Malonate and glycolate salts of EGFR inhibitors

Abstract

The present application provides salts and crystalline forms, and polymorphic crystalline forms, compositions thereof, methods for their preparation, and methods for their use, of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 422,365, filed November 3, 2022, U.S. Provisional Application No. 63 / 464,133, filed May 4, 2023, and U.S. Provisional Application No. 63 / 591,670, filed October 19, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] Provided herein are salts and crystalline forms, and polymorphic crystalline forms, compositions thereof, methods for their preparation, and methods of use of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide (hereinafter referred to as “Compound I” or “Compound 1”). [Background technology]

[0003] Compound I is an inhibitor of the epidermal growth factor receptor (EGFR) and is used to treat various cancers in individuals, including humans, in need of such treatment. The present disclosure relates to the identification of novel salt forms of Compound I, and novel polymorphic forms of the disclosed salt forms. The disclosed salt forms, and the disclosed polymorphic forms, have physical properties that make them advantageous for the development of Compound I as a therapeutic agent for the treatment of cancer in individuals in need thereof. Summary of the Invention [Means for solving the problem]

[0004] In one aspect, provided herein is a malonate salt of Formula (I).

[0005] In one aspect, provided herein is a glycolate salt of Formula (I).

[0006] In another aspect, provided herein are compositions containing the malonate or glycolate salts of Compound I described herein.

[0007] In another aspect, provided herein is a method of treating cancer using a malonate or glycolate salt of Compound I in an individual in need thereof.

[0008] In another aspect, provided herein is a method of using a malonate or glycolate salt of Compound I, or a pharmaceutical composition comprising such salts, in the treatment of cancer in an individual in need thereof.

[0009] In another aspect, provided herein is a method of using a malonate or glycolate salt of Compound I, or a pharmaceutical composition comprising such salts, in the manufacture of a medicament for treating cancer in an individual in need thereof.

[0010] In another aspect, provided herein is a method for preparing a malonate or glycolate salt of Compound I.

[0011] Various embodiments are contemplated herein. For example, in embodiment 1, there is provided a malonate salt of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0012] Embodiment 2: The malonate salt of embodiment 1, wherein the salt is a hemimalonate salt.

[0013] Embodiment 3: The malonate salt of embodiment 1 or embodiment 2, wherein the salt is in a crystalline form.

[0014] Embodiment 4: The malonate salt of embodiment 3, wherein the crystalline form of the salt retains at least 95% of the crystalline form after storage in an open container at 40° C. and 75% relative humidity for at least 7 days, wherein the amount of crystalline form of the salt is measured by XRPD.

[0015] Embodiment 5: The malonate salt of embodiment 4, wherein the crystalline form of the salt retains at least 95% of the crystalline form after storage in an open container at 40° C. and 75% relative humidity for at least 14 days, wherein the amount of crystalline form of the salt is measured by XRPD.

[0016] Embodiment 6: The malonate salt of any one of embodiments 2-5, wherein the crystalline form of the salt retains at least 95% of the crystalline form after storage in a closed container at 40° C. and 75% relative humidity for at least 7 days, wherein the amount of crystalline form of the salt is measured by XRPD.

[0017] Embodiment 7: The malonate salt of any one of embodiments 2-6, wherein the crystalline form of the salt retains at least 95% of its crystalline form after storage in a closed container at 40° C. and 75% relative humidity for at least 14 days, wherein the amount of crystalline form of the salt is measured by XRPD.

[0018] Embodiment 8: The malonate salt of any one of embodiments 1-7, wherein the malonate salt has a pH of about 4.5 and a solubility, calculated as the amount of free base of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, of greater than about 2 mg / mL in aqueous solution at a temperature of about 37° C.

[0019] Embodiment 9: The malonate salt of any one of embodiments 1-8, wherein the malonate salt has a pH of about 2.9 and a solubility, calculated as the amount of free base of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, of greater than about 2 mg / mL in aqueous solution at a temperature of about 37° C.

[0020] Embodiment 10: The malonate salt of any one of embodiments 3 to 9, wherein the malonate salt exhibits an XRPD pattern comprising a peak at 5.9±0.2 degrees 2θ.

[0021] Embodiment 11: The malonate salt of embodiment 10, further comprising a peak at 6.8±0.2 degrees 2θ in said XRPD pattern.

[0022] Embodiment 12: The malonate salt of embodiment 11, further comprising a peak at 16.0±0.2 degrees 2θ in said XRPD pattern.

[0023] Embodiment 13: The malonate salt of embodiment 12, further comprising peaks at 17.1±0.2, 19.0±0.2, and 21.6±0.2 degrees two-theta in the XRPD pattern.

[0024] Embodiment 14: The malonate salt of embodiment 13, further comprising peaks at 12.2±0.2, 20.5±0.2, and 23.7±0.2 degrees two-theta in the XRPD pattern.

[0025] Embodiment 15: The malonate salt of any one of embodiments 1 to 14, wherein the malonate salt exhibits a differential scanning calorimetry trace comprising a peak at about 147°C to about 151°C.

[0026] Embodiment 16: A crystalline form of a malonate salt of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 5.9±0.2 degrees two-theta, and (b) a differential scanning calorimetry trace comprising a peak from about 147° C. to about 151° C.

[0027] Embodiment 17: The malonate salt of embodiment 16, further comprising a peak at 6.8±0.2 degrees 2θ in said XRPD pattern.

[0028] Embodiment 18: The malonate salt of embodiment 17, further comprising a peak at 16.0±0.2 degrees 2θ in said XRPD pattern.

[0029] Embodiment 19: The malonate salt of embodiment 18, further comprising peaks at 17.1±0.2, 19.0±0.2, and 21.6±0.2 degrees two-theta in the XRPD pattern.

[0030] Embodiment 20: The malonate salt of embodiment 19, further comprising peaks at 12.2±0.2, 20.5±0.2, and 23.7±0.2 degrees two-theta in said XRPD pattern.

[0031] Embodiment 21: The malonate salt of any one of embodiments 16-20, wherein the malonate salt has a pH of about 4.5 and a solubility, calculated as the amount of the free base of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, of greater than about 2 mg / mL in aqueous solution at a temperature of about 37° C.

[0032] Embodiment 22: The malonate salt of any one of embodiments 16-21, wherein the malonate salt has a pH of about 2.9 and a solubility, calculated as the amount of free base of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, of greater than about 2 mg / mL in aqueous solution at a temperature of about 37° C.

[0033] Embodiment 23: (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide glycolate salt.

[0034] Embodiment 24: The glycolate salt of embodiment 23, wherein the salt is a hemiglycolate salt.

[0035] Embodiment 25: The glycolate salt of embodiment 23 or embodiment 24, wherein the salt is in a crystalline form.

[0036] Embodiment 26: The glycolate salt of embodiment 25, wherein the glycolate salt exhibits an XRPD pattern comprising a peak at 14.1±0.2 degrees two-theta.

[0037] Embodiment 27: The glycolate salt of embodiment 26, further comprising a peak at 19.4±0.2 degrees two-theta in the XRPD pattern.

[0038] Embodiment 28: The glycolate salt of embodiment 27, further comprising a peak at 20.1±0.2 degrees two-theta in the XRPD pattern.

[0039] Embodiment 29: The glycolate salt of embodiment 28, further comprising peaks at 5.4±0.2, 9.6±0.2, 13.0±0.2, 15.5±0.2, and 22.4±0.2 degrees two-theta in the XRPD pattern.

[0040] Embodiment 30: The glycolic acid salt of any one of embodiments 23 to 29, wherein the glycolic acid salt exhibits a differential scanning calorimetry trace comprising a peak at about 162°C to about 165°C.

[0041] Embodiment 31: The glycolate salt of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide in a crystalline form, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 14.1±0.2 degrees two-theta, and (b) a differential scanning calorimetry trace comprising a peak from about 162° C. to about 165° C.

[0042] Embodiment 32: The glycolate salt of embodiment 31, further comprising a peak at 20.1±0.2 degrees two-theta in the XRPD pattern.

