Combination therapy with ERK1 / 2 and SHP2 inhibitors

Abstract

The present disclosure relates generally to the combined use of SHP2 inhibitors and ERK1 / 2 inhibitors to treat cancer, particularly solid tumors.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 214,769, filed June 24, 2021, U.S. Provisional Patent Application No. 63 / 277,550, filed November 9, 2021, U.S. Provisional Patent Application No. 63 / 280,521, filed November 17, 2021, and U.S. Provisional Patent Application No. 63 / 321,615, filed March 18, 2022, which are incorporated by reference in their entireties herein. [Background technology]

[0002] ERK1 and ERK2 (collectively referred to as "ERK1 / 2") are related protein serine / threonine kinases that are particularly involved in the Ras-Raf-MEK-ERK signaling pathway, sometimes referred to as the mitogen-activated protein kinase (MAPK) pathway. This pathway is believed to play a central role in regulating many fundamental cellular processes, including one or more of cell proliferation, survival, adhesion, cycle progression, migration, differentiation, metabolism and transcription. Activation of the MAPK pathway has been reported in many tumor types, including lung, colon, pancreatic, renal and ovarian cancers. Thus, substances that can reduce activation may be of interest for possible treatment. Summary of the Invention

[0003] ERK1 / 2 appear to be activated by MEK through phosphorylation at both threonine and tyrosine residues, namely Tyr204 / 187 and Thr202 / 185. Once activated, ERK1 / 2 catalyzes the phosphorylation of serine / threonine residues of over 100 substrates, activating both cytoplasmic and nuclear proteins associated with cell growth, proliferation, survival, angiogenesis, and differentiation, all hallmarks of the cancer phenotype. Therefore, it may be beneficial to develop and use ERK1 / 2 inhibitors as a way to target ERK1 and ERK2 to inhibit tumor growth.

[0004] Furthermore, ERK inhibitors may have utility in combination with other kinases, such as MAPK inhibitors.Recently, researchers have reported that the dual inhibition of MEK and ERK with small molecule inhibitors is synergistic and acts to overcome acquired resistance to MEK inhibitors.See Hatzivassiliou et al.,ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition,Mol.Cancer Ther.2012,11,1143-1154.

[0005] In addition to ERK1 / 2, SHP2 also operates upstream of the RAS pathway. SHP2 is a protein tyrosine phosphatase and a key positive regulator of growth signals from RTK growth factor receptors to intracellular signaling pathways (including RAS / MAPK and PI3K) that promote the growth and survival of normal and cancer cells. Thus, SHP2 is a convergence node for upstream RTK signaling: activated SHP2 upregulates ("turns up") positive signals and downregulates ("turns down") negative signals in the signaling cascade. SHP2 also serves as a central node in relaying growth and survival signals from RTKs such as EGFR and FLT3 to RAS / MAPK and other intracellular pathways. SHP2 is an attractive target because SHP2 inhibition ubiquitously blocks growth signals from multiple RTKs and prevents cancer cells from bypassing blockade to specific RTKs (e.g., EGFR inhibitors) via activation of other RTK growth factor receptors (e.g., MET).

[0006] The possibility of targeting signaling pathways from multiple angles and potentially improving the feedback loop upstream of Ras via ERK1 / 2 and SHP2 offers the potential for developing methods using combination therapies.

[0007] The present embodiments disclosed herein generally relate to compositions and methods relating to combination therapies for treating cancer that utilize an ERK1 / 2 inhibitor in conjunction with an SHP2 inhibitor, providing an unexpected degree of synergy.

[0008] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0009] [ka] or a pharma- ceutically acceptable salt thereof, and (ii) administering an SHP2 inhibitor.

[0010] In some embodiments, the SHP2 inhibitor is sodium stibogluconate, RMC-4550, NSC87877, SPI-112, TNO155, IACS-13909, SHP099 HCl, or compound 2.

[0011] [ka] or a pharma- ceutically acceptable salt thereof.

[0012] Further disclosed herein is a method of treating cancer in a subject in need of such treatment, the method comprising administering to a subject in need of cancer treatment a therapeutically effective amount of (i) Compound 1

[0013] [ka] or a pharma- ceutically acceptable salt thereof, and (ii) Compound 2

[0014] [ka] or a pharma- ceutically acceptable salt thereof.

[0015] Further 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 1

[0016] [ka] or a pharma- ceutically acceptable salt thereof; (ii) Compound 2

[0017] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering osimertinib.

[0018] In some embodiments, osimertinib is administered in an amount of about 80 mg / day.

[0019] Further 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 1

[0020] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0021] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering cetuximab.

[0022] In some embodiments, cetuximab is administered at 500 mg / m 2 400 mg / m once every 2 weeks 2 once every 2 weeks or 300 mg / m2 It is administered once every two weeks.

[0023] Further 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 1

[0024] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0025] [ka] or a pharma- ceutically acceptable salt thereof, (iii) encorafenib, and (iv) administering osimertinib.

[0026] In some embodiments, encorafenib is administered in an amount of about 100 mg / day to about 500 mg / day.

[0027] In some embodiments, encorafenib is administered in an amount of about 450 mg / day, 300 mg / day, 225 mg / day, or 150 mg / day.

[0028] In some embodiments, osimertinib is administered in an amount of about 80 mg / day.

[0029] Further 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 1

[0030] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0031] [ka] or a pharma- ceutically acceptable salt thereof, (iii) encorafenib, and (iv) administering cetuximab.

[0032] In some embodiments, encorafenib is administered in an amount of about 100 mg / day to about 500 mg / day.

[0033] In some embodiments, encorafenib is administered in an amount of about 450 mg / day, about 300 mg / day, about 225 mg / day, or about 150 mg / day.

[0034] In some embodiments, cetuximab is administered at 500 mg / m 2 400 mg / m once every 2 weeks 2 once every 2 weeks or 300 mg / m 2 It is administered once every two weeks.

[0035] Further 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 1

[0036] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0037] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering gilteritinib.

[0038] In some embodiments, gilteritinib is administered in an amount of about 120 mg / day.

[0039] Further 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 1

[0040] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0041] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering sotorasib.

[0042] In some embodiments, sotorasib is administered in an amount of about 960 mg / day.

[0043] Further 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 1

[0044] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0045] [ka] or a pharma- ceutically acceptable salt thereof, (iii) administering adagrasib.

[0046] In some embodiments, adagrasib is administered in an amount of about 1200 mg / day.

[0047] Further 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 1

[0048] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0049] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering palbociclib.

[0050] In some embodiments, palbociclib is administered in an amount of about 50 mg / day to about 500 mg / day.

[0051] In some embodiments, palbociclib is administered in an amount of about 75 mg / day, about 100 mg / day, about 125 mg / day, or about 150 mg / day.

[0052] In some embodiments, palbociclib is administered in an amount of about 50 mg once weekly to about 650 mg once weekly.

[0053] In some embodiments, palbociclib is administered in an amount of about 200 mg once per week, 300 mg once per week, 400 mg once per week, 500, or 600 mg once per week.

[0054] In some embodiments, compound 2, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0055] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 1 mg / day to about 500 mg / day.

[0056] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 20 mg / day to about 400 mg / day.

[0057] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 30 mg / day to about 300 mg / day.

[0058] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered QD or BID for 2 weeks on and 1 week off (21 day schedule).

[0059] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered QD or BID for 3 weeks on and 1 week off (28 day schedule).

[0060] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered QD or BID three times per week, for example, on days 1, 3, and 5 (D1D3D5 TIW).

[0061] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered twice weekly, eg, twice daily on days 1 and 2 (BID-D1D2-BIW).

[0062] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered in daily doses once a day (QD) at a dose of 20 mg / day to 60 mg / day, 40 mg / day, or 60 mg / day.

[0063] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered twice daily (BID) at a dose of 20 mg / day to 80 mg / day.

[0064] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered twice daily (BID) at a dose of 10 mg / day to 100 mg / day.

[0065] In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a mandelate salt.

[0066] In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer.

[0067] In some embodiments, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

[0068] In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK.

[0069] 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.

[0070] 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.

[0071] In some embodiments, the cancer is a BRAF V600E, or V600K mutant tumor.

[0072] In some embodiments, the cancer is MAPKm / MAPKi naive pancreatic cancer, or PDAC.

[0073] In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of EGFR gene copy number gain, EGFR gene amplification, chromosome 7 polysomy, L858R, exon 19 deletion / insertion, L861Q, G719C, G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, Vvi, and Vii), A289D, A289T, A289V, G598A, G598V, T790M, and C797S.

[0074] In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

[0075] In some embodiments, the cancer is a liquid tumor.

[0076] In some embodiments, the cancer is leukemia.

[0077] In some embodiments, the leukemia is acute myeloid leukemia (AML).

[0078] In some embodiments, the AML is relapsed and / or refractory AML.

[0079] In some embodiments, the AML is FLT3 mutated AML.

[0080] In some embodiments, the cancer is a solid tumor.

[0081] 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.

[0082] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is EGFR mutated NSCLC. In some embodiments, the NSCLC is KRAS G12C mutated NSCLC. In some embodiments, the NSCLC is KRAS G12D mutated NSCLC. In some embodiments, the NSCLC is KRAS G12S mutated NSCLC. In some embodiments, the NSCLC is KRAS G12V mutated NSCLC. In some embodiments, the NSCLC is KRAS G12A mutated NSCLC. In some embodiments, the NSCLC is KRAS G13D mutated NSCLC. In some embodiments, the NSCLC is KRAS Q61H mutated NSCLC. In some embodiments, the NSCLC is KRAS Q61K mutated NSCLC. In some embodiments, the NSCLC is NRAS Q61R mutated NSCLC. In some embodiments, the cancer is MAPKm / MAPKi naive NSCLC. In some embodiments, the cancer is BRAFi treated V600 NSCLC. In some embodiments, the cancer is KRAS treated G12C NSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS treated G12S NSCLC. In some embodiments, the cancer is KRAS treated G12V NSCLC. In some embodiments, the cancer is KRAS treated G13D NSCLC. In some embodiments, the cancer is KRAS treated Q61H NSCLC. In some embodiments, the cancer is KRAS treated Q61K NSCLC. In some embodiments, the cancer is NRAS treated Q61R NSCLC.

[0083] In some embodiments, the cancer is pancreatic cancer.

[0084] In some embodiments, the cancer is MAPKm / MAPKi naive pancreatic cancer.

[0085] In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

[0086] In some embodiments, the cancer is melanoma.

[0087] In some embodiments, the melanoma has an NF1 loss-of-function (NF1-LoF) mutation.

[0088] In some embodiments, the melanoma is a BRAF V600E, or V600K mutated tumor.

[0089] In some embodiments, the cancer is BRAFi-treated V600 melanoma.

[0090] In some embodiments, the cancer is a salivary gland tumor.

[0091] In some embodiments, the cancer is thyroid cancer.

[0092] 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 mutated CRC. In some embodiments, the CRC is a KRAS G12C mutated CRC. In some embodiments, the CRC is a KRAS G12D mutated CRC. In some embodiments, the CRC is a KRAS G12S mutated CRC. In some embodiments, the CRC is a KRAS G12V mutated CRC. In some embodiments, the CRC is a KRAS G13D mutated CRC. In some embodiments, the CRC is a KRAS Q61H mutated CRC. In some embodiments, the CRC is a KRAS Q61K mutated CRC. In some embodiments, the CRC is a NRAS mutated CRC. In some embodiments, the CRC is a NRAS Q61R mutated CRC.

