765A, T783A, exon 20 insertions, EGFR splice variants (Viii, Vvi, and Vii), A289D, A289T, A289V, G598A, G598V, T790M, and C797S.

27. The method of any one of claims 1-9, wherein the cancer comprises one or more EGFR mutation selected from the group consisting of L858R, exon 19 deletion, and T790M.

28. The method of any one of claims 1-27, wherein the cancer is a solid tumor.

29. The method of any one of claims 1-28, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

30. The method of any one of claims 1-28, wherein the cancer is non-small cell lung cancer (NSCLC).

31. The method of claim 30, wherein the NSCLC is an EGFR mutant NSCLC.

32. The method of claim 30, wherein the NSCLC is a KRAS^G12C mutant NSCLC.

33. The method of claim 30, wherein the NSCLC is a KRAS^G12D mutant NSCLC.

34. The method of claim 30, wherein the NSCLC is a KRAS^G12S mutant NSCLC.

35. The method of claim 30, wherein the NSCLC is a KRAS^G12V mutant NSCLC.

36. The method of claim 30, wherein the NSCLC is a KRAS^G13D mutant NSCLC.

37. The method of claim 30, wherein the NSCLC is a KRAS^Q61H mutant NSCLC.

38. The method of claim 30, wherein the NSCLC is a KRAS^Q61K mutant NSCLC.

39. The method of claim 30, wherein the NSCLC is a NRAS^Q61R mutant NSCLC.

40. The method of claim 30, wherein the cancer is a MAPKm/MAPKi-naive NSCLC.

41. The method of claim 30, wherein the cancer is a BRAFi-treated V600 NSCLC.

42. The method of claim 30, wherein the cancer is a KRAS-treated G12C NSCLC.

43. The method of claim 30, wherein the cancer is a KRAS-treated G12D NSCLC.

44. The method of claim 30, wherein the cancer is a KRAS-treated G12S NSCLC.

45. The method of claim 30, wherein the cancer is a KRAS-treated G12V NSCLC.

46. The method of claim 30, wherein the cancer is a KRAS-treated G13D NSCLC.

47. The method of claim 30, wherein the cancer is a KRAS-treated Q61H NSCLC.

48. The method of claim 30, wherein the cancer is a KRAS-treated Q61K NSCLC.

49. The method of claim 30, wherein the cancer is a NRAS-treated Q61R NSCLC.

50. The method of any one of claims 1-28, wherein the cancer is pancreatic cancer.

51. The method of claim 50, wherein the cancer is a MAPKm/MAPKi-naive pancreatic cancer or PD AC.

52. The method of any one of claims 1-28, wherein the cancer is melanoma.

53. The method of claim 52, wherein the melanoma is a BRAF V600E or V600K mutant tumor.

54. The method of claim 52, wherein the cancer is a BRAFi-treated V600 melanoma.

55. The method of any one of claims 1-28, wherein the cancer is salivary gland tumor.

56. The method of any one of claims 1-28, wherein the cancer is thyroid cancer.

57. The method of any one of claims 1-28, wherein the cancer is colorectal cancer (CRC).

58. The method of claim 57, wherein the CRC is a BRAF V600E CRC.

59. The method of claim 57, wherein the CRC is a KRAS mutant CRC.

60. The method of claim 59, wherein the CRC is a KRAS^G12C mutant CRC.

61. The method of claim 59, wherein the CRC is a KRAS^G12D mutant CRC.

62. The method of claim 59, wherein the CRC is a KRAS^G12S mutant CRC.

63. The method of claim 59, wherein the CRC is a KRAS^G12V mutant CRC.

64. The method of claim 59, wherein the CRC is a KRAS^G13D mutant CRC.

65. The method of claim 59, wherein the CRC is a KRAS^Q61H mutant CRC.

66. The method of claim 59, wherein the CRC is a KRAS^Q61K mutant CRC.

67. The method of claim 59, wherein the CRC is a NRAS mutant CRC.

68. The method of claim 67, wherein the CRC is a NRAS^Q61R mutant CRC.

69. The method of any one of claims 1-28, wherein the cancer is esophageal cancer.

70. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg/day and about 300 mg/day.

71. The method of any one of claims 1-70, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between 25 mg/day and 150 mg/day.

72. The method of any one of claims 1-71, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

73. The method of any one of claims 1-72, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

74. The method of any one of claims 1-72, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 250 mg/day.

75. The method of any one of claims 1-74, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day (QD).

76. The method of any one of claims 1-74, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day (BID).

77. The method of any one of claims 1-74, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered three times a day (TID).

78. The method of any one of claims 1-77, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week.

79. The method of any one of claims 1-77, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a week.

80. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 300 mg twice a day, once a week (BID-QW).

81. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 250 mg twice a day, once a week (BID-QW).

82. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is between about 25 mg and about 150 mg twice a day, once a week (BID-QW).

83. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

84. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, once a week (BID-QW).

85. The method of any one of claims 1-69, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 125 mg twice a day, once a week (BID- QW).

86. The method of any one of claims 1-85, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

87. The method of any one of claims 1-86, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered on day 1, day 8, day 15, and day 22 of a 28-day cycle.

88. The method of any one of claims 1-86, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered on day 1, day 8, day 15 of a 28-day cycle.

89. The method of any one of claims 1-88, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

90. The method of any one of claims 1-89, wherein the method further comprises administering an additional MAPK pathway inhibitor.

91. The method of claim 90, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAF1 inhibitor, MEK1 inhibitor, MEK2 inhibitor, c-Mycv, CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor.

92. The method of claim 91, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor.

93. The method of claim 91, wherein the additional MAPK pathway inhibitor is a BRAF inhibitor.

94. The method of claim 91, wherein the additional MAPK pathway inhibitor is an EGFR inhibitor.

95. The method of claim 91, wherein the additional MAPK pathway inhibitor is a CDK4/6.

96. The method of claim 91, wherein the additional MAPK pathway inhibitor is a FLT3 inhibitor.

97. The method of claim 91, wherein the additional MAPK pathway inhibitor is adagrasib, afatinib, ASTX029, binimetinib, cetuximab, cobimetinib, dabrafenib, dacomitinib, encorafenib, erlotinib, gefitinib, gilteritinib, lapatinib, LTT462, LY3214996, necitumumab, neratinib, nimotuzumab, osimertinib, panitumumab, selumetinib, sotorasib, trametinib, ulixertinib, vandetanib, or vemurafenib.

98. The method of claim 91, wherein the additional MAPK pathway inhibitor is adagrasib.

99. The method of claim 91, wherein the additional MAPK pathway inhibitor is cetuximab.

100. The method of claim 91, wherein the additional MAPK pathway inhibitor is dabrafenib.

101. The method of claim 91, wherein the additional MAPK pathway inhibitor is encorafenib.

102. The method of claim 91, wherein the additional MAPK pathway inhibitor is gilteritinib.

103. The method of claim 91, wherein the additional MAPK pathway inhibitor is panitumumab.

104. The method of claim 91, wherein the additional MAPK pathway inhibitor is sotorasib.