[0043] Embodiment 33: The glycolate salt of embodiment 32, further comprising peaks at 5.4±0.2, 9.6±0.2, 13.0±0.2, 14.1±0.2, 15.5±0.2, and 22.4±0.2 degrees two-theta in the XRPD pattern.

[0044] Embodiment 34: A pharmaceutical composition comprising the malonate salt of any one of embodiments 1 to 22 and a pharmaceutically acceptable carrier.

[0045] Embodiment 34: A pharmaceutical composition comprising the glycolic acid salt of any one of embodiments 23 to 33 and a pharmaceutically acceptable carrier.

[0046] Embodiment 36: A method of treating cancer in an individual in need thereof, comprising administering to the individual (a) a malonate salt of any one of embodiments 1 to 22, (b) a glycolate salt of any one of embodiments 22 to 33, (c) a pharmaceutical composition of embodiment 34, or (d) a pharmaceutical composition of embodiment 35.

[0047] Embodiment 37: The method of embodiment 36, wherein the cancer comprises a mutation in epidermal growth factor receptor (EGFR), or one or more wild-type or mutant kinases selected from ERBB2 and ERBB4.

[0048] Embodiment 38: The method of embodiment 36 or 37, wherein the cancer is non-small cell lung cancer, and the cancer is determined to contain one or more mutations selected from: (a) an EGFR exon 20 insertion mutation, (b) a HER2 exon 20 insertion mutation, and (c) HER2 amplification or overexpression.

[0049] Embodiment 39: The method of embodiment 36 or 37, wherein the cancer is non-small cell lung cancer, and the cancer is determined to contain one or more mutations selected from: (a) an EGFR exon 20 insertion mutation, and (b) a HER2 exon 20 insertion mutation.

[0050] Embodiment 40: The method of embodiment 36 or 37, wherein the cancer has been determined to contain one or more mutations selected from (a) an EGFR exon 20 insertion mutation, (b) a HER2 exon 20 insertion mutation, and (c) HER2 amplification or overexpression, using an FDA-approved test.

[0051] Embodiment 41: The method of embodiment 36 or 37, wherein the cancer is non-small cell lung cancer, and the cancer has been determined to contain one or more mutations selected from (a) an EGFR exon 20 insertion mutation, (b) a HER2 exon 20 insertion mutation, and (c) HER2 amplification or overexpression, using an FDA-approved test.

[0052] Embodiment 42: The method of embodiment 36 or 37, wherein the cancer in the individual has been determined to contain one or more mutations selected from: (a) an EGFR exon 20 insertion mutation, and (b) a HER2 exon 20 insertion mutation, by use of any nucleic acid-based diagnostic test.

[0053] Embodiment 43: The method of embodiment 36 or 37, wherein the cancer in the individual is non-small cell lung cancer, and the cancer has been determined to contain one or more mutations selected from: (a) an EGFR exon 20 insertion mutation, and (b) a HER2 exon 20 insertion mutation, by use of any nucleic acid-based diagnostic test.

[0054] Embodiment 44: The method of embodiment 36 or 37, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more EGFR exon 20 insertion mutations or one or more HER2 exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed during or after platinum-based chemotherapy.

[0055] Embodiment 45: The method of embodiment 36 or 37, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more EGFR exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed during or after platinum-based chemotherapy.

[0056] Embodiment 46: The method of embodiment 36 or 37, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more HER2 exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed during or after platinum-based chemotherapy.

[0057] Embodiment 47: The method of embodiment 36 or 37, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more EGFR exon 20 insertion mutations or one or more HER2 exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed after a previous EGFR exon 20 insertion therapy or HER2 exon 20 insertion therapy.

[0058] Embodiment 48: The method of embodiment 36 or 37, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more EGFR exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed after prior EGFR exon 20 insertion mutation therapy.

[0059] Embodiment 49: The method of embodiment 36 or 37, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more HER exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed after a prior HER exon 20 insertion mutation therapy.

[0060] Embodiment 50: The method of any one of embodiments 36 to 38, wherein the cancer comprises one or more mutations in ERBB2 selected from the group consisting of EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, EGFR exon 20 ins ASV, and Her2 exon 20 ins YVMA.

[0061] Embodiment 51: The cancer is selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, epithelial ovarian cancer, ovarian germ cell cancer, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal cancer, kidney cancer, heart cancer, duodenal cancer, 39. The method of any one of embodiments 36-38, wherein the cancer is selected from the group consisting of malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, Wilms' carcinoma, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain tumor, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

[0062] Embodiment 52: The method of embodiment 51, wherein the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.

[0063] Embodiment 53: The method of embodiment 52, wherein the cancer is a metastatic brain tumor.

[0064] Embodiment 54: The method of embodiment 52, wherein the cancer is breast cancer.

[0065] Embodiment 55: The method of embodiment 52, wherein the cancer is non-small cell lung cancer.

[0066] Embodiment 56: The method of any one of embodiments 38, 40, or 41, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein.

[0067] Embodiment 57: The method of embodiment 56, wherein the cancer of the individual has been identified as containing HER2 amplification or overexpression by the use of immunohistochemistry (IHC) or in situ hybridization (ISH) testing.

[0068] Embodiment 58: The method of any one of embodiments 36 to 57, wherein the cancer is a locally advanced cancer.

[0069] Embodiment 59: The method of any one of embodiments 36 to 57, wherein the cancer is a metastatic solid tumor.

[0070] Embodiment 60: The method of any one of embodiments 36 to 59, wherein the cancer is unresectable.

[0071] Embodiment 61: The method of any one of embodiments 36 to 60, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).

[0072] Embodiment 62: The method of any one of embodiments 36, 38, 40, 41, and 50-61, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein.

[0073] Embodiment 63: The method of any one of embodiments 36, 38, 40, 41, and 50-62, wherein the cancer has been determined to exhibit one or more of (i)-(v) prior to administration of the salt or pharmaceutical composition: (i) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer reveals at least six copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (ii) a dual-probe ISH test performed on a sample from said cancer shows a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8; (iii) a dual-probe ISH test performed on a sample from the cancer shows (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of centromeres of chromosome 17 per interphase nucleus of at least 2.0, and (b) at least four copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (iv) an immunohistochemistry (IHC) test performed on a sample from said cancer shows at least 10% of cancer cells to be 3+ positive; or (v) (a) an immunohistochemistry (IHC) test performed on a sample derived from the cancer reveals at least 10% of cancer cells as 2+ positive, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer yields a positive result.

[0074] Embodiment 64: The method of any one of embodiments 36-45, 47, 48, 50-55, and 58-61, wherein the cancer comprises one or more mutations in the epidermal growth factor receptor (EGFR) protein.

[0075] Embodiment 65: The one or more mutations in the EGFR protein are G309A, G309E, S310F, R678Q, R678Q and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR del 19, EGFR L858R / C797S, EGFR del19 / C797S, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, and EGFR exon 20 ins 65. The method of embodiment 64, comprising one or more mutations selected from the group consisting of ASV.

[0076] Embodiment 66: The method of any one of embodiments 36-44, 46, 47, 49, 51-55, and 58-61, wherein the cancer comprises one or more mutations in the HER2 protein, and the one or more mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG.

[0077] Embodiment 67: The method of any one of embodiments 36 to 66, wherein the cancer does not comprise an EGFR T790M mutation.

[0078] Embodiment 68: The method of any one of embodiments 36-43 and 50-67, wherein the individual has not undergone one or more prior therapies for the treatment of the cancer prior to administration of the salt or pharmaceutical composition to the individual.

[0079] Embodiment 69: The method of embodiment 68, wherein the individual has not received prior therapy for the treatment of the cancer with an EGFR exon 20 mutation inhibitor prior to administration of the salt or pharmaceutical composition to the individual.

[0080] Embodiment 70: The method of embodiment 69, wherein the cancer is non-small cell lung cancer and the individual has not received prior therapy for the treatment of the cancer with an EGFR exon 20 mutation inhibitor prior to administering the salt or pharmaceutical composition to the individual.