[0093] In some embodiments, the cancer is esophageal cancer.

[0094] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 25 mg / day to about 300 mg / day.

[0095] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 25 mg / day to 150 mg / day.

[0096] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 25 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, or about 250 mg / day.

[0097] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 25 mg / day, about 50 mg / day, about 100 mg / day, or about 150 mg / day.

[0098] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once a day, once a week, in an amount of about 250 mg / day.

[0099] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once daily (QD).

[0100] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily (BID).

[0101] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered three times daily (TID).

[0102] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once a week.

[0103] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice weekly.

[0104] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 300 mg.

[0105] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 250 mg.

[0106] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 150 mg.

[0107] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of 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.

[0108] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg.

[0109] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 125 mg.

[0110] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered for at least one 28 day cycle.

[0111] In some embodiments, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1, 8, 15, and 22 of a 28 day cycle.

[0112] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1, 8, and 15 of a 28 day cycle.

[0113] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0114] 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, a NRAS inhibitor, a HRAS inhibitor, a PDGFRA inhibitor, a PDGFRB inhibitor, a MET inhibitor, a FGFR inhibitor, an ALK inhibitor, a ROS1 inhibitor, a TRKA inhibitor, a TRKB inhibitor, a TRKC inhibitor, an EGFR inhibitor, an IGFR1R inhibitor, a GRB2 inhibitor, a SOS inhibitor, an ARAF inhibitor, a BRAF inhibitor, a RAF1 inhibitor, a MEK1 inhibitor, a MEK2 inhibitor, a c-Mycv, a CDK4 / 6 inhibitor, a CDK2 inhibitor, a FLT3 inhibitor, or an 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 inhibitor.

[0115] In some embodiments, the additional MAPK pathway inhibitor is an 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, sotrasib, 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 palbociclib. In some embodiments, the additional MAPK pathway inhibitor is panitumumab. In some embodiments, the additional MAPK pathway inhibitor is sotorasib.

[0116] Incorporation by Reference 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 herein. [Brief description of the drawings]

[0117] 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 disclosure are utilized, and the accompanying drawings. [Figure 1A] 1 shows in vivo data for Compound 1 + Compound 2 in a mutant RAS CDX model (NCI-H441). [Figure 1B]Shown is in vivo data for Compound 1 + Compound 2 in mutant RAS CDX model (NCI-H2009). [Figure 2A] 1 shows the benefit of the combination of Compound 1 + Compound 2 in vitro in the KRAS G12V mutant NSCLC cell line, NCI-H441, in a 14-day clonogenic assay. [Figure 2B] 1 shows the benefit of the combination of Compound 1 + Compound 2 in vitro in the KRAS Gp2D mutant NSCLC cell line, Gp2D, in a 14-day clonogenic assay. [Figure 3A] FIG. 1 shows the benefit of the combination of Compound 1 + Compound 2 in vitro in the KRAS G12D mutant pancreatic cell line, Panc 04.03, in a 14-day clonogenic assay. [Figure 3B] Shows the benefit of the combination of Compound 1 + Compound 2 in vitro in KRAS G12D mutant PDAC cell lines, HPAC in a 14-day clonogenic assay. [Figure 4] Showing the benefit of the Compound 1 + Compound 2 combination in vivo in the KRAS G12D mutant PDAC PDX model, PAN092. [Diagram 5] Showing the benefit of the Compound 1 + Compound 2 combination in vivo in the KRAS G12D mutant PDAC PDX model, PAN026. [Figure 6] 13 shows the benefit of the Compound 1 + Compound 2 combination in vivo in the NF1 LoF mutant melanoma CDX model, MeWo. [Figure 7] Showing the benefit of the Compound 1 + Compound 2 combination in vivo in the KRAS G13D mutant CRC CDX model, LoVo. [Figure 8] 1 shows the benefit of the combination of Compound 1 + Compound 2 in vitro in the KRAS G12V mutant PDAC cell line, Capan-2, in a 14-day clonogenic assay. [Figure 9]1 shows the benefit of the in vitro combination of Compound 1 + Compound 2 in the KRAS G12D mutant PDAC cell line, Panc 10.05, in a 14-day clonogenic assay. [Figure 10] 1 shows the benefit of the in vitro combination of Compound 1 + Compound 2 in the KRAS G12V mutant PDAC cell line, Panc 1, in a 14-day clonogenic assay. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0118] 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, a reference to "an agent" includes a plurality of such agents, a reference to "a cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges relating to physical properties, such as molecular weight, or chemical properties, such as chemical formulas, are used herein, all combinations and subcombinations of the ranges, and specific embodiments within the ranges, are intended to be encompassed. The term "about," when referring to a number or range of numbers, means that the referenced number or range of numbers is an approximation within experimental variation (or within statistical experimental error), and thus the number or range of numbers may vary, in some cases, by 1% to 15% of the stated number or range of numbers. 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, embodiments, such as, for example, any composition of matter, composition, method, or process described herein, "consist of" or "consist essentially of" the described features.

[0119] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0120] As used herein, the term "therapeutic agent" refers to an agent utilized to treat, eradicate, cure, prevent, or ameliorate an undesirable disease or disorder in a patient. In some embodiments, such therapeutic agents, one compound is directed to the treatment and / or amelioration of cancer.

[0121] "Administering" when used in conjunction with a therapeutic agent means administering the therapeutic agent systemically or locally, such as directly into or on a target tissue, or administering the therapeutic agent to a patient so that the therapeutic agent positively affects the targeted tissue. Thus, as used herein, the term "administering" when used in conjunction with the compositions described herein includes, but is not limited to, providing the composition in or on a target tissue, providing the composition systemically to a patient, for example, by oral administration, so that the therapeutic agent reaches the target tissue or cell. "Administering" a composition can be accomplished by injection, topical administration, and oral administration or other methods, alone or in combination with other known techniques.

[0122] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and livestock animals. As used herein, the terms "patient," "subject," and "individual" are intended to include organisms in which a particular disease may occur as described herein. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In preferred embodiments, 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 a child. In further instances, the human is under the age of 12. In certain instances, the human is an elderly person. In other instances, the human is over the age of 60. Other examples of subjects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The laboratory animal may be an animal model of a disorder (e.g., a transgenic mouse with a condition of hypertension).

[0123] 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.

[0124] The term "pharmaceutical composition" means a composition comprising at least one active ingredient, whereby the composition is applicable for investigation for a specified efficacious outcome in a mammal (e.g., but not limited to, a human). Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0125] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician, including one or more of the following: (1) preventing a disease; e.g., preventing a disease, illness, or disorder in an individual who may be prone to the disease, illness, or disorder but has not yet experienced or exhibited the symptoms or symptomology of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, illness, or disorder (i.e., halting further progression of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, illness, or disorder; and (3) reversing a disease; e.g., reversing a disease, illness, or disorder (i.e., reversing the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, illness, or disorder.

[0126] The terms "treat," "treated," "treatment," or "treating" as used herein refer to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, the purpose of which is to prevent or delay (lessen) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. For purposes described herein, a beneficial or desired clinical outcome includes, but is not limited to, alleviation of symptoms; reduction in the extent of the disease, disorder, or disease; stabilization (i.e., not worsening) of the disease, disorder, or disease state; delaying the onset or slowing the progression of the disease, disorder, or disease; amelioration of the disease, disorder, or disease state; and remission (whether partial or total), or enhancement or amelioration of the disease, disorder, or disease, whether detectable or undetectable. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment further includes extending survival time as compared to expected survival time in the absence of treatment. Prophylactic benefits of treatment include prevention of disease, slowing the progression of disease, stabilization of disease, or reducing the incidence of disease. As used herein, "treat," "treated," "treatment," or "treating" includes prevention, in some embodiments.

[0127] The term "substantially the same" as used herein refers to an X-ray powder diffraction pattern or a differential scanning calorimetry pattern that is not identical to that depicted herein, but is within the limits of experimental error as considered by one of ordinary skill in the art.

[0128] compound 1 Disclosed herein is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

[0129] [ka] or a pharma- ceutically acceptable salt thereof.

[0130] In some embodiments, the salt of Compound 1 is a mandelate salt. In some embodiments, the salt of Compound 1 is a benzenesulfonate salt. In some embodiments, the salt of Compound 1 is a hydrochloride salt. In some embodiments, the salt of Compound 1 is a p-toluenesulfonate salt.

[0131] In some embodiments, the salt of Compound 1 is a benzenesulfonate salt.

[0132] SHP2 inhibitors SHP2 plays a key role in fundamental cellular functions including proliferation, differentiation, cell cycle maintenance and motility, and regulates multiple intracellular signaling pathways in response to a wide range of growth factors, cytokines, and hormones. Cell signaling processes involving SHP2 include MAPK, PI3K and JAK pathways. SHP2 inhibitors may be broad-spectrum anticancer drugs, attenuating upstream RTK signaling that often drives oncogenic signaling and adaptive tumor escape overall.

[0133] In some embodiments, the SHP2 inhibitor is Sodium stibogluconate, RMC-4550, NSC87877, SPI-112, TNO155, IACS-13909, GDC01971, or SHP099 HCl.

[0134] In some embodiments, the SHP2 inhibitor is compound 2.

[0135] compound 2 Disclosed herein is (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decano-8-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol:

[0136] [ka] or a pharma- ceutically acceptable salt thereof.

[0137] EGFR inhibitors EGFR inhibitors are drugs that bind to EGFR and slow or stop cell proliferation, and can be classified as either tyrosine kinase inhibitors (TKIs) or monoclonal antibodies.

[0138] TKI is an inhibitor that binds to the tyrosine kinase domain in the epidermal growth factor receptor and stops the activity of EGFR. Examples include, but are not limited to, afatinib, dacomitinib, erlotinib, gefitinib, lapatinib, lazertinib, lifirafenib, mobocertinib, nazartinib, neratinib, osimertinib, and vandetanib.

[0139] Monoclonal antibody inhibitors are drugs that bind to the extracellular component of EGFR and prevent epidermal growth factor from binding to its own receptor, thus preventing cell division. Examples include, but are not limited to, amivantamab, cetuximab, mirzotamab, cleztoclax, nimotuzumab, and necitumumab.

[0140] In some embodiments, the EGFR inhibitor is afatinib, amivantamab, canertinib, cetuximab, dacomitinib, dafnetin, erlotinib, gefitinib, icotinib, lapatinib, lazertinib, lifirafenib, mirzotamab-creditoclax, mobocertinib, nazartinib, necitumumab, neratinib, osimertinib, panitumamab, pelitinib, poziotinib, tivozanib, rociletinib, sapitinib, vandetinib, or varlitinib.

[0141] In some embodiments, the EGFR inhibitor is AC480, AEE788, AG-1478, AG-18, AG-490, AST-1306, AV-412, AZ5104, AZD3759, BIBX 1382, CGP-52411, CL-387785, CNX-2006, CUDC-101, OSI-420, PD153035 HCl, PD168393, TAK-285, Tyrphostin 9, Tyrphostin AG 183, WHI-P154, WHI-P180, WZ3146, or WZ4002.