[0081] Embodiment 71: The method of any one of embodiments 36-46 and 49-70, wherein the individual has not received treatment with an EGFR exon 20 mutation inhibitor prior to administering the salt or pharmaceutical composition to the individual.

[0082] Embodiment 72: The method of any one of embodiments 36-52 and 55-70, wherein the cancer is non-small cell lung cancer and the individual has not been treated with an EGFR exon 20 mutation inhibitor prior to administering the salt or pharmaceutical composition to the individual.

[0083] Embodiment 73: The method of any one of embodiments 36 to 67, wherein the individual has undergone one or more prior therapies for the treatment of the cancer prior to administration of the salt or pharmaceutical composition to the individual.

[0084] Embodiment 74: The method of any one of embodiments 36 to 67, wherein the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer prior to administration of the salt or pharmaceutical composition to the individual.

[0085] Embodiment 75: The method of any one of embodiments 36-52, 55-67, 73, and 74, wherein the cancer is non-small cell lung cancer and the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer prior to administering the salt or pharmaceutical composition to the individual.

[0086] Embodiment 76: The method of any one of embodiments 36 to 74, wherein the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer prior to administration of the salt or the pharmaceutical composition to the individual, and the individual is further administered a bispecific EGF receptor-directed and MET receptor-directed antibody.

[0087] Embodiment 77: The method of any one of embodiments 36 to 52, 55 to 67, and 73 to 76, wherein the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer prior to administration of the salt or the pharmaceutical composition to the individual, wherein the cancer is non-small cell lung cancer, and wherein the individual is further administered a bispecific EGF receptor-directed and MET receptor-directed antibody.

[0088] Embodiment 78: The method of embodiment 77, wherein the bispecific EGF receptor-directed and MET receptor-directed antibody is amivantamab.

[0089] Embodiment 79: The method of any one of embodiments 36-52, 58-67, and 73-78, wherein (a) the cancer is non-small cell lung cancer; and (b) the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for treatment of the cancer prior to administration of the salt or the pharmaceutical composition to the individual, and the individual is further administered amivantamab.

[0090] Embodiment 80: The method of any one of embodiments 36-52, 58-67, and 73-75, wherein the individual has received one or more prior therapies for the treatment of the cancer prior to administering the salt or the pharmaceutical composition to the individual, and the one or more prior therapies comprise an EGFR exon 20 mutation inhibitor and a bispecific EGF receptor-directed and MET receptor-directed antibody.

[0091] Embodiment 81: The method of any one of embodiments 36-52, 58-67, and 73-80, wherein the cancer is non-small cell lung cancer, and the individual has received one or more prior therapies for the treatment of the cancer before administering the salt or the pharmaceutical composition to the individual, and the one or more prior therapies include an EGFR exon 20 mutation inhibitor and a bispecific EGF receptor-directed and MET receptor-directed antibody.

[0092] Embodiment 82: The method of any one of embodiments 36-52, 58-67, and 73-81, wherein prior to administering the salt or the pharmaceutical composition to the individual, the individual has received one or more prior therapies for the treatment of the cancer, and the one or more prior therapies include an EGFR exon 20 mutation inhibitor and amivantamab.

[0093] Embodiment 83: The method of any one of embodiments 36-52, 58-67, and 73-82, wherein the cancer is non-small cell lung cancer and the individual has received one or more prior therapies for the treatment of the cancer prior to administering the salt or the pharmaceutical composition to the individual, wherein the one or more prior therapies comprise an EGFR exon 20 mutation inhibitor and amivantamab.

[0094] Embodiment 84: The method of embodiment 73, wherein the one or more prior therapies comprise one or more anti-HER2-based regimens.

[0095] Embodiment 85: The method of embodiment 84, wherein the one or more anti-HER2-based regimens are administered to the individual in a metastatic state.

[0096] Embodiment 86: The method of any one of embodiments 84-85, wherein the individual has failed the one or more prior therapies prior to administration of the salt or the pharmaceutical composition to the individual.

[0097] Embodiment 87: The method of embodiment 73, wherein prior to administering the salt or pharmaceutical composition to the individual, the individual has failed one or more prior therapies, and the one or more prior therapies are selected from: (a) a bispecific EGF receptor-directed and MET receptor-directed antibody, and (b) chemotherapy.

[0098] Embodiment 88: The method of embodiment 73, wherein the one or more prior therapies comprises a bispecific EGF receptor-directed and MET receptor-directed antibody that is amivantamab.

[0099] Embodiment 89: The method of embodiment 73, wherein the one or more prior therapies comprises chemotherapy.

[0100] Embodiment 90: The method of embodiment 89, wherein the one or more prior therapies comprising chemotherapy comprise platinum-based chemotherapy.

[0101] Embodiment 91: The method of embodiment 89, wherein the one or more prior therapies comprising chemotherapy do not include platinum-based chemotherapy.

[0102] Embodiment 92: The method of any one of embodiments 36-38, 40, 41, 51-63, and 67-91, wherein the cancer comprises overexpression of HER2.

[0103] Embodiment 93: The method of embodiment 92, wherein the cancer sample shows HER2 expression of 3+ when examined using an immunohistochemistry (IHC) test.

[0104] Embodiment 94: The method of any one of embodiments 36, 37, 42-55, 58-61, and 64-91, wherein the cancer does not involve overexpression of HER2.

[0105] Embodiment 95: The method of any one of embodiments 36-38, 40, 41, 51-63, and 67-91, wherein the cancer comprises an amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein.

[0106] Embodiment 96: The method of any one of embodiments 36, 37, 42-55, 58-61, and 64-91, wherein the cancer does not comprise an amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein.

[0107] Embodiment 97: The method of any one of embodiments 36 to 96, wherein the method further comprises administering one or more additional anti-cancer agents to the individual in need thereof.

[0108] Embodiment 98: The method of embodiment 73, wherein the one or more additional anticancer agents comprise one or more agents selected from a HER2 inhibitor, a HER2-CD3 bispecific antibody, a HER2 immunotargeting bispecific antibody, an anti-HER2 chimeric antigen receptor (CAR) T cell, an anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocyte (CTL), an anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cell, an anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cell, an epidermal growth factor receptor (EGFR) inhibitor, a poly-ADP-ribose polymerase (PARP) inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and a chemotherapeutic agent.

[0109] Embodiment 99: The method of embodiment 97, wherein the one or more additional anticancer agents comprise a bispecific EGF receptor-directed and MET receptor-directed antibody.

[0110] Embodiment 100: The method of embodiment 99, wherein the bispecific EGF receptor-directed and MET receptor-directed antibody is amivantamab.

[0111] Embodiment 101: The one or more additional anticancer agents are trastuzumab, trastuzumab and hyaluronidase, capecitabine, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, margetuximab, trastuzumab emtansine, trastuzumab dealuxtecan, ZW49 (Zymeworks), A166 (Krauss Pharma), ARX788 (Ambrix), RC48-ADC (Remegen), vic-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, nekitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, bevacizumab 98. The method of embodiment 97, wherein the agent is selected from the group consisting of riparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemipilimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189.

[0112] Embodiment 102: The method of embodiment 97, wherein the one or more additional anticancer agents are selected from antibody-drug conjugates.

[0113] Embodiment 103: The method of embodiment 102, wherein the antibody-drug conjugate is selected from trastuzumab emtansine and trastuzumab deruxtecan.

[0114] Embodiment 104: The method of embodiment 97, wherein the one or more additional anti-cancer agents comprise one or more chemotherapeutic agents.

[0115] Embodiment 105: The method of embodiment 104, wherein the one or more chemotherapeutic agents are selected from the group consisting of doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxiplatin, and eribulin.

[0116] Embodiment 106: The method of embodiment 105, wherein the one or more additional anticancer agents comprise trastuzumab and capecitabine.

[0117] Embodiment 107: The method of any one of embodiments 36 to 106, wherein the method further comprises treating the individual in need thereof with radiation.

[0118] Embodiment 108: The method of any one of embodiments 36 to 107, wherein the method further comprises identifying the individual based on said individual having a HER2-amplified or HER2-overexpressing cancer.