[0142] In some embodiments, the EGFR inhibitor is a small molecule inhibitor. In some embodiments, the EGFR inhibitor is osimertinib. In some embodiments, the EGFR inhibitor is cetuximab. In some embodiments, the EGFR inhibitor is afatinib. In some embodiments, the EGFR inhibitor is dacomitinib.

[0143] In some embodiments, the EGFR inhibitor is erlotinib. In some embodiments, the EGFR inhibitor is gefitinib. In some embodiments, the EGFR inhibitor is lapatinib. In some embodiments, the EGFR inhibitor is lazertinib. In some embodiments, the EGFR inhibitor is lifirafenib. In some embodiments, the EGFR inhibitor is mobocertinib. In some embodiments, the EGFR inhibitor is nazartinib. In some embodiments, the EGFR inhibitor is neratinib. In some embodiments, the EGFR inhibitor is vandetanib.

[0144] In some embodiments, the EGFR inhibitor is not an anti-EGFR antibody inhibitor.

[0145] Osimertinib Osimertinib

[0146] [ka] Osimertinib is a small molecule EGFR tyrosine kinase inhibitor used to treat locally advanced or metastatic NSCLC. It was approved by the FDA in November 2015 for the specific treatment of metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R mutation and EGFR T790M mutation-positive NSCLC. Osimertinib is marketed as Tagrisso® by AstraZeneca.

[0147] Cetuximab Cetuximab is a chimeric monoclonal antibody EGFR inhibitor used to treat metastatic CRC and head and neck cancer. In July 2009, cetuximab was approved by the FDA for the treatment of colon cancer with wild-type KRAS. Cetuximab is marketed as Erbitux® by Eli Lilly and Company.

[0148] BRAF inhibitors BRAF inhibitors selectively target the BRAF kinase, thus disrupting the MAPK signaling pathway that regulates the proliferation and survival of melanoma cells. BRAF inhibitors also have beneficial effects on the tumor microenvironment and antitumor immune responses in BRAF-mutated melanoma, thus exerting an immunomodulatory effect on the MAPK pathway, promoting the recognition of tumor cells by the immune system and enhancing antitumor T cell responses.

[0149] In some embodiments, the BRAF inhibitor is encorafenib. In some embodiments, the BRAF inhibitor is dabrafenib.

[0150] Encorafenib Encorafenib

[0151] [ka] Encorafenib is a drug for treating certain melanomas. It is a small molecule BRAF inhibitor that targets a key enzyme in the MAPK signaling pathway. This pathway occurs in a variety of cancers, including melanoma and colorectal cancer. In June 2018, it was approved by the FDA for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma in combination with binimetinib. Encorafenib is marketed as Braftovi® by Pfizer.

[0152] Dabrafenib Dabrafenib

[0153] [ka] Dabrafenib is a drug for treating cancers associated with mutated forms of the gene BRAF. Dabrafenib acts as an inhibitor of the related enzyme B-Raf, which plays a role in regulating cell proliferation. Dabrafenib has clinical activity with a manageable safety profile in phase 1 and 2 clinical trials in patients with BRAF(V600) mutated metastatic melanoma. Dabrafenib is marketed as Tafmlar® by Novartis.

[0154] CDK4 / 6 inhibitors CDK4 / 6 inhibitors act at the G1-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 retinoblastoma-related protein (pRb), thereby releasing pRb's repression of the E2F transcription factor family and allowing the cell to progress through the cell cycle. In HR+ cancers, cyclin D overexpression is common and loss of pRb is rare, making the Gi-S checkpoint an ideal therapeutic.

[0155] In some embodiments, the CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, FCN-437c, or albociclib.

[0156] In some embodiments, the CDK4 / 6 inhibitor is palbociclib.

[0157] Palbociclib Palbociclib

[0158] [ka] Palbociclib is a kinase inhibitor used to treat HR+ / HER2 advanced or metastatic breast cancer. Palbociclib is marketed as Ibrance® by Pfizer.

[0159] FLT3 inhibitors FLT3 inhibitors are tyrosine kinase inhibitors that compete with the ATP binding site in the active domain of the kinase, thus preventing phosphorylation of the protein and reducing its activity.

[0160] Type I inhibitors bind to the ATP binding site when the receptor is active, whereas type II inhibitors interact with the hydrophobic region immediately adjacent to the ATP binding site, which is accessible when the receptor is in its inactive conformation. Type I inhibitors include sunitinib, lestaurtinib, midostaurin, crenolanib, and gilteritinib, while type II inhibitors include sorafenib, quizartinib, and ponatinib.

[0161] In some embodiments, the FLT3 inhibitor is crenolanib, gilteritinib, ibrutinib, lestaurtinib, midostaurin, ponatinib, quizartinib, sorafenib, sunitinib, or tandotutinib. In some embodiments, the FLT3 inhibitor is crenolanib. In some embodiments, the FLT3 inhibitor is gilteritinib. Gilteritinib is sold under the brand name Xospata® by Astellas Pharma US, Inc. In some embodiments, the FLT3 inhibitor is ibrutinib. In some embodiments, the FLT3 inhibitor is lestaurtinib. In some embodiments, the FLT3 inhibitor is midostaurin. In some embodiments, the FLT3 inhibitor is ponatinib. In some embodiments, the FLT3 inhibitor is quizartinib. In some embodiments, the FLT3 inhibitor is sorafenib. In some embodiments, the FLT3 inhibitor is sunitinib. In some embodiments, the FLT3 inhibitor is tandutinib. In some embodiments, the FLT3 inhibitor is ibrutinib, ponatinib, quizartinib, cleolanib, or gilteritinib. In some embodiments, the FLT3 inhibitor is sorafenib, lestaurtinib, midostaurin, sunitinib, or tandututinib. In some embodiments, the combination of two or more of the FLT3 inhibitors listed above can be combined, such as combining a type I FLT3 inhibitor with a type II FLT3 inhibitor. For example, gilteritinib can be combined with quizartinib.

[0162] KRAS G12C inhibitors KRAS is a key regulator of signaling pathways involved in cell proliferation, differentiation, and survival. KRAS is the most frequently mutated oncogene in human cancers, and mutations in KRAS can lead to continuous cell proliferation and cancer development. The G12C mutation is a single point mutation with a glycine to cysteine ​​substitution at codon 12. This substitution favors an activated state of KRAS, amplifying the signaling pathway that leads to carcinogenesis.

[0163] Sotrasiv Sotorasibe, sold under the brand names Lumakras® and Lumykras®

[0164] [ka] Sotorasib is an anti-cancer drug marketed by Amgen and used to treat non-small cell lung cancer (NSCLC). It targets the specific mutation G12C in the protein K-Ras, which is encoded by the gene KRAS, which is responsible for various forms of cancer. Sotorasib is an inhibitor of the RAS GTPase family.

[0165] Sotorasib is the first approved targeted therapy for tumors with any KRAS mutation, which accounts for approximately 25% of mutations in non-small cell lung cancer. The KRAS G12C mutation occurs in approximately 13% of patients with non-small cell lung cancer.

[0166] In May 2021, sotalasib was approved by the FDA for the treatment of KRAS G12C-mutated NSCLC.

[0167] Use in combination Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0168] [ka] or a pharma- ceutically acceptable salt thereof, and (ii) administering an SHP2 inhibitor.

[0169] In some embodiments, the SHP2 inhibitor is compound 2

[0170] [ka] or a pharma- ceutically acceptable salt thereof.

[0171] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0172] [ka] or a pharma- ceutically acceptable salt thereof, and (ii) Compound 2

[0173] [ka] or a pharma- ceutically acceptable salt thereof.

[0174] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0175] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0176] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering an EGFR inhibitor.

[0177] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0178] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0179] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) osimertinib, (iii) administering an EGFR inhibitor.

[0180] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0181] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0182] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering cetuximab.

[0183] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0184] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0185] [ka] or a pharma- ceutically acceptable salt thereof, (iii) a BRAF inhibitor, and (iv) administering an EGFR inhibitor.

[0186] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0187] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0188] [ka] or a pharma- ceutically acceptable salt thereof, (iii) encorafenib, and (iv) administering osimertinib.

[0189] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0190] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0191] [ka] or a pharma- ceutically acceptable salt thereof, (iii) encorafenib, and (iv) administering cetuximab.

[0192] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0193] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0194] [ka] or a pharma- ceutically acceptable salt thereof, (iii) administering an FLT3 inhibitor.

[0195] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0196] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0197] [ka] or a pharma- ceutically acceptable salt thereof, (iii) administering gilteritinib.

[0198] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0199] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0200] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering a KRAS G12C inhibitor.

[0201] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0202] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0203] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering sotorasib.

[0204] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0205] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0206] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering adagrasib.

[0207] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0208] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0209] [ka] or a pharma- ceutically acceptable salt thereof, and (iii) administering a CDK4 / 6 inhibitor.

[0210] Disclosed herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to a subject in need thereof a therapeutically effective amount of (i) Compound 1

[0211] [ka] or a pharma- ceutically acceptable salt thereof, (ii) Compound 2

[0212] [ka] or a pharma- ceutically acceptable salt thereof, (iii) administering palbociclib.

[0213] Further combinations In some embodiments, the method includes administering an additional MAPK pathway inhibitor. Without being limited by theory, suppression of MAPK signaling in cancer cells can result in downregulation of PD-L1 expression, increasing the likelihood that the cancer cells are detected by the immune system. Such a third MAPK pathway inhibitor can be based on other mutations of proteins in the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor inhibits proteins in the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor inhibits proteins outside the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, a NRAS inhibitor, a HRAS inhibitor, a PDGFRA inhibitor, a PDGFRB inhibitor, a MET inhibitor, a FGFR inhibitor, an ALK inhibitor, a ROS1 inhibitor, a TRKA inhibitor, a TRKB inhibitor, a TRKC inhibitor, an EGFR inhibitor, an IGFR1R inhibitor, a GRB2 inhibitor, a SOS inhibitor, an ARAF inhibitor, a BRAF inhibitor, a RAF1 inhibitor, a MEK1 inhibitor, a MEK2 inhibitor, a c-Mycv, a CDK4 / 6 inhibitor, a CDK2 inhibitor, a FLT3 inhibitor, or an ERK1 / 2 inhibitor. Exemplary MAPK pathway inhibitors include, but are not limited to, adagrasib, afatinib, ASTX029, binimetinib, cetuximab, cobimetinib, dabrafenib, dacomitinib, encorafenib, erlotinib, gefitinib, gilteritinib, lapatinib, LTT462, LY3214996, necitumumab, neratinib, nimotuzumab, osimertinib, panitumumab, selumetinib, sotrasib, trametinib, ulixertinib, vandetanib, and vemurafenib.

[0214] In some embodiments, the additional MAPK pathway inhibitor is adagrasib. In some embodiments, the additional MAPK pathway inhibitor is afatinib. In some embodiments, the additional MAPK pathway inhibitor is binimetinib. In some embodiments, the additional MAPK pathway inhibitor is cetuximab. In some embodiments, the additional MAPK pathway inhibitor is cobimetinib. In some embodiments, the additional MAPK pathway inhibitor is dabrafenib. In some embodiments, the additional MAPK pathway inhibitor is dacomitinib. In some embodiments, the additional MAPK pathway inhibitor is encorafenib. In some embodiments, the additional MAPK pathway inhibitor is erlotinib. In some embodiments, the additional MAPK pathway inhibitor is gefitinib. In some embodiments, the additional MAPK pathway inhibitor is gilteritinib. In some embodiments, the additional MAPK pathway inhibitor is lapatinib. In some embodiments, the additional MAPK pathway inhibitor is LTT462. In some embodiments, the additional MAPK pathway inhibitor is LY3214996. In some embodiments, the additional MAPK pathway inhibitor is necitumumab. In some embodiments, the additional MAPK pathway inhibitor is neratinib. In some embodiments, the additional MAPK pathway inhibitor is nimotuzumab. In some embodiments, the additional MAPK pathway inhibitor is osimertinib. In some embodiments, the additional MAPK pathway inhibitor is palbociclib. In some embodiments, the additional MAPK pathway inhibitor is panitumumab. In some embodiments, the additional MAPK pathway inhibitor is selumetinib. In some embodiments, the additional MAPK pathway inhibitor is sotorasib. In some embodiments, the additional MAPK pathway inhibitor is trametinib. In some embodiments, the additional MAPK pathway inhibitor is ulixertinib. In some embodiments, the additional MAPK pathway inhibitor is vandetanib.

[0215] cancer Disclosed herein are methods of treating cancer using the combinations disclosed herein.

[0216] "Cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals (e.g., humans), including, but not limited to, leukemia, lymphoma, myeloma, carcinoma, and sarcoma.Exemplary cancers that can be treated using the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colon cancer, pancreatic cancer (such as pancreatic adenocarcinoma, PDAC), medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, Hodgkin's disease, and non-Hodgkin's lymphoma.Exemplary cancers that can be treated using the compounds or methods provided herein include blood, thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus cancer. Further examples include thyroid cancer, hepatic ductal carcinoma, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, 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 tumor, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesion, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, tumor of the endocrine or exocrine pancreas, thyroid bone marrow cancer, thyroid bone marrow tumor, melanoma, colon cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. In some embodiments, the cancer has a class 1 B-Raf mutation.

[0217] In some embodiments, the cancer harbors at least one of an EGFR, KRAS, BRAF (eg, BRAF class III) and / or NF1 (eg, loss of function) mutation.

[0218] In some embodiments, the mutated B-Raf comprises a V600 mutation. In some embodiments, the mutation in B-Raf comprises a V600E mutation. In some embodiments, the mutation is V600K. In some embodiments, the mutation is V600D. In some embodiments, the mutation is V600L. In some embodiments, the mutation is V600R. In some embodiments, the cancer is a BRAF V600E or V600K mutated tumor.

[0219] In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer.

[0220] In some embodiments, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

[0221] In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK.

[0222] 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.

[0223] 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 G12R 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 G12W KRAS mutation. In some embodiments, the cancer has a G13D KRAS mutation. In some embodiments, the cancer has a H95D KRAS mutation. In some embodiments, the cancer has a H95Q KRAS mutation. In some embodiments, the cancer has a H95R KRAS mutation. In some embodiments, the cancer has a Q16H KRAS mutation. In some embodiments, the cancer has a Q61H KRAS mutation. In some embodiments, the cancer has a Q16K KRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation. In some embodiments, the cancer has a R68S KRAS mutation.

[0224] In some embodiments, the cancer is MAPKm / MAPKi naive pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

[0225] In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of EGFR gene copy number gain, EGFR gene amplification, chromosome 7 polysomy, L858R, exon 19 deletion / insertion, L718Q, L861Q, G719C, G719S, G724S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, Vvi, and Vii), A289D, A289T, A289V, G598A, G598V, T790M, S768I, C797X, and C797S. In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

[0226] In some embodiments, the cancer is a liquid tumor. In some embodiments, the liquid tumor is leukemia. In some embodiments, the liquid tumor is acute myeloid leukemia (AML). In some embodiments, the AML is relapsed and / or resistant AML. In some embodiments, the AML is FLT3 mutated AML.

[0227] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced or metastatic solid tumor.

[0228] 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.

[0229] In some embodiments, the cancer is colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), hepatic ductal carcinoma, appendix 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.

[0230] In some embodiments, the cancer is gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is anal cancer, bile duct cancer, colon cancer, rectal cancer, esophageal cancer, gallbladder cancer, liver cancer, pancreatic cancer, small intestine cancer, or gastric cancer (stomach cancer).

[0231] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is EGFR mutated NSCLC. In some embodiments, the NSCLC is KRAS G12C mutated NSCLC. In some embodiments, the NSCLC is KRAS G12D mutated NSCLC. In some embodiments, the NSCLC is KRAS G12S mutated NSCLC. In some embodiments, the NSCLC is KRAS G12V mutated NSCLC. In some embodiments, the NSCLC is KRAS G13D mutated NSCLC. In some embodiments, the NSCLC is KRAS Q61H mutated NSCLC. In some embodiments, the NSCLC is KRAS Q61K mutated NSCLC. In some embodiments, the EGFR mutation is an acquired EGFR mutation. In some embodiments, the acquired EGFR mutation is C797X. In some embodiments, the acquired EGFR mutation is L718Q. In some embodiments, the acquired EGFR mutation is EGFR gene amplification. In some embodiments, the acquired EGFR mutation is G724S. In some embodiments, the acquired EGFR mutation is S768I.

[0232] In some embodiments, the NSCLC is NRAS Q61R mutant NSCLC. In some embodiments, the cancer is MAPKm / MAPKi naive NSCLC. In some embodiments, the cancer is BRAFi treated V600 NSCLC. In some embodiments, the cancer is KRAS treated G12C NSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS treated G12S NSCLC. In some embodiments, the cancer is KRAS treated G12V NSCLC. In some embodiments, the cancer is KRAS treated G13D NSCLC. In some embodiments, the cancer is KRAS treated Q61H NSCLC. In some embodiments, the cancer is KRAS treated Q61K NSCLC. In some embodiments, the cancer is NRAS treated Q61R NSCLC. In some embodiments, the cancer is KRAS treated G12R NSCLC. In some embodiments, the cancer is KRAS treated G12W NSCLC. In some embodiments, the cancer is KRAS treated H95D NSCLC. In some embodiments, the cancer is KRAS treated H95Q NSCLC. In some embodiments, the cancer is KRAS treated H95R NSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS treated R68S NSCLC.

[0233] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is MAPKm / MAPKi naive pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

[0234] 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.

[0235] In some embodiments, the cancer is a salivary gland tumor.

[0236] In some embodiments, the cancer is thyroid cancer.

[0237] In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is BRAF V600E CRC. In some embodiments, the CRC is KRAS mutated CRC.

[0238] In some embodiments, the CRC is a KRAS G12C mutated CRC. In some embodiments, the CRC is a KRAS G12D mutated CRC. In some embodiments, the CRC is a KRAS G12R mutated CRC. In some embodiments, the CRC is a KRAS G12S mutated CRC. In some embodiments, the CRC is a KRAS G12V mutated CRC. In some embodiments, the CRC is a KRAS G12W mutated CRC. In some embodiments, the CRC is a KRAS G13D mutated CRC. In some embodiments, the CRC has a H95D KRAS mutation. In some embodiments, the CRC has a H95Q KRAS mutation. In some embodiments, the CRC has a H95R KRAS mutation. In some embodiments, the CRC is a KRAS Q61H mutated CRC. In some embodiments, the CRC is a KRAS Q61K mutated CRC. In some embodiments, the CRC is a NRAS mutated CRC. In some embodiments, the CRC is NRAS Q61R mutated CRC. In some embodiments, the CRC has a R68S KRAS mutation.

[0239] In some embodiments, the cancer is esophageal cancer.

[0240] In some embodiments, the cancer has one or more acquired mutations. In some embodiments, the acquired mutations are due to a first line treatment. In some embodiments, the first line treatment is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is osimertinib. In some embodiments, the first line treatment is a KRAS inhibitor. In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor. In some embodiments, the KRASG12C inhibitor is adagrasib. In some embodiments, the KRASG12C inhibitor is sotorasib. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is NSCLC.

[0241] In some embodiments, the EGFR mutation is an acquired EGFR mutation. In some embodiments, the acquired EGFR mutation is C797X. In some embodiments, the acquired EGFR mutation is L718Q. In some embodiments, the acquired EGFR mutation is EGFR amplification. In some embodiments, the acquired EGFR mutation is G724S. In some embodiments, the acquired mutation is S768I.

[0242] In some embodiments, the acquired mutation is an acquired amplification mutation. In some embodiments, the acquired mutation is a MET gene amplification. In some embodiments, the acquired mutation is a HER2 gene amplification.

[0243] In some embodiments, the acquired mutation is an acquired oncogenic fusion. In some embodiments, the acquired oncogenic fusion is SPTBN1-ALK. In some embodiments, the acquired oncogenic fusion is a RET fusion. In some embodiments, the acquired oncogenic fusion is a BRAF fusion.

[0244] In some embodiments, the acquired mutation is an acquired MAPK-PI3K mutation. In some embodiments, the acquired MAPK-PI3K mutation is BRAF-V600E. In some embodiments, the acquired MAPK-PI3K mutation is PI3KCA. In some embodiments, the acquired MAPK-PI3K mutation is KRAS. In some embodiments, the acquired MAPK-PI3K mutation is HER2.

[0245] In some embodiments, the acquired mutation is an acquired KRAS mutation. In some embodiments, the acquired mutation is KRAS G12C. In some embodiments, the acquired mutation is KRAS G12D. In some embodiments, the acquired mutation is KRAS G12R. In some embodiments, the acquired mutation is KRAS G12V. In some embodiments, the acquired mutation is KRAS G12W. In some embodiments, the acquired mutation is KRAS G13D. In some embodiments, the acquired mutation is KRAS H95D. In some embodiments, the acquired mutation is KRAS H95D. In some embodiments, the acquired mutation is KRAS H95Q. In some embodiments, the acquired mutation is KRAS H95R. In some embodiments, the acquired mutation is KRAS Q61H. In some embodiments, the acquired mutation is KRAS R68S.

[0246] In some embodiments, the acquired mutation is an acquired MAPK pathway mutation. In some embodiments, the acquired MAPK pathway mutation is MAP2K1 K57N. In some embodiments, the acquired MAPK pathway mutation is MAP2K1 K57T. In some embodiments, the acquired MAPK pathway mutation is CCDC6-RET. In some embodiments, the acquired MAPK pathway mutation is RITI P128L. In some embodiments, the acquired MAPK pathway mutation is PTEN G209V. In some embodiments, the acquired MAPK pathway mutation is BRAF V600E. In some embodiments, the acquired MAPK pathway mutation is MAP2K1 199_K104del. In some embodiments, the acquired MAPK pathway mutation is MAP2K1 K57N. In some embodiments, the acquired MAPK pathway mutation is EML4-ALK. In some embodiments, the acquired MAPK pathway mutation is EGFR A289A. In some embodiments, the acquired MAPK pathway mutation is FGFR3-TACC3. In some embodiments, the acquired MAPK pathway mutation is AKAP9-BRAF. In some embodiments, the acquired MAPK pathway mutation is RAF1-CCDC176. In some embodiments, the acquired MAPK pathway mutation is RAF1-TRAK1. In some embodiments, the acquired MAPK pathway mutation is NRAS Q61K. In some embodiments, the acquired MAPK pathway mutation is MAP2K1 E102_1103DEL. In some embodiments, the acquired MAPK pathway mutation is NRF1-BRAF.