[0119] Embodiment 109: The method of any one of embodiments 36 to 108, wherein the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein.

[0120] Embodiment 110: The method of embodiment 109, wherein the mutations in the PIK3CA protein comprise one or more mutations at histidine 1047.

[0121] Embodiment 111: The method of embodiment 110, wherein said mutation at histidine 1047 in said PIK3CA protein is selected from H1047L and H1047R.

[0122] Embodiment 112: The method according to any one of embodiments 36 to 111, wherein (a) the malonate salt according to any one of embodiments 1 to 22, (b) the glycolate salt according to any one of embodiments 22 to 33, (c) the pharmaceutical composition according to embodiment 34, or (d) the pharmaceutical composition according to embodiment 35 is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to the individual in need thereof.

[0123] Embodiment 113: The individual receives (a) more than 10 mg but less than about 45 mg, (b) more than about 45 mg but less than about 200 mg, (c) between about 45 mg and about 60 mg, (d) between about 45 mg and about 90 mg, (e) between about 45 mg and about 120 mg, (f) about 45 mg, or (g) about 60 mg 113. The method of any one of embodiments 36-112, wherein the salt or pharmaceutical composition is administered in an amount providing a total daily dose of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide selected from: (h) about 75 mg, (i) about 80 mg, (j) about 90 mg, (k) about 100 mg, (l) about 120 mg, (m) about 150 mg, (n) about 175 mg, (o) about 200 mg, and (p) greater than about 120 mg but less than about 200 mg.

[0124] Embodiment 114: An individual receives a dose of (a) greater than 10 mg but less than about 45 mg, (b) greater than about 45 mg but less than about 200 mg, (c) between about 45 mg and about 60 mg, (d) between about 45 mg and about 90 mg, (e) between about 45 mg and about 120 mg, (f) about 45 mg, (g) about 60 mg, (h) about 75 mg, (i) about 80 mg, (j) about 90 mg, (k) about 100 mg, (l) about 120 mg, (m) about 150 mg, (n) about 175 mg, (o) about 200 mg, and (p 114. The method of any one of embodiments 36-113, wherein the malonate salt is administered in an amount providing a total daily dose of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide selected from greater than about 120 mg and less than about 200 mg.

[0125] Embodiment 115: The method of any one of embodiments 36 to 114, wherein the individual is administered the malonate or the pharmaceutical composition in an amount that is about 30 mg BID, about 40 mg BID, about 45 mg QD, about 50 mg BID, about 60 mg QD, about 75 mg QD, about 90 mg QD, or about 120 mg QD.

[0126] Embodiment 116: The method of any one of embodiments 36 to 91, wherein the individual is administered the malonate salt or the pharmaceutical composition in an amount that provides a mean unbound concentration of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide in the individual's plasma of 0.1 nM for at least 8 hours after administration of the salt or pharmaceutical composition to the individual.

[0127] Embodiment 117: The method of any one of embodiments 36 to 116, wherein the individual is a human.

[0128] Embodiment 118: The method of any one of embodiments 36 to 117, wherein the individual achieves stable disease, a partial response, or a complete response in the individual's target tumor according to RECIST 1.1.

[0129] Embodiment 119: The method of embodiment 118, wherein said response according to RECIST 1.1 is a partial response or a complete response.

[0130] Embodiment 120: The method of any one of embodiments 36 to 119, wherein the individual does not experience a grade 3 or grade 4 treatment-related adverse event following administration of the salt or pharmaceutical composition to the individual.

[0131] Embodiment 121: A method for preparing the malonate salt of any one of embodiments 1 to 22, comprising: (1) forming a mixture of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide and malonic acid in a solvent; and (2) removing the solvent from step (1) to obtain the malonate salt.

[0132] Embodiment 122: The method of embodiment 121, wherein the molar ratio of malonic acid to (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 1:1.

[0133] Embodiment 123: The method of embodiment 121, wherein the molar ratio of malonic acid to (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 2:1.

[0134] Embodiment 124: A method for preparing the glycolic acid salt of any one of embodiments 23 to 33, comprising: (1) forming a mixture of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide and glycolic acid in a solvent; and (2) removing the solvent from step (1) to obtain the glycolic acid salt.

[0135] Embodiment 125: The method of embodiment 124, wherein the molar ratio of glycolic acid to (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 1:1.

[0136] Embodiment 126: The method of embodiment 124, wherein the molar ratio of glycolic acid to (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 2:1.

[0137] Embodiment 127: The method of any one of embodiments 121-126, wherein the solvent in step (1) comprises an aprotic solvent or a protic solvent.

[0138] Embodiment 128: The method of embodiment 127, wherein the solvent comprises an aprotic solvent.

[0139] Embodiment 129: The method of embodiment 128, wherein the aprotic solvent is acetone.

[0140] Embodiment 130: The method of embodiment 127, wherein the solvent comprises a protic solvent.

[0141] Embodiment 131: The method of any one of embodiments 121 to 130, wherein the mixture of step (1) is stirred at 23±3°C.

[0142] Embodiment 132: The method of any one of embodiments 121 to 131, wherein removing the solvent comprises vacuum drying.

[0143] Embodiment 133: The method of any one of embodiments 121 to 131, wherein step (2) further comprises centrifugation or vacuum filtration. [Brief explanation of the drawings]

[0144] [Figure 1A] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the malonate salt of Compound I prepared according to Example 1.

[0145] [Figure 1B] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the malonate salt of Compound I prepared according to Example 2.

[0146] [Figure 1C] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the malonate salt of Compound I prepared according to Example 3.

[0147] [Figure 1D] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of the malonate salt of Compound I prepared according to Example 1.

[0148] [Figure 1E] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of the malonate salt of Compound I prepared according to Example 2.

[0149] [Figure 1F] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of the malonate salt of Compound I prepared according to Example 3.

[0150] [Figure 1G] 1 shows the proton nuclear magnetic resonance ( 1 H NMR) spectrum of the malonate salt of Compound I prepared according to Example 1.

[0151] [Figure 1H] 1 shows the proton nuclear magnetic resonance ( 1 H NMR) spectrum of the malonate salt of Compound I prepared according to Example 2.

[0152] [Figure 1I] 1 shows the proton nuclear magnetic resonance ( 1 H NMR) spectrum of the malonate salt of Compound I prepared according to Example 3.

[0153] [Figure 1J] 1 shows a dynamic vapor sorption (DVS) isotherm plot of the malonate salt of Compound I prepared according to Example 1.

[0154] [Figure 2A] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the glycolic acid salt of Compound I.

[0155] [Figure 2B] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of the glycolic acid salt of Compound I.

[0156] [Figure 2C] 1 shows the proton nuclear magnetic resonance ( 1 H NMR) spectrum of the glycolate salt of Compound I.

[0157] [Figure 2D] 1 shows a dynamic vapor sorption (DVS) isotherm plot of the glycolate salt of Compound 1.

[0158] [Figure 3]The bioavailability and concentrations of unbound tucatinib and Compound I in the brain or plasma are provided at 1, 4, and 8 hours after oral administration of a single dose of either tucatinib (50 mg / kg) or Compound I (3 mg / kg) to mice.

[0159] [Figure 4] Figure 1 shows the sensitivity of 25 breast cancer cell lines, including cell lines exhibiting amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein and / or overexpression of HER2 protein, to treatment with Compound I compared to tucatinib and lapatinib, as indicated by the calculated half-maximal effect concentration (EC50).

[0160] [Figure 5A] 1 shows the mean tumor volumes in mice in the Compound 1, Tucatinib, and vehicle control groups after 28 days of treatment in Example 9.

[0161] [Figure 5B] 1 shows tumor volumes in individual mice in the vehicle control group of Example 9.

[0162] [Figure 5C] 1 shows the tumor volumes in individual mice in the Compound 1 group of Example 9.

[0163] [Figure 5D] 1 shows tumor volumes in individual mice in the tucatinib group of Example 9.

[0164] [Figure 5E] The average body weights of mice in the Compound 1 group of Example 9, the Tucatinib group, and the vehicle control group are shown (vehicle group = circles, Compound 1 group = triangles, Tucatinib group = squares).