[0247] In some embodiments, the acquired mutation is a KRAS G12C reactivating mutation. In some embodiments, the KRAS G12C reactivating mutation is a RKRAS G12C gene amplification. In some embodiments, the KRAS G12C reactivating mutation is NF1 R22637 (LoF).

[0248] In some embodiments, the acquired mutation is a non-G12C activating KRAS mutation. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12D. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12R. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12V. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12W. In some embodiments, the non-G12C activating KRAS mutation is KRAS G13D. In some embodiments, the non-G12C activating KRAS mutation is KRAS Q61H. In some embodiments, the non-G12C activating KRAS mutation is KRAS Q61K.

[0249] In some embodiments, the acquired mutation is a sterically hindering KRAS G12C mutation. In some embodiments, the sterically hindering KRAS G12C mutation is KRAS R68S. In some embodiments, the sterically hindering KRAS G12C mutation is KRAS H95D. In some embodiments, the sterically hindering KRAS G12C mutation is KRAS H95Q. In some embodiments, the sterically hindering KRAS G12C mutation is KRAS H95R. In some embodiments, the sterically hindering KRAS G12C mutation is KRAS Y96C.

[0250] In some embodiments, the acquired mutation is an RTK activating mutation. In some embodiments, the RTK activating mutation is EGFR A289V. In some embodiments, the RTK activating mutation is RET M918T. In some embodiments, the RTK activating mutation is MET gene amplification. In some embodiments, the RTK activating mutation is EML-ALK. In some embodiments, the RTK activating mutation is CCDC6-RET. In some embodiments, the RTK activating mutation is FGFR3-TACC3.

[0251] In some embodiments, the acquired mutation is a downstream RAS / MAPK activating mutation. In some embodiments, the downstream RAS / MAPK activating mutation is BRAF V600E. In some embodiments, the downstream RAS / MAPK activating mutation is MAP2K I99_K104del. In some embodiments, the downstream RAS / MAPK activating mutation is MAP2K1 I99_K104del. In some embodiments, the downstream RAS / MAPK activating mutation is MAP2K1 E102_I103del. In some embodiments, the downstream RAS / MAPK activating mutation is a RAF fusion.

[0252] In some embodiments, the acquired mutation is a parallel pathway activating mutation. In some embodiments, the parallel pathway activating mutation is PIK3CA H1047R. In some embodiments, the parallel pathway activating mutation is PIK3R1 S361fs. In some embodiments, the parallel pathway activating mutation is PTEN N48K. In some embodiments, the parallel pathway activating mutation is PTEN G209V. In some embodiments, the parallel pathway activating mutation is RIT1 P128L.

[0253] dosage In one embodiment, the compositions described herein are used for the treatment of the diseases and disorders described herein. Additionally, a method for treating any of the diseases or disorders described herein in a subject in need of such treatment comprises administering a therapeutically effective amount of the composition to the subject.

[0254] The dose of the compositions described herein may be determined by any suitable method. The maximum tolerated dose (MTD) and maximum response dose (MRD) of Compound 1, or its pharma- ceutically acceptable salts, may be determined through established animal and human experimental protocols, as well as the examples described herein. For example, the toxicity and therapeutic effects of Compound 1, or its pharma- ceutically acceptable salts, may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, 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 effect and the therapeutic effect is the therapeutic index, which may be expressed as the ratio between the LD50 and the ED50. The data obtained from cell culture assays and animal studies may be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably located within a range of circulating concentrations that includes the ED50 with minimal toxicity. Dosages may vary within this range depending on the dosage form used and the route of administration utilized. The relative dose of addition, expressed as a percentage of the maximum response or maximum tolerated dose, is readily available via the protocol.

[0255] In some embodiments, the amount of a given formulation comprising Compound 1 or a pharma- ceutically acceptable salt thereof that corresponds to such an amount will vary depending on factors such as the molecular weight of the particular salt or form, the disease state and its severity, the identity of the subject or host in need of treatment (e.g., age, weight, sex), etc., but may nevertheless be determined depending on the particular circumstances surrounding the case, including, for example, the particular agent being administered, the type of liquid formulation, the disease being treated, and the subject or host being treated.

[0256] In some embodiments, the amount of Compound 1, or a pharma- ceutically acceptable salt thereof, relates to the free base equivalent of Compound 1, as described herein.

[0257] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0258] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount from about 25 mg / day to about 300 mg / day.

[0259] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount between 25 mg / day and 150 mg / day.

[0260] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 25 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, or about 250 mg / day.

[0261] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 25 mg / day, about 50 mg / day, about 100 mg / day, or about 150 mg / day.

[0262] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 300 mg.

[0263] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 250 mg.

[0264] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 200 mg.

[0265] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 150 mg.

[0266] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 100 mg.

[0267] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 50 mg.

[0268] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 300 mg.

[0269] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 250 mg.

[0270] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 200 mg.

[0271] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 150 mg.

[0272] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 100 mg.

[0273] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 100 mg to about 300 mg.

[0274] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 100 mg to about 250 mg.

[0275] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 100 mg to about 200 mg.

[0276] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 100 mg to about 150 mg.

[0277] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 150 mg to about 300 mg.

[0278] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 150 mg to about 250 mg.

[0279] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 150 mg to about 200 mg.

[0280] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 175 mg to about 300 mg.

[0281] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 175 mg to about 250 mg.

[0282] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 175 mg to about 200 mg.

[0283] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 200 mg to about 300 mg.

[0284] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 200 mg to about 250 mg.

[0285] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 225 mg to about 300 mg.

[0286] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, is administered twice daily, once weekly (BID-QW) in an amount of about 225 mg to about 250 mg.

[0287] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 25 mg to about 300 mg.

[0288] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 50 mg to about 250 mg.

[0289] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 100 mg to about 300 mg.

[0290] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 100 mg to about 250 mg.

[0291] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 150 mg to about 300 mg.

[0292] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 150 mg to about 250 mg.

[0293] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 100 mg. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 150 mg. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 200 mg. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once weekly (QW) in an amount of about 250 mg.

[0294] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 300 mg.

[0295] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 250 mg.

[0296] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 150 mg.

[0297] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of 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.

[0298] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg.

[0299] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 125 mg.

[0300] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once a day, once a week, in an amount of about 250 mg.

[0301] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 25 mg, 30 mg, 40 mg, 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 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.

[0302] In some embodiments, each of the amounts detailed above may be administered QD, QW, BID, BID-QD, or BID-QW.

[0303] In some embodiments, compound 2, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0304] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered in an amount from about 1 mg / day to about 500 mg / day.

[0305] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered in an amount from about 20 mg / day to about 400 mg / day.

[0306] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered in an amount from about 30 mg / day to about 300 mg / day.

[0307] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 25 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, about 275 mg / day, about 300 mg / day, about 325 mg / day, about 350 mg / day, or about 400 mg / day.

[0308] In some embodiments, compound 2, or a pharma- ceutically acceptable salt thereof, is administered QD or BID for 2 weeks on and 1 week off (a 21-day schedule). In some embodiments, compound 2, or a pharma- ceutically acceptable salt thereof, is administered QD or BID for 3 weeks on and 1 week off (a 28-day schedule). In some embodiments, compound 2, or a pharma- ceutically acceptable salt thereof, is administered QD or BID 3 times a week, for example, on days 1, 3, and 5 (D1D3D5 TIW). In some embodiments, compound 2, or a pharma- ceutically acceptable salt thereof, is administered twice a day / twice a week, for example, on days 1 and 2 (BID-D1D2-BIW).

[0309] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered continuously once a day (QD) at a dose of 20 mg / day to 60 mg / day, 40 mg / day, or 60 mg / day. In some embodiments, Compound 2, or a pharma-ceutically acceptable salt thereof, is administered continuously twice a day (BID) at a dose of 20 mg / day to 80 mg / day. In some embodiments, Compound 2, or a pharma-ceutically acceptable salt thereof, is administered continuously twice a day (BID) at a dose of 10 mg / day to 100 mg / day.

[0310] In some embodiments, each of the amounts detailed above may be administered QD, QW, BID, BID-QD, or BID-QW.

[0311] In some embodiments, osimertinib is administered in an amount of about 50 mg / day to about 300 mg / day. In some embodiments, osimertinib is administered in an amount of about 20 mg / day. In some embodiments, osimertinib is administered in an amount of about 40 mg / day. In some embodiments, osimertinib is administered in an amount of about 60 mg / day. In some embodiments, osimertinib is administered in an amount of about 80 mg / day. In some embodiments, osimertinib is administered in an amount of about 100 mg / day. In some embodiments, osimertinib is administered in an amount of about 120 mg / day. In some embodiments, osimertinib is administered in an amount of about 140 mg / day.

[0312] In some embodiments, cetuximab is administered at 400 mg / m over 120 minutes once weekly. 2 followed by 250 mg / m for 60 min. 2 In some embodiments, cetuximab is administered at 500 mg / m 2 In some embodiments, cetuximab is administered at 400 mg / m 2 In some embodiments, cetuximab is administered at 300 mg / m 2 It is administered once every two weeks.

[0313] In some embodiments, encorafenib is administered in an amount of about 100 mg / day to about 500 mg / day. In some embodiments, encorafenib is administered in an amount of about 450 mg / day. In some embodiments, encorafenib is administered in an amount of about 300 mg / day. In some embodiments, encorafenib is administered in an amount of about 225 mg / day. In some embodiments, encorafenib is administered in an amount of about 150 mg / day.

[0314] In some embodiments, dabrafenib is administered in an amount between about 100 mg / day and about 500 mg / day. In some embodiments, dabrafenib is administered in an amount of about 450 mg / day. In some embodiments, dabrafenib is administered in an amount of about 300 mg / day. In some embodiments, dabrafenib is administered in an amount of about 225 mg / day. In some embodiments, dabrafenib is administered in an amount of about 150 mg / day. In some embodiments, dabrafenib is administered in an amount of about 100 mg / day.

[0315] In some embodiments, gilteritinib is administered in an amount of about 100 mg / day to about 500 mg / day. In some embodiments, gilteritinib is administered in an amount of about 450 mg / day. In some embodiments, gilteritinib is administered in an amount of about 300 mg / day. In some embodiments, gilteritinib is administered in an amount of about 225 mg / day. In some embodiments, gilteritinib is administered in an amount of about 150 mg / day. In some embodiments, gilteritinib is administered in an amount of about 120 mg / day. In some embodiments, gilteritinib is administered in an amount of about 100 mg / day.

[0316] In some embodiments, sotorasib is administered in an amount between about 500 mg / day and about 1500 mg / day. In some embodiments, sotorasib is administered in an amount of about 1000 mg / day. In some embodiments, sotorasib is administered in an amount of about 960 mg / day. In some embodiments, sotorasib is administered in an amount of about 900 mg / day. In some embodiments, sotorasib is administered in an amount of about 800 mg / day. In some embodiments, sotorasib is administered in an amount of about 700 mg / day. In some embodiments, sotorasib is administered in an amount of about 600 mg / day. In some embodiments, sotorasib is administered in an amount of about 500 mg / day.

[0317] In some embodiments, adagrasib is administered in an amount of about 500 mg / day to about 1500 mg / day. In some embodiments, adagrasib is administered in an amount of about 1200 mg / day. In some embodiments, adagrasib is administered in an amount of about 1000 mg / day. In some embodiments, adagrasib is administered in an amount of about 800 mg / day. In some embodiments, adagrasib is administered in an amount of about 600 mg / day. In some embodiments, adagrasib is administered in an amount of about 400 mg / day.

[0318] In some embodiments, palbociclib is administered in an amount between about 50 mg / day and about 500 mg / day. In some embodiments, palbociclib is administered in an amount of about 150 mg / day. In some embodiments, palbociclib is administered in an amount of about 125 mg / day. In some embodiments, palbociclib is administered in an amount of about 100 mg / day. In some embodiments, palbociclib is administered in an amount of about 75 mg / day. In some embodiments, palbociclib is administered in an amount of about 50 mg / day.

[0319] In some embodiments, palbociclib is administered once a week: It is administered in an amount of about 50 mg to about 650 mg once per week. In some embodiments, palbociclib is administered in an amount of between about 600 mg once per week. In some embodiments, palbociclib is administered in an amount of between about 500 mg once per week. In some embodiments, palbociclib is administered in an amount of between about 400 mg once per week. In some embodiments, palbociclib is administered in an amount of between about 300 mg once per week. In some embodiments, palbociclib is administered in an amount of between about 200 mg once per week.

[0320] Administration Administration of compound 1, or its pharmaceutically acceptable salt, and combination partner described herein is performed in dosage amounts described herein, or other dosage levels and compositions as determined and contemplated by a physician. In some embodiments, compound 1, or its pharmaceutically acceptable salt, is administered for prophylactic and / or therapeutic treatment. In some therapeutic applications, compound 1, or its pharmaceutically acceptable salt, and combination partner 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 symptoms. The amount effective for such use depends on the age of the patient, the severity of the disease, previous treatments, the patient's health, weight, and response to the composition, as well as the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0321] In preventive applications, the compositions described herein are administered to patients susceptible to or at risk of a particular disease, such as cancer. Such an amount is defined as a "prophylactically effective amount or dose." In this application, the exact amount also depends on the patient's age, health, weight, etc. When used in patients, the amount effective for this application depends on the risk or susceptibility to developing a particular disease, previous treatments, the patient's health and response to the composition, and the judgment of the treating physician.

[0322] In certain embodiments in which the patient's disease is not improved, at the discretion of the physician, administration of the compositions described herein is administered chronically, i.e., for the entire lifespan of the patient, to improve or otherwise control or limit the symptoms of the patient's disease, hi other embodiments, administration of the compositions continues until a complete or partial response of the disease occurs.

[0323] In some embodiments, compound 1 as described herein, or a pharmaceutically acceptable salt thereof, and combination partner are administered once a day.In some embodiments, compound 1 as described herein, or a pharmaceutically acceptable salt thereof, and combination partner are administered twice a day.In some embodiments, compound 1 as described herein, or a pharmaceutically acceptable salt thereof, and combination partner are administered three times a day.

[0324] In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered twice daily. In some embodiments, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered three times daily.

[0325] In some embodiments, compound 1, or a pharma- ceutically acceptable salt thereof, and combination partner described herein is administered to a subject in a fasting state. Fasting state refers to a subject who has been fasting or fasting for a certain period of time. Typical 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 pharma- ceutically acceptable salt thereof, is administered to a subject in a fasting state for at least 8 hours. In other embodiments, compound 1, or a pharma- ceutically acceptable salt thereof, and combination partner described herein is administered to a subject in a fasting state for at least 10 hours. In still other embodiments, compound 1, or a pharma- ceutically acceptable salt thereof, and combination partner described herein is administered to a subject in a fasting state for at least 12 hours. In other embodiments, compound 1, or a pharma- ceutically acceptable salt thereof, and combination partner described herein is administered to a subject who has been fasting overnight.

[0326] In other embodiments, compound 1, or a pharma- ceutically acceptable salt thereof, as described herein, and combination partner are administered to a subject in a fed state. Fed state refers to a subject that is ingesting food or eating a meal. In certain embodiments, the composition is administered to a subject in a fed state 5 minutes after a meal, 10 minutes after a meal, 15 minutes after a meal, 20 minutes after a meal, 30 minutes after a meal, 40 minutes after a meal, 50 minutes after a meal, 1 hour after a meal, or 2 hours after a meal. In some examples, compound 1, or a pharma- ceutically acceptable salt thereof, as described herein, is administered to a subject in a fed state 30 minutes after a meal. In other examples, compound 1, or a pharma- ceutically acceptable salt thereof, as described herein, and combination partner are administered to a subject in a fed state 1 hour after a meal. In further embodiments, compound 1, or a pharma- ceutically acceptable salt thereof, is administered to a subject with food.

[0327] The length of the treatment cycle depends on the treatment being given. In some embodiments, the length of the treatment cycle ranges from 2 to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 3 to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 3 to 4 weeks. In some embodiments, the length of the treatment cycle is 3 weeks (or 21 days). In some embodiments, the length of the treatment cycle is 4 weeks (28 days). In some embodiments, the length of the treatment cycle is 5 weeks (35 days). In some embodiments, the length of the treatment cycle is 56 days. In some embodiments, the treatment cycle lasts 1, 2, 3, 4, or 5 weeks. In some embodiments, the treatment cycle lasts 3 weeks. In some embodiments, the treatment cycle lasts 4 weeks. In some embodiments, the treatment cycle lasts 5 weeks. The number of treatment administrations scheduled within each cycle also varies depending on the drug being given.

[0328] In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered in a 28-day cycle. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered over multiple 28-day cycles. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered over at least one 28-day cycle. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered over at least two 28-day cycles. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered over at least three 28-day cycles. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered over at least four 28-day cycles. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for at least five 28-day cycles. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for at least six 28-day cycles.

[0329] In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.

[0330] In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 1 of a 28-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 8 of a 28-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 15 of a 28-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 22 of a 28-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is not administered twice daily on day 22 of a 28-day cycle.

[0331] In some embodiments of the methods of treating cancer, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on days 1, 8, and 15 of a 28-day cycle.

[0332] In some embodiments of the methods of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is not administered on days 2-7, days 9-14, days 16-21, and days 23-28 of a 28 day cycle.

[0333] In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered in a 35-day cycle. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for multiple 35-day cycles. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for at least one 35-day cycle. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for at least two 35-day cycles. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for at least three 35-day cycles. In some embodiments of the method of treating cancer, compound 1 described herein, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for at least four 35-day cycles. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for at least five 35-day cycles. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, and combination partner are administered for at least six 35-day cycles.

[0334] In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-7 of each 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-14 of each 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-21 of each 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-28 of each 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered on days 1-35 of each 35-day cycle.

[0335] In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 1 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 8 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 15 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 22 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on day 29 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is not administered twice daily on day 29 of a 35-day cycle.

[0336] In some embodiments of the methods of treating cancer, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

[0337] In some embodiments of the methods of treating cancer, compound 1, or a pharma- ceutically acceptable salt thereof, is not administered on days 2-7, 9-14, 16-21, 23-28, and 30-35 of a 28-day cycle. EXAMPLES

[0338] Example 1: In vivo assay Vehicle / control substances, 0.5% methylcellulose and 0.1% Tween 80, or 100 mM acetic acid in deionized water with the pH adjusted to 4.8-5.0, were prepared and stored under ambient conditions throughout the study period.

[0339] Formulation of test articles The test article, Compound 1, was prepared fresh weekly in a vehicle of 0.5% methylcellulose and 0.1% Tween 80 and stored under ambient conditions. The co-agent, Compound 2, was prepared fresh weekly in a vehicle of 100 mM acetate buffer and stored under ambient conditions.

[0340] animal Female Balb / c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were housed in a vivarium facility with a specific pathogen-free (SPF) environment and were acclimated to their new environment for at least 3 days before the start of any experiment. Mice were 6-8 weeks old at the time of transplantation.

[0341] All procedures related to the handling, care, and treatment of animals in this study were carried out in accordance with protocols and guidelines approved by the Institutional Animal Care and Use Committee (iACUC) of GenenDesign and WuXi AppTec. The animal facility and program are operated under the standards of the Guide for the Care and Use of Laboratory Animals (NRC, 2011) and are accredited by the International Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all parts of this study performed at GenenDesign and WuXi AppTec complied with research protocols reviewed and approved by the IACUC and applicable standard operating procedures (SOPs).

[0342] Preparation of xenograft models NCI-H441 is a KRAS G12V The NCI-H441 cell line was purchased from the American Type Culture Collection (ATCC® HTB-174™). NCI-H441 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS) at 37°C in an atmosphere of 5% CO2 in air. 5 × 10 6 Mice were implanted subcutaneously with NCI-H441 cells in a 200 μL cell suspension containing 100 μL of cells. Tumor volumes were 200 mm on average. 3 When the tumor-bearing mice reached 100%, they were randomized into different groups with 8 mice in each group and treatment was started on the day of randomization.

[0343] NCI-H2009 is a KRAS G12A The NCI-H2009 cell line was purchased from the American Type Culture Collection (ATCC® CRL-5911). NCI-H2009 cells were cultured in RPMI-1640 with 10% fetal bovine serum (FBS) supplemented with glutamax and pyruvate at 37°C in an atmosphere of 5% CO2 in air. 5 × 10 6 Mice were implanted subcutaneously with NCI-H2009 cells in 100 μL of cell suspension containing the cells. Tumor volumes averaged 200 mm3 When the tumor-bearing mice reached 100%, they were randomized into different groups with 8 mice in each group and treatment was started on the day of randomization.

[0344] treatment In the monotherapy treatment groups, mice were administered vehicle control solution, compound 1, or compound 2 by oral administration. Mice were administered a combination containing compound 1 and compound 2 by oral administration. The dose was 5 mL / kg for each compound, with an interval of 8 hours for the BID regimen. In the combination of compound 1 and compound 2, compound 1 was administered 1 hour after the QD or first BID administration of compound 2. In addition to regular food and water supply, DietGel (ClearH2O, US) was added to cages in which at least two mice showed a BWL of 10% or more. The study was completed at the end of 4 weeks of treatment or when tumor volumes in the vehicle control group reached 2,000 mm 3 It ended when it reached

[0345] result In the KRAS G12V NSCLC CDX model NCI-H441, as illustrated in Figure 1A, the combination of compound 1 at 30 mg / kg QD and compound 2 at 15 mg / kg QD achieved a statistically significant TGI of 113% (p-value < 0.001), demonstrating a statistically significant advantage over the respective monotherapy doses of both compound 1 at 30 mg / kg QD and compound 2 at 15 mg / kg QD (p-value < 0.01). Compound 1 as monotherapy at doses of 30 mg / kg BID and 30 mg / kg QD achieved statistically significant TGI of 115% (p-value < 0.001) and 94% (p-value < 0.001), respectively. Compound 2 as monotherapy at doses of 30 mg / kg QD and 15 mg / kg QD achieved statistically significant TGI of 101% (p-value < 0.001) and 87% (p-value < 0.001), respectively. Figure 1A shows the tumor growth curves for this study.