[0165] [Figure 6]1 shows the mean unbound plasma concentrations of Compound I at steady state from Day 1 of Dosing Cycle 2 in human subjects administered Compound I as described in Example 10. DETAILED DESCRIPTION OF THE INVENTION

[0166] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Furthermore, any methods or materials similar or equivalent to those described herein can be used in the practice of this application. For purposes of this application, the following terms are defined:

[0167] It is understood that embodiments of the present application described herein include "consisting of" and / or "consisting essentially of" the embodiments.

[0168] Reference herein to "about" a value or parameter includes (and describes) a variation about that value or parameter itself. For example, a reference to "about X" includes a reference to "X."

[0169] As used herein, the term "about X to Y" has the same meaning as "about X to about Y." As used herein, the expression "about X, Y, and / or Z" has the same meaning as "about X, about Y, and / or about Z."

[0170] As used herein, reference to "not being" a value or parameter generally means and describes "other than" the value or parameter. For example, not using the method to treat cancer type X means using the method to treat cancer types other than type X.

[0171] As used herein, the terms "a," "an," or "the" include not only embodiments with one member, but also embodiments with more than one member. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, a reference to "the agent" includes a reference to one or more agents known to those of skill in the art, and so forth.

[0172] As used herein, the term "polymorph" or "polymorphic form" refers to a crystalline form of a compound. Different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectra, as a result of the arrangement or conformation of molecules or ions within the crystal lattice. The differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can be due to changes in chemical reactivity (e.g., differences in oxidation, such as a dosage form consisting of one polymorph fading more rapidly than one consisting of another), mechanical changes (e.g., a tablet disintegrating during storage as a kinetically favorable polymorph converts to a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are susceptible to disintegration at high humidity). As a result of differences in solubility / disintegration, some polymorphic transitions may be ineffective at one extreme or toxic at the other. In addition, the physical properties of the crystalline form may be important in processing; for example, some polymorphs may be more likely to form solvates or may be difficult to filter and wash free of impurities (e.g., particle shape and size distribution may differ between polymorphs).

[0173] As used herein, the term "substantially as shown," for example, when referring to an XRPD pattern, DSC graph, TGA graph, or GVS graph, includes patterns or graphs that are not necessarily identical to those shown herein, but that fall within the limits of experimental error or deviation as recognized by one of ordinary skill in the art.

[0174] In some embodiments, the term "substantially pure" means that the salt or polymorphic form contains less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% by weight of impurities. In other embodiments, "substantially pure" refers to a material that is free of impurities. Impurities may include, for example, by-products or residual reagents from chemical reactions, contaminants, degradation products, other salt forms, other polymorphic forms, water, and solvents.

[0175] As used herein, the term "substantially free" means that the composition, including the salt form or polymorphic form, contains less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the specified substance or substances.

[0176] As used herein, "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms attributable to the disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the worsening of the disease), preventing or slowing the spread of the disease (e.g., metastasis), preventing or slowing the recurrence of the disease, reducing the rate of disease recurrence, slowing or delaying the progression of the disease, improving the disease state, providing remission (partial or total) of the disease, reducing the dosage of one or more other drugs required to treat the disease, slowing the progression of the disease, improving quality of life, and / or extending survival. In some embodiments, treatment reduces the severity of one or more symptoms associated with cancer by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to the corresponding symptoms in the same subject before treatment or compared to the corresponding symptoms in another subject not receiving treatment. Alleviation of the pathological consequences of cancer is also encompassed by “treatment.” The methods of the present application contemplate any one or more of these aspects of treatment.

[0177] As used herein, the term "effective amount" refers to an amount of a compound or composition sufficient to treat a particular disorder, condition, or disease, such as improving, alleviating, mitigating, and / or delaying one or more of its symptoms in an individual. With respect to cancer, an effective amount includes an amount sufficient to shrink a tumor and / or reduce the rate of tumor growth (such as an amount sufficient to inhibit tumor growth), or prevent or delay other undesirable cell proliferation of cancer in an individual. In some embodiments, an effective amount is an amount sufficient to delay the onset of cancer in an individual. In some embodiments, an effective amount is an amount sufficient to prevent or delay the recurrence of cancer in an individual. In some embodiments, an effective amount is an amount sufficient to reduce the recurrence rate of cancer in an individual. An effective amount can be administered to an individual in one or more administrations. An effective amount of a drug or composition may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, suppress, slow to some extent, and preferably stop, cancer cell invasion into peripheral organs; (iv) inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay tumor onset and / or recurrence; and / or (vii) alleviate to some extent one or more symptoms associated with cancer.

[0178] As understood in the art, an effective amount may be one or more doses; i.e., a single administration or multiple administrations may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in the context of administration of one or more therapeutic agents, and the compounds or compositions described herein may be, or may be considered to be administered in an effective amount if, optionally in combination with one or more other agents, a desired or beneficial result is achieved. Components of the combination therapy of the present application (e.g., first and second therapies) may be administered sequentially, simultaneously, or concurrently to an individual using the same or different routes of administration for each component. Thus, an effective amount of a combination therapy includes an amount of the first therapy and an amount of the second therapy that, when administered sequentially, simultaneously, or concurrently to an individual, will produce a desired result in that individual.

[0179] As used herein, a "therapeutically effective amount" refers to an amount administered to an individual that produces a desired pharmacological and / or physiological effect for the individual's condition. The effect in the individual may be prophylactic, in that the condition or its symptoms are completely or partially prevented, and / or therapeutic, in that the condition and / or adverse effects resulting from the condition are partially or completely cured.

[0180] As used herein, "individual" means a mammal, including a human, dog, cat, or domestic animal. In one embodiment, "individual" means a human.

[0181] "In conjunction with" or "in combination with" refers to the administration of one therapy in addition to another therapy, e.g., the administration of a compound or composition described herein in addition to the administration of other agents to the same individual under the same treatment regimen. Thus, "in conjunction with" or "in combination with" refers to the administration of one therapy before, during, or after the delivery of another therapy to an individual.

[0182] The term "co-administration," as used herein, means that the first and second therapies in a combination therapy are administered at a time interval of about 15 minutes or less, e.g., about 10 minutes or less, 5 minutes or less, or 1 minute or less. When the first and second therapies are administered at the same time, the first and second therapies may be contained in the same composition (e.g., a composition containing both the first and second therapeutic agents) or may be contained in separate compositions (e.g., the first therapy in one composition and the second therapy in another composition).

[0183] As used herein, the term "sequential administration" means that the first and second therapies in a combination therapy are administered at an interval of more than about 15 minutes, for example, more than about 20 minutes, more than 30 minutes, more than 40 minutes, more than 50 minutes, more than 60 minutes, or more. Either the first or second therapy may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.

[0184] As used herein, the term "co-administration" means that the administration of a first therapy and the administration of a second therapy in a combination therapy overlap with each other.

[0185] As used herein, "pharmaceutically acceptable" or "pharmaceutically compatible" means a material that is biologically or otherwise undesirable; e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients preferably have met the required standards of toxicology and manufacturing testing and / or are listed in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0186] The disclosures of all publications, patents, patent applications and published patent applications mentioned herein are hereby incorporated by reference in their entirety.

[0187] Compound I Compound I is a compound that has been demonstrated to have inhibitory activity against epidermal growth factor receptor (EGFR) mutants and HER2 mutants. The chemical name of Compound I is N-[2-[4-(4-cyclopropyl-1-piperazinyl)-1-piperidinyl]-5-[6-[(3R)-3-(3,5-difluorophenyl)-2-isoxazolidinyl]-4-pyrimidinyl]amino]-4-methoxyphenyl]-2-propenamide. Compound I has the following structure: [ka] Compound I can also be named (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide. Compound I has been assigned the CAS Registry Number 2489185-38-6.

[0188] Compound I is described in WO2020 / 190119 and may be prepared by the methods described therein. The contents of WO2020 / 190119 are incorporated herein by reference for this purpose. Alternatively, Compound I may be prepared by methods known to those skilled in the art.

[0189] salt In one aspect, provided herein are salts of Compound I. Salts may have chemical or physical properties that make them suitable for medical or pharmaceutical uses, such as enhanced bioavailability or stability under certain conditions. References herein to "a salt or pharmaceutical composition provided herein" are understood to refer to a salt of Compound I, including a pharmaceutically acceptable salt of Compound I, or a pharmaceutical composition comprising Compound I, or a salt of Compound I, including a pharmaceutically acceptable salt of Compound I.

[0190] Salts of Compound I may offer bioavailability and stability advantages and may be suitable for use as an active agent in pharmaceutical compositions. Variations in the salt form of a drug substance can affect the drug's dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to prepare uniform doses of known strengths, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.). Such variations can affect the preparation and formulation of pharmaceutical compositions in different dosage and delivery forms, such as solid oral dosage forms, including tablets and capsules. Salt forms of drug substances may provide desirable or preferred hygroscopicity, dissolution rate, solubility, absorption, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Thus, salts of the compound may offer advantages such as improving the manufacturing process of the active agent or the stability or shelf life of the active agent's pharmaceutical form, or having suitable bioavailability and / or stability as the active agent.

[0191] The use of certain conditions, such as the use of different solvents and / or temperatures, has been found to produce different salts of Compound I, and different polymorphs of those salts, including the malonate and glycolate salts described herein, which may exhibit one or more advantageous properties described herein. The processes for preparing the malonate and glycolate salts described herein, as well as the properties of these salts, are described in further detail below.

[0192] Malonate In some embodiments, provided herein is a malonate salt of Compound I.

[0193] In some embodiments, the malonate salt of Compound I is a hemimalonate salt.

[0194] In some embodiments, the malonate salt of Compound I is in a crystalline form.

[0195] In some embodiments, the crystalline form of the malonate salt maintains at least 95% crystalline form after storage in an open container at 40° C. and 75% relative humidity for at least 7 days, as measured by XRPD. In some embodiments, the crystalline form of the malonate salt maintains at least 95% crystalline form (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.25%, at least 99.5%, at least 99.75%, at least 99.8%, or at least 99.9%) after storage in an open container at 40° C. and 75% relative humidity for at least about 7 days (e.g., 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months), as measured by XRPD. In some embodiments, the crystalline form of the malonate salt maintains at least 95% crystalline form after storage in an open container at 40° C. and 75% relative humidity for at least 14 days, as measured by XRPD. In some embodiments, the crystalline form of the malonate salt maintains at least 95% crystalline form (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.25%, at least 99.5%, at least 99.75%, at least 99.8%, or at least 99.9%) after storage in an open container at 40° C. and 75% relative humidity for at least about 14 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months), as measured by XRPD.

[0196] In some embodiments, the crystalline form of the malonate salt maintains at least 95% crystalline form after storage in a closed container at 40° C. and 75% relative humidity for at least 7 days, as measured by XRPD. In some embodiments, the crystalline form of the malonate salt maintains at least 95% crystalline form (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.25%, at least 99.5%, at least 99.75%, at least 99.8%, or at least 99.9%) after storage in a closed container at 40° C. and 75% relative humidity for at least about 7 days (e.g., 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months), as measured by XRPD. In some embodiments, the crystalline form of the malonate salt maintains at least 95% crystalline form after storage in a closed container at 40° C. and 75% relative humidity for at least 14 days, where the amount of crystalline form of the salt is measured by XRPD. In some embodiments, the crystalline form of the malonate salt maintains at least 95% crystalline form (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.25%, at least 99.5%, at least 99.75%, at least 99.8%, or at least 99.9%) after storage in a closed container at 40° C. and 75% relative humidity for at least about 14 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months), where the amount of crystalline form of the salt is measured by XRPD.

[0197] In some embodiments, the malonate salt has a solubility of greater than about 2 mg / mL (e.g., greater than about 2.5 mg / mL, greater than about 2.75 mg / mL, greater than about 3 mg / mL, greater than about 3.25 mg / mL, greater than about 3.5 mg / mL, greater than about 3.75 mg / mL, greater than about 4 mg / mL, greater than about 4.25 mg / mL, greater than about 4.5 mg / mL, greater than about 4.75 mg / mL, or greater than about 5 mg / mL) calculated as the amount of free base of Compound I in an aqueous solution having a pH of about 4.5 and at a temperature of about 37°C. In some embodiments, the malonate salt has a solubility of greater than about 2 mg / mL (e.g., greater than about 2.5 mg / mL, greater than about 2.75 mg / mL, greater than about 3 mg / mL, greater than about 3.25 mg / mL, greater than about 3.5 mg / mL, greater than about 3.75 mg / mL, greater than about 4 mg / mL, greater than about 4.25 mg / mL, greater than about 4.5 mg / mL, greater than about 4.75 mg / mL, or greater than about 5 mg / mL), calculated as the amount of free base of Compound I, in an aqueous solution having a pH of about 2.9 and at a temperature of about 37°C.

[0198] In some embodiments, the malonate salt has an XRPD pattern substantially as shown in Figure 1 A. The angles and peak intensities measured in degrees 2θ that may be observed for the malonate salt using XRPD are shown in Table 1. [Table 1]

[0199] In some embodiments, the malonate salt has an XRPD pattern exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at degrees 2θ with maximum intensity substantially as shown in FIG. 1A or as provided in Table 1. It should be understood that peak intensities may vary depending on many factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to obtain the spectrum. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for malonate salts, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0200] In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 12.2±0.2, 16.0±0.2, 17.1±0.2, 19.0±0.2, 20.5±0.2, 20.9±0.2, 21.6±0.2, 23.7±0.2, and 25.6±0.2 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 12.2±0.2, 16.0±0.2, 17.1±0.2, 19.0±0.2, 21.6±0.2, and 23.7±0.2 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 16.0±0.2, and 17.1±0.2 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 12.2±0.4, 16.0±0.4, 17.1±0.4, 19.0±0.4, 20.5±0.4, 20.9±0.4, 21.6±0.4, 23.7±0.4, and 25.6±0.4 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 12.2±0.4, 16.0±0.4, 17.1±0.4, 19.0±0.4, 21.6±0.4, and 23.7±0.4 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 16.0±0.4, and 17.1±0.4 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 12.2±0.6, 16.0±0.6, 17.1±0.6, 19.0±0.6, 20.5±0.6, 20.9±0.6, 21.6±0.6, 23.7±0.6, and 25.6±0.6 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 12.2±0.6, 16.0±0.6, 17.1±0.6, 19.0±0.6, 21.6±0.6, and 23.7±0.6 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 16.0±0.6, and 17.1±0.6 degrees 2θ.It should be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1A or provided in Table 1 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0201] In some embodiments, the malonate salt has an XRPD pattern substantially as shown in Figure 1B. The angles and peak intensities measured in degrees 2θ that may be observed for the malonate salt using XRPD are shown in Table 2. [Table 2]

[0202] In some embodiments, the malonate salt has an XRPD pattern exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at degrees 2θ with maximum intensity substantially as shown in FIG. 1B or as provided in Table 2. It should be understood that peak intensities may vary depending on many factors, including sample preparation, mounting, and the instrumentation, analytical procedures, and settings used to obtain the spectrum. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for malonate salts, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0203] In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 10.8±0.2, 12.2±0.2, 13.9±0.2, 16.0±0.2, 17.1±0.2, 18.5±0.2, 19.0±0.2, 20.4±0.2, 21.6±0.2, 23.7±0.2, 26.4±0.2, and 32.1±0.2 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 12.2±0.2, 16.0±0.2, 17.1±0.2, 18.5±0.2, 19.0±0.2, 20.4±0.2, 21.6±0.2, and 23.7±0.2 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 16.0±0.2, 17.1±0.2, and 21.6±0.2 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 10.8±0.4, 12.2±0.4, 13.9±0.4, 16.0±0.4, 17.1±0.4, 18.5±0.4, 19.0±0.4, 20.4±0.4, 21.6±0.4, 23.7±0.4, 26.4±0.4, and 32.1±0.4 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 12.2±0.4, 16.0±0.4, 17.1±0.4, 18.5±0.4, 19.0±0.4, 20.4±0.4, 21.6±0.4, and 23.7±0.4 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 16.0±0.4, 17.1±0.4, and 21.6±0.4 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 10.8±0.6, 12.2±0.6, 13.9±0.6, 16.0±0.6, 17.1±0.6, 18.5±0.6, 19.0±0.6, 20.4±0.6, 21.6±0.6, 23.7±0.6, 26.4±0.6, and 32.1±0.6 degrees 2θ.In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 12.2±0.6, 16.0±0.6, 17.1±0.6, 18.5±0.6, 19.0±0.6, 20.4±0.6, 21.6±0.6, and 23.7±0.6 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 16.0±0.6, 17.1±0.6, and 21.6±0.6 degrees 2θ. It should be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1B or provided in Table 2 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0204] In some embodiments, the malonate salt has an XRPD pattern substantially as shown in Figure 1C. The angles and peak intensities measured in degrees 2θ that may be observed for the malonate salt using XRPD are shown in Table 3. [Table 3]