[0346] In the KRAS G12A NSCLC CDX model NCI-H2009, as illustrated in FIG. 1B, the combination of compound 1 at 30 mg / kg QD and compound 2 at 15 mg / kg QD achieved a statistically significant TGI of 107% (p-value < 0.001). The combination of compound 1 and compound 2 achieved a statistically significant combination benefit compared to the respective monotherapy doses of both compound 1 at 30 mg / kg QD and compound 2 at 15 mg / kg QD (p-value < 0.01). The combination also showed a statistically significantly superior TGI compared to compound 1 monotherapy at 30 mg / kg BID (p-value < 0.05) and compound 2 monotherapy at 30 mg / kg QD (p-value < 0.01). These doses represent the maximum monotherapy non-clinical effective doses of compound 1 and compound 2. Compound 1 as monotherapy at 30 mg / kg BID achieved a statistically significant TGI of 93%. Compound 2 as monotherapy at doses of 30 mg / kg QD and 15 mg / kg QD achieved statistically significant TGI of 90% (p-value < 0.001) and 73% (p-value < 0.001), respectively. Figure 1B shows the tumor growth curves for this study.

[0347] Compound 1 and Compound 2 demonstrated combination benefit in vivo in the mutant RAS CDX model.

[0348] Example 2: In vitro studies of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in NSCLC cell lines Cells (8000 cells per well) were seeded on 6-well plates in 2 ml of cell culture medium. Cells were incubated overnight and treated with the above concentrations of Compound 1 and Compound 2. After 7 days of incubation, the medium was replaced with fresh medium and cells were treated again with the same concentrations of Compound 1 and Compound 2 and incubated for another 7 days. After a total of 14 days of incubation, cells were washed twice with PBS and fixed with 4% formaldehyde for 30 minutes. Cells were washed twice with PBS and incubated with 0.1% crystal violet for 60 minutes. After crystal violet staining, cells were washed five times with water and dried at room temperature. After drying the plates, the crystal stain was destained with 1 ml of 10% acetic acid and absorbance was measured at 560 nM.

[0349] As illustrated in Figure 2A, compound 1 and compound 2 demonstrated the benefit of combination in KRAS G12V mutant NSCLC cell line, NCI-H441. As illustrated in Figure 2B, compound 1 and compound 2 demonstrated the benefit of combination in KRAS G12D mutant NSCLC cell line, Gp2D.

[0350] Example 3: In vitro studies of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in mutant pancreatic and pancreatic cancer cell lines Cells were seeded in 12-well plates and allowed to adhere overnight. The next day, vehicle or compound was added to the wells in 1 mL of medium. After 7 days of incubation, the medium was replaced with fresh medium containing vehicle or compound. After 14 days of incubation, cells were washed twice with 1×PBS and fixed with 4% formaldehyde for 30 minutes, then washed twice with 1×PBS. Cells were stained with 0.1% crystal violet for 60 minutes, then washed five times with 1×PBS. Plates were dried at room temperature for 2 hours and imaged. Cells were then destained with 10% acetic acid and absorbance was measured using the BCA protocol or absorbance at 560 nm.

[0351] As illustrated in Figure 3A, Compound 1 and Compound 2 demonstrated a combination benefit in the KRAS G12D mutant pancreatic cell line, Panc 04.03. As illustrated in Figure 3B, Compound 1 and Compound 2 demonstrated a combination benefit in the KRAS G12D mutant PDAC cell line, HPAC.

[0352] Example 4: In vivo study of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in the KRAS G12D mutant PDAC PDX model, PAN092 Vehicle / control substance, 100 mM acetic acid in deionized water with pH adjusted to 4.8-5.0, was prepared and stored under ambient conditions throughout the 28 days of administration to mice.

[0353] Test article Compound 2 was prepared weekly in a vehicle of 100 mM acetate buffer and stored under ambient conditions. Test article Compound 1 was prepared weekly in a vehicle of 0.5% MC and 0.1% Tween 80 solution and stored under ambient conditions throughout the 28-day administration to mice.

[0354] Female Balb / c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were housed in a vivarium facility with a special pathogen-free (SPF) environment and were allowed to acclimate to their new environment for at least 3 days prior to the start of any experiment. Mice were 6–8 weeks old at the time of implantation. All procedures related to the handling, care, and treatment of animals in this study were performed in accordance with protocols and guidelines approved by GenenDesign's Institutional Animal Care and Use Committee (iACUC). The animal facility and program are operated under the standards of the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) and are accredited by the International Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all parts of this study performed at GenenDesign complied with research protocols reviewed and approved by the IACUC and applicable standard operating procedures (SOPs).

[0355] Preparation of PDX The PAN092 model was established for a preclinical efficacy study at GenenDesign (Shanghai, China). The PDX model was derived from a 65-year-old Chinese male PDAC patient carrying the KRAS G12D mutation. The KRAS G12D mutation in the PDX model PAN092 was confirmed by whole-exome sequencing and PCR sequencing. Tumor fragments harvested from the PDX model were subcutaneously implanted into the right flank of female Balb / c nude mice. Mice were anesthetized with isoflurane and anesthesia was maintained throughout the implantation procedure. The right flank of the mice was sterilized with appropriate surgical scrubs and alcohol, and aseptic surgical procedures were used. A small skin incision was made using the sharp end of a trocar, and a 1.5 cm subcutaneous pocket along the right chest wall was formed by blunt dissection with the stylet of a 10–12 g trocar needle. The tumor fragments (15–30 mm 3 ) was placed into a trocar needle and advanced into a subcutaneous pocket in the right flank. The trocar incision was closed with sutures or wound clips, which were removed 1 week after closure. 3 When the tumor reached an average volume of 1000 mg / kg, the tumor-bearing mice were randomized into test groups with 8 mice per group. The randomization day was designated as treatment day 0.

[0356] treatment Treatment was initiated on the same day of randomization. The day treatment was initiated was designated treatment day 0. Mice were administered vehicle control solution, 15 mg / kg QD of compound 2, and 30 mg / kg QD of compound 1 by oral administration as monotherapy. The compound 1 + compound 2 treatment group received 30 mg / kg QD of compound 1 and 15 mg / kg QD of compound 2. The dosing volume of each compound was 5 mL / kg. In the compound 1 + compound 2 treatment group, compound 1 was administered 1 hour after administration of compound 2. The study was terminated on treatment day 28 as defined in the study protocol.

[0357] Compound 1 and Compound 2 demonstrated the benefit of the combination in vivo in the KRAS G12D mutant PDAC PDX model, PAN092, as illustrated by Figure 4. No significant weight changes were observed in the control and treatment groups.

[0358] Example 5: In vivo study of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in the KRAS G12D mutant PDAC PDX model, PAN026 Vehicle / control substance, 100 mM acetic acid in deionized water with pH adjusted to 4.8-5.0, was prepared and stored under ambient conditions throughout the 28 days of administration to mice.

[0359] Test substance Compound 2 was prepared weekly in a vehicle of 100 mM acetate buffer and stored under ambient conditions. Test substance Compound 1 was prepared weekly in a vehicle of 0.5% MC and 0.1% Tween 80 solution and stored under ambient conditions throughout the 28-day administration to mice.

[0360] Female Balb / c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were housed in a vivarium facility with a special pathogen-free (SPF) environment and were allowed to acclimate to their new environment for at least 3 days prior to the start of any experiment. Mice were 6–8 weeks old at the time of implantation. All procedures related to the handling, care, and treatment of animals in this study were performed in accordance with protocols and guidelines approved by GenenDesign's Institutional Animal Care and Use Committee (iACUC). The animal facility and program are operated under the standards of the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) and are accredited by the International Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all parts of this study performed at GenenDesign complied with research protocols reviewed and approved by the IACUC and applicable standard operating procedures (SOPs).

[0361] Preparation of PDX The PAN026 model was established for a preclinical efficacy study at GenenDesign (Shanghai, China). The PDX model was derived from a 58-year-old Chinese male PDAC patient carrying the 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 subcutaneously implanted into the right flank of female Balb / c nude mice. Mice were anesthetized with isoflurane and anesthesia was maintained throughout the implantation procedure. The right flank of the mice was sterilized with appropriate surgical scrubs and alcohol, and aseptic surgical procedures were used. A small skin incision was made using the sharp end of a trocar, and a 1.5 cm subcutaneous pocket along the right chest wall was formed by blunt dissection with the stylet of a 10–12 g trocar needle. The tumor fragments (15–30 mm 3 ) was placed into a trocar needle and advanced into a subcutaneous pocket in the right flank. The trocar incision was closed with sutures or wound clips, which were removed 1 week after closure. 3 When the tumor reached an average volume of 1000 mg / kg, the tumor-bearing mice were randomized into test groups with 8 mice per group. The randomization day was designated as treatment day 0.

[0362] treatment Treatment was initiated on the same day of randomization. The day treatment was initiated was designated treatment day 0. Mice were administered vehicle control solution, compound 2 at 15 mg / kg QD, and compound 1 at 30 mg / kg QD by oral administration as monotherapy. The compound 1 + compound 2 combination treatment group received compound 1 at 30 mg / kg QD and compound 2 at 15 mg / kg QD. The dosing volume of each compound was 5 mL / kg. In the compound 1 + compound 2 combination treatment group, compound 1 was administered 1 hour after administration of compound 2. The study was terminated on treatment day 28 as defined in the study protocol.

[0363] Compound 1 and Compound 2 demonstrated the benefit of the combination in vivo in the KRAS G12D mutant PDAC PDX model, PAN026, as illustrated by Figure 5. No significant weight changes were observed in the control and treatment groups.

[0364] Example 6: In vivo study of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in the NF1 LoF mutant melanoma CDX model, MeWo Vehicle / control substance, 100 mM acetic acid in deionized water with pH adjusted to 4.8-5.0, was prepared and stored under ambient conditions throughout the 28-day administration to mice.

[0365] Test substance Compound 2 was prepared weekly in a vehicle of 100 mM acetate buffer and stored under ambient conditions. Test substance Compound 1 was prepared weekly in a vehicle of 0.5% MC and 0.1% Tween 80 solution and stored under ambient conditions throughout the 28-day administration to mice.

[0366] Female Balb / c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co.,Ltd. Mice were housed in a vivarium facility with a special pathogen-free (SPF) environment and were allowed to acclimate to their new environment for at least 3 days prior to the start of any experiment. Mice were 6-8 weeks old at the time of implantation. All procedures related to the handling, care, and treatment of animals in this study were performed in accordance with protocols and guidelines approved by GenenDesign's Institutional Animal Care and Use Committee (iACUC). The animal facility and program are operated under the standards of the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) and are accredited by the International Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all parts of this study performed at GenenDesign complied with research protocols reviewed and approved by the IACUC and applicable standard operating procedures (SOPs).

[0367] Preparation of CDX MeWo is a genetic variant of the NF1LOF mutation (NF1 Q1336 * ) was a human melanoma cell line carrying the MeWo gene. The MeWo cell line was purchased from the American Type Culture Collection (ATCC® HTB-65™). MeWo cells were cultured in medium containing Minimum Essential Medium (MEM) and 10% fetal bovine serum (FBS) at 37°C in an atmosphere of 5% CO2 in air. The medium was refreshed every 2-3 days, and tumor cells were routinely passaged at 80-90% confluence by trypsin-EDTA. Cells growing in the exponential growth phase were harvested and counted for inoculation. MeWo tumor cells were implanted subcutaneously into mice. 5 × 10 6 200 μL of cell suspension containing tumor cells was subcutaneously implanted into the right flank of the mice using a syringe. Animal health and tumor growth were monitored daily. Tumor volumes were measured twice weekly by caliper when tumors were palpable and measurable. Tumor volumes averaged 195 mm 3 When the tumor-bearing mice reached 0.5 mg / kg / day, the tumor-bearing mice were randomized into different groups with 8 mice in each group. The randomization day was designated as treatment day 0.

[0368] treatment Treatment was initiated on the same day of randomization. The day treatment was initiated was designated treatment day 0. Mice were administered vehicle control solution, compound 2 at 15 mg / kg QD, and compound 1 at 30 mg / kg QD by oral administration as monotherapy. The compound 1 + compound 2 combination treatment group received compound 1 at 30 mg / kg QD and compound 2 at 15 mg / kg QD. The dosing volume of each compound was 5 mL / kg. In the compound 1 + compound 2 combination treatment group, compound 1 was administered 1 hour after administration of compound 2. The study was terminated on treatment day 28 as defined in the study protocol.

[0369] Compound 1 and Compound 2 demonstrated the benefit of the combination in vivo in the NF1 LoF mutant melanoma CDX model, MeWo, as illustrated by Figure 6. No significant weight changes were observed in the control and treatment groups.

[0370] Example 7: In vivo study of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in the KRAS G13D mutant CRC CDX model, LoVo Vehicle / control substance, 100 mM acetic acid in deionized water with pH adjusted to 4.8-5.0, was prepared and stored under ambient conditions throughout the 28-day administration to mice.

[0371] Test substance Compound 2 was prepared weekly in a vehicle of 100 mM acetate buffer and stored under ambient conditions. Test substance Compound 1 was prepared weekly in a vehicle of 0.5% MC and 0.1% Tween 80 solution and stored under ambient conditions throughout the 28-day administration to mice.

[0372] Female Balb / c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co.,Ltd. Mice were housed in a vivarium facility with a special pathogen-free (SPF) environment and were allowed to acclimate to their new environment for at least 3 days prior to the start of any experiment. Mice were 6-8 weeks old at the time of implantation. All procedures related to the handling, care, and treatment of animals in this study were performed in accordance with protocols and guidelines approved by GenenDesign's Institutional Animal Care and Use Committee (iACUC). The animal facility and program are operated under the standards of the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) and are accredited by the International Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all parts of this study performed at GenenDesign complied with research protocols reviewed and approved by the IACUC and applicable standard operating procedures (SOPs).

[0373] Preparation of CDX LoVo is a human CRC cell line harboring the 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 refreshed every 2-3 days, and tumor cells were routinely passaged at 80-90% confluency. Cells growing in exponential phase were harvested using trypsin-EDTA, counted for inoculation, and then subcutaneously implanted into mice. 2 × 10 6 200 μL of cell suspension containing tumor cells was subcutaneously implanted into the right flank of the mice using a syringe. Animal health and tumor growth were monitored daily. Tumor volumes were measured twice weekly by caliper when tumors were palpable and measurable. Tumor volumes averaged 190 mm 3 When the tumor-bearing mice reached 0.5 mg / kg / day, the tumor-bearing mice were randomized into different groups with 8 mice in each group. The randomization day was designated as treatment day 0.

[0374] treatment Treatment was initiated on the same day of randomization. The day treatment was initiated was designated treatment day 0. Mice were administered vehicle control solution, compound 2 at 15 mg / kg QD, and compound 1 at 30 mg / kg QD by oral administration as monotherapy. The compound 1 + compound 2 combination treatment group received compound 1 at 30 mg / kg QD and compound 2 at 15 mg / kg QD. The dosing volume of each compound was 5 mL / kg. In the compound 1 + compound 2 combination treatment group, compound 1 was administered 1 hour after administration of compound 2. The study was terminated on treatment day 28 as defined in the study protocol.

[0375] Compound 1 and Compound 2 demonstrated the benefit of the combination in vivo in the KRAS G13D mutant CRC CDX model, LoVo, as illustrated by Figure 7. No significant weight changes were observed in the control and treatment groups.

[0376] Example 8 - In vitro study of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in the KRAS G12V mutant PDAC cell line, Capan-2, in a 4-day clonogenic assay Capan-2 cells were seeded in 12-well plates at a density of 4000 cells / well and allowed to adhere overnight (see table below). The following day, compounds were added to the wells in 1 mL of medium. After 7 days of incubation, the medium was replaced with fresh medium containing vehicle or compound. After 14 days of incubation, cells were washed twice with 1×PBS and fixed with 4% formaldehyde for 30 minutes, then washed twice with 1×PBS. Cells were stained with 0.1% crystal violet for 60 minutes, then washed five times with 1×PBS. Plates were dried at room temperature for 2 hours and imaged. Cells were then destained with 10% acetic acid and absorbance was measured using the BCA protocol or absorbance at 560 nm.

[0377] As illustrated by FIG. 8, Compound 1 and Compound 2 demonstrated combination benefit in the KRAS G12V mutant PDAC cell line, Capan-2.

[0378] Example 9-1 In vitro study of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in the KRAS G12V mutant PDAC cell line, Panc 10.05, in a 4-day clonogenic assay Panc 10.05 cells were seeded in 12-well plates at a density of 2000 cells / well and allowed to adhere overnight (see table below). The following day, compounds were added to the wells in 1 mL of medium. After 7 days of incubation, the medium was replaced with fresh medium containing vehicle or compound. After 14 days of incubation, cells were washed twice with 1×PBS and fixed with 4% formaldehyde for 30 minutes, then washed twice with 1×PBS. Cells were stained with 0.1% crystal violet for 60 minutes, then washed five times with 1×PBS. Plates were dried at room temperature for 2 hours and imaged. Cells were then destained with 10% acetic acid and absorbance was measured using the BCA protocol or absorbance at 560 nm.

[0379] As illustrated by FIG. 9, Compound 1 and Compound 2 demonstrated combination benefit in the KRAS G12V mutant PDAC cell line, Panc 10.05.

[0380] Example 10-In vitro study of Compound 1 alone, Compound 2 alone, and the combination of Compound 1 + Compound 2 in the KRAS G12V mutant PDAC cell line, Panc 1, in a clonogenic assay over 14 days Panc-1 cells were seeded in 12-well plates at a density of 4000 cells / well and allowed to adhere overnight (see table below). The following day, compounds were added to the wells in 1 mL of medium. After 7 days of incubation, the medium was replaced with fresh medium containing vehicle or compound. After 14 days of incubation, cells were washed twice with 1×PBS and fixed with 4% formaldehyde for 30 minutes, then washed twice with 1×PBS. Cells were stained with 0.1% crystal violet for 60 minutes, then washed five times with 1×PBS. Plates were dried at room temperature for 2 hours and imaged. Cells were then destained with 10% acetic acid and absorbance was measured using the BCA protocol or absorbance at 560 nm.

[0381] As illustrated by FIG. 10, Compound 1 and Compound 2 demonstrated combination benefit in the KRAS G12V mutant PDAC cell line, Panc 1.

Claims

1. In the manufacture of a medicament for treating cancer in a subject in need of cancer treatment, (i) Compound 1 【Chemical 1】 or a pharmaceutically acceptable salt thereof, and (ii) Compound 2 【Chemical 2】 or a pharmaceutically acceptable salt thereof, wherein a therapeutically effective amount of said medicament is administered to said subject in need of cancer treatment.

2. The use according to claim 1, wherein said Compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 30 mg / day to about 300 mg / day.

3. The use according to claim 1, wherein the pharmaceutically acceptable salt of said Compound 1 is mandelate.

4. The use according to claim 1, wherein said cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer, a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

5. The use according to claim 1, wherein said cancer comprises at least one cancer cell driven by deregulated ERK.

6. The use according to claim 1, wherein said cancer has at least one mutation in RAS, RAF, or MEK.

7. The use according to claim 1, wherein said cancer has a G12C KRAS mutation, a G12D KRAS mutation, a G12S KRAS mutation, a G12V KRAS mutation, a G13D KRAS mutation, a Q16H KRAS mutation, a Q16K KRAS mutation, or a Q61R NRAS mutation.

8. The use according to claim 1, wherein said cancer is a BRAF V600E or V600K mutant tumor.

9. The use according to claim 1, wherein said cancer is MAPKm / MAPKi-naïve pancreatic cancer, or PDAC.

10. The use according to claim 1, wherein said cancer comprises one or more EGFR mutations selected from the group consisting of EGFR gene copy number increase, EGFR gene amplification, chromosome 7 polysomy, EGFR L858R, EGFR exon 19 deletion / EGFR exon 19 insertion, EGFR L861Q, EGFR G719C, EGFR G719S, EGFR G719A, EGFR V765A, EGFR T783A, EGFR exon 20 insertion, EGFR splice variant, EGFR A289D, EGFR A289T, EGFR A289V, EGFR G598A, EGFR G598V, EGFR T790M, and EGFR C797S.

11. The use according to claim 1, wherein said cancer is leukemia.

12. The use according to claim 11, wherein the leukemia is acute myeloid leukemia (AML).

13. The use according to claim 1, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

14. The use according to claim 13, wherein the NSCLC is an EGFR mutation, optionally a G12C, G12D, G12S, G12V, G12A, G13D, Q61H, or Q61K KRAS mutation treated with KRAS, optionally anNRAS Q61R mutation treated with NRAS, and the NSCLC is optionally a MAPKm / MAPKi naive or BRAFi-treated V600 mutation NSCLC.

15. The use according to claim 1, wherein the cancer is pancreatic cancer.

16. The use according to claim 15, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

17. The use according to claim 1, wherein the cancer is melanoma.

18. The use according to claim 17, wherein the melanoma has an NF1 loss-of-function (NF1-LoF) mutation, a BRAF V600E or V600K mutation tumor, or the melanoma is a BRAFi-treated V600 melanoma.

19. The use according to claim 1, wherein the cancer is a salivary gland tumor.

20. The use according to claim 1, wherein the cancer is thyroid cancer.

21. The use according to claim 1, wherein the cancer is colorectal cancer (CRC).

22. The use according to claim 21, wherein the CRC is a BRAF V600E mutation, a G12C, G12D, G12S, G12V, G13D, Q61H, or Q61K mutation, or a Q61R NRAS mutation CRC.

23. The use according to claim 1, wherein the cancer is esophageal cancer.

24. The use according to claim 1, wherein the compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg / day to about 300 mg / day.

25. The use according to claim 1, wherein the compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day (QD), twice a day (BID), three times a day (TID), once a week, or twice a week.

26. The use according to claim 1, wherein the agent further comprises an additional MAPK pathway inhibitor. **Claim 27**: The method according to claim 26, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor, an NRAS inhibitor, an HRAS inhibitor, a PDGFRA inhibitor, a PDGFRB inhibitor, a MET inhibitor, an FGFR inhibitor, an ALK inhibitor, a ROS1 inhibitor, a TRKA inhibitor, a TRKB inhibitor, a TRKC inhibitor, an EGFR inhibitor, an IGF1R inhibitor, a GRB2 inhibitor, a SOS inhibitor, an ARAF inhibitor, a BRAF inhibitor, a RAF1 inhibitor, a MEK1 inhibitor, a MEK2 inhibitor, a c-Myc inhibitor, a CDK4 / 6 inhibitor, a CDK2 inhibitor, an FLT3 inhibitor, or an ERK1 / 2 inhibitor. **Claim 28**: The use according to claim 27, 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 bemrafenib.

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