[0205] In some embodiments, the malonate salt has an XRPD pattern exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at degrees 2θ with maximum intensity substantially in the XRPD pattern, as shown in FIG. 1C or provided in Table 3. It should be understood that peak intensities may vary depending on many factors, including sample preparation, mounting, and the instrumentation, analytical procedures, and settings used to obtain the spectrum. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for malonate salts, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0206] In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 10.8±0.2, 11.8±0.2, 12.2±0.2, 13.9±0.2, 16.0±0.2, 17.1±0.2, 18.5±0.2, 19.0±0.2, 19.9±0.2, 20.4±0.2, 20.9±0.2, 21.7±0.2, 23.7±0.2, 25.6±0.2, 26.3±0.2 degrees 2-theta. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 11.8±0.2, 12.2±0.2, 16.0±0.2, 17.1±0.2, 18.5±0.2, 19.0±0.2, 19.9±0.2, 20.4±0.2, 21.7±0.2, and 23.7±0.2 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.2, 6.8±0.2, 16.0±0.2, 17.1±0.2, 19.0±0.2, and 21.7±0.2 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 10.8±0.4, 11.8±0.4, 12.2±0.4, 13.9±0.4, 16.0±0.4, 17.1±0.4, 18.5±0.4, 19.0±0.4, 19.9±0.4, 20.4±0.4, 20.9±0.4, 21.7±0.4, 23.7±0.4, 25.6±0.4, 26.3±0.4 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 11.8±0.4, 12.2±0.4, 16.0±0.4, 17.1±0.4, 18.5±0.4, 19.0±0.4, 19.9±0.4, 20.4±0.4, 21.7±0.4, and 23.7±0.4 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 16.0±0.4, 17.1±0.4, 19.0±0.4, and 21.7±0.4 degrees 2Θ.In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 10.8±0.6, 11.8±0.6, 12.2±0.6, 13.9±0.6, 16.0±0.6, 17.1±0.6, 18.5±0.6, 19.0±0.6, 19.9±0.6, 20.4±0.6, 20.9±0.6, 21.7±0.6, 23.7±0.6, 25.6±0.6, 26.3±0.6 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 11.8±0.6, 12.2±0.6, 16.0±0.6, 17.1±0.6, 18.5±0.6, 19.0±0.6, 19.9±0.6, 20.4±0.6, 21.7±0.6, and 23.7±0.6 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 16.0±0.6, 17.1±0.6, 19.0±0.6, and 21.7±0.6 degrees 2θ. It should be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1C or those provided in Table 3 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0207] In some embodiments, the malonate salt has an XRPD pattern including peaks at 5.9±0.2 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern including peaks at 5.9±0.2 and 6.8±0.2 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern including peaks at 5.9±0.2, 6.8±0.2, 16.0±0.2, and 16.0±0.2 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern including peaks at 5.9±0.2, 6.8±0.2, 16.0±0.2, 17.1±0.2, 19.0±0.2, and 21.6±0.2 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern including peaks at 5.9±0.2, 6.8±0.2, 12.2±0.2, 16.0±0.2, 17.1±0.2, 19.0±0.2, 20.5±0.2, 21.6±0.2, and 23.7±0.2 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern including peaks at 5.9±0.4 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern including peaks at 5.9±0.4 and 6.8±0.4 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern including peaks at 5.9±0.4, 6.8±0.4, and 16.0±0.4 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 16.0±0.4, 17.1±0.4, 19.0±0.4, and 21.6±0.4 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.4, 6.8±0.4, 12.2±0.4, 16.0±0.4, 17.1±0.4, 19.0±0.4, 20.5±0.4, 21.6±0.4, and 23.7±0.4 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6 and 6.8±0.6 degrees 2θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, and 16.0±0.6 degrees 2θ.In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 16.0±0.6, 17.1±0.6, 19.0±0.6, and 21.6±0.6 degrees 2Θ. In some embodiments, the malonate salt has an XRPD pattern comprising peaks at 5.9±0.6, 6.8±0.6, 12.2±0.6, 16.0±0.6, 17.1±0.6, 19.0±0.6, 20.5±0.6, 21.6±0.6, and 23.7±0.6 degrees 2Θ.

[0208] In some embodiments, the malonate salt has a differential scanning calorimetry trace substantially as shown in FIG. 1D. In some embodiments, the malonate salt has a differential scanning calorimetry trace substantially as shown in FIG. 1E. In some embodiments, the malonate salt has a differential scanning calorimetry trace substantially as shown in FIG. 1F. In some embodiments, the malonate salt is characterized by a differential scanning calorimetry trace including a peak from about 147°C to about 151°C. In some embodiments, the malonate salt is characterized by a differential scanning calorimetry trace including a peak at 147±4°C (e.g., 147±3°C, 147±2°C, or 147±1°C). In some embodiments, the malonate salt is characterized by a differential scanning calorimetry trace including a peak at 149±4°C (e.g., 149±3°C, 149±2°C, or 149±1°C). In some embodiments, the malonate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 151±4°C (e.g., 151±3°C, 151±2°C, or 151±1°C). In some embodiments, the malonate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 147°C to about 150°C. In some embodiments, the malonate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 148°C to about 151°C. In some embodiments, the malonate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 148°C to about 150°C. In some embodiments, the malonate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 147°C to about 149°C. In some embodiments, the malonate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 149°C to about 151°C.

[0209] In some embodiments of the malonate salt, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(h) are true: (a) Malonate is a hemimalonate; (b) The malonate salt is in crystalline form; (c) the crystalline form of the malonate salt retains at least 95% of its crystalline form after storage in an open container for at least 7 days at 40°C and 75% relative humidity, wherein the amount of crystalline form of the salt is determined by XRPD; (d) the crystalline form of the Malonate Salt retains at least 95% of its crystalline form after storage in a closed container at 40°C and 75% relative humidity for at least 7 days, wherein the amount of crystalline form of the salt is determined by XRPD. (e) the malonate salt has a solubility, calculated as the amount of Compound I free base, of greater than about 2 mg / mL in an aqueous solution at a temperature of about 37° C. having a pH of about 4.5; (f) the malonate salt has a solubility, calculated as the amount of Compound I free base, of greater than about 2 mg / mL in an aqueous solution at a temperature of about 37° C., having a pH of about 2.9; (g) Malonate (i) a peak at 5.9±0.2 degrees 2θ; (ii) peaks at 5.9±0.2 and 6.8±0.2 degrees 2θ; (iii) peaks at 5.9±0.2, 6.8±0.2, and 16.0±0.2 degrees 2θ; (iv) peaks at 5.9±0.2, 6.8±0.2, 16.0±0.2, 17.1±0.2, 19.0±0.2, and 21.6±0.2 degrees 2θ; or (v) exhibits an XRPD pattern containing peaks at 5.9±0.2, 6.8±0.2, 12.2±0.2, 16.0±0.2, 17.1±0.2, 19.0±0.2, 20.5±0.2, 21.6±0.2, and 23.7±0.2 degrees 2θ; and (h) The malonate salt exhibits a differential scanning calorimetry trace containing peaks between about 147°C and about 151°C. In some embodiments, (a) and (b) apply; in some embodiments, (a), (b) and (c) apply; in some embodiments, (a), (b), (c) and (d) apply; in some embodiments, (a), (b), (c), (d) and (e) apply; in some embodiments, (a), (b), (c), (d), (e) and (f) apply; in some embodiments, (a), (b), (c), (d), (e), (f) and (g) apply; in some embodiments, (a), (b), (c), (d), (e), (f), (g) and (h) apply; in some embodiments, (g) and (h) apply; in some embodiments, (g)(i) and (h) apply; in some embodiments, (g)(ii) and (h) apply. In some embodiments, (g)(iii) and (h) apply. In some embodiments, (g)(iv) and (h) apply. In some embodiments, (g)(v) and (h) apply. In some embodiments, (e), (g) and (h) apply. In some embodiments, (e), (g)(i) and (h) apply. In some embodiments, (e), (g)(ii) and (h) apply. In some embodiments, (e), (g)(iii) and (h) apply. In some embodiments, (e), (g)(iv) and (h) apply. In some embodiments, (e), (g)(v) and (h) apply. In some embodiments, (f), (g) and (h) apply. In some embodiments, (f), (g)(i) and (h) apply. In some embodiments, (f), (g)(ii) and (h) apply. In some embodiments, (f), (g)(iii), and (h) apply. In some embodiments, (f), (g)(iv), and (h) apply. In some embodiments, (f), (g)(v), and (h) apply. In some embodiments, (e), (f), (g), and (h) apply. In some embodiments, (e), (f), (g)(i), and (h) apply. In some embodiments, (e), (f), (g)(ii), and (h) apply.In some embodiments, (e), (f), (g)(iii), and (h) apply. In some embodiments, (e), (f), (g)(iv), and (h) apply. In some embodiments, (e), (f), (g)(v), and (h) apply.

[0210] glycolate In some embodiments, provided herein is a glycolic acid salt of Compound I.

[0211] In some embodiments, the glycolate salt of Compound I is a hemiglycolate salt.

[0212] In some embodiments, the glycolic acid salt of Compound I is in a crystalline form.

[0213] In some embodiments, the glycolate salt has an XRPD pattern substantially as shown in Figure 2A. The angles and peak intensities measured in degrees 2θ that may be observed for the glycolate salt using XRPD are shown in Table 4. [Table 4]

[0214] In some embodiments, the glycolate salt has an XRPD pattern exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at degrees 2θ with maximum intensity substantially in the XRPD pattern, as shown in FIG. 2A or as provided in Table 4. It should be understood that peak intensities may vary depending on many factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to obtain the spectrum. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for the glycolate salt, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0215] In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.2, 6.7±0.2, 7.1±0.2, 7.4±0.2, 9.6±0.2, 10.4±0.2, 10.7±0.2, 13.0±0.2, 13.3±0.2, 14.1±0.2, 15.5±0.2, 16.9±0.2, 17.5±0.2, 19.4±0.2, 20.1±0.2, 20.9±0.2, 21.5±0.2, 22.4±0.2, 22.9±0.2, 23.3±0.2, 23.7±0.2, 24±0.2, 26.1±0.2, 32.5±0.2 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.2, 6.7±0.2, 7.1±0.2, 7.4±0.2, 9.6±0.2, 10.4±0.2, 13.0±0.2, 13.3±0.2, 14.1±0.2, 15.5±0.2, 16.9±0.2, 19.4±0.2, 20.1±0.2, 21.5±0.2, 22.4±0.2, and 22.9±0.2 degrees 2Θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.2, 9.6±0.2, 13.0±0.2, 14.1±0.2, 15.5±0.2, 19.4±0.2, 20.1±0.2, and 22.4±0.2 degrees 2Θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.4, 6.7±0.4, 7.1±0.4, 7.4±0.4, 9.6±0.4, 10.4±0.4, 10.7±0.4, 13.0±0.4, 13.3±0.4, 14.1±0.4, 15.5±0.4, 16.9±0.4, 17.5±0.4, 19.4±0.4, 20.1±0.4, 20.9±0.4, 21.5±0.4, 22.4±0.4, 22.9±0.4, 23.3±0.4, 23.7±0.4, 24±0.4, 26.1±0.4, 32.5±0.4 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.4, 6.7±0.4, 7.1±0.4, 7.4±0.4, 9.6±0.4, 10.4±0.4, 13.0±0.4, 13.3±0.4, 14.1±0.4, 15.5±0.4, 16.9±0.4, 19.4±0.4, 20.1±0.4, 21.5±0.4, 22.4±0.4, 22.9±0.4 degrees 2θ.In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.4, 9.6±0.4, 13.0±0.4, 14.1±0.4, 15.5±0.4, 19.4±0.4, 20.1±0.4, and 22.4±0.4 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.6, 6.7±0.6, 7.1±0.6, 7.4±0.6, 9.6±0.6, 10.4±0.6, 10.7±0.6, 13.0±0.6, 13.3±0.6, 14.1±0.6, 15.5±0.6, 16.9±0.6, 17.5±0.6, 19.4±0.6, 20.1±0.6, 20.9±0.6, 21.5±0.6, 22.4±0.6, 22.9±0.6, 23.3±0.6, 23.7±0.6, 24±0.6, 26.1±0.6, 32.5±0.6 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.6, 6.7±0.6, 7.1±0.6, 7.4±0.6, 9.6±0.6, 10.4±0.6, 13.0±0.6, 13.3±0.6, 14.1±0.6, 15.5±0.6, 16.9±0.6, 19.4±0.6, 20.1±0.6, 21.5±0.6, 22.4±0.6, and 22.9±0.6 degrees 2Θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.6, 9.6±0.6, 13.0±0.6, 14.1±0.6, 15.5±0.6, 19.4±0.6, 20.1±0.6, and 22.4±0.6 degrees 2Θ. It should be understood that additional peaks in the XRPD pattern other than those shown in FIG. 2A or those provided in Table 4 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0216] In some embodiments, the glycolate salt has an XRPD pattern including a peak at 14.1±0.2 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including peaks at 14.1±0.2 and 19.4±0.2 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including peaks at 14.1±0.2, 19.4±0.2, and 20.1±0.2 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including peaks at 5.4±0.2, 9.6±0.2, 13.0±0.2, 14.1±0.2, 15.5±0.2, 19.4±0.2, 20.1±0.2, and 22.4±0.2 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including a peak at 14.1±0.4 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including peaks at 14.1±0.4 and 19.4±0.4 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including peaks at 14.1±0.4, 19.4±0.4, and 20.1±0.4 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including peaks at 5.4±0.4, 9.6±0.4, 13.0±0.4, 14.1±0.4, 15.5±0.4, 19.4±0.4, 20.1±0.4, and 22.4±0.4 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including peaks at 14.1±0.6 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern including peaks at 14.1±0.6 and 19.4±0.6 degrees 2θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 14.1±0.6, 19.4±0.6, and 20.1±0.6 degrees 2Θ. In some embodiments, the glycolate salt has an XRPD pattern comprising peaks at 5.4±0.6, 9.6±0.6, 13.0±0.6, 14.1±0.6, 15.5±0.6, 19.4±0.6, 20.1±0.6, and 22.4±0.6 degrees 2Θ.

[0217] In some embodiments, the glycolate salt has a differential scanning calorimetry trace substantially as shown in FIG. 2B. In some embodiments, the glycolate salt is characterized by a differential scanning calorimetry trace including a peak from about 162°C to about 165°C. In some embodiments, the glycolate salt is characterized by a differential scanning calorimetry trace including a peak at 162±4°C (e.g., 162±3°C, 162±2°C, or 162±1°C). In some embodiments, the glycolate salt is characterized by a differential scanning calorimetry trace including a peak at 163±4°C (e.g., 163±3°C, 163±2°C, or 163±1°C). In some embodiments, the glycolate salt is characterized by a differential scanning calorimetry trace including a peak at 165±4°C (e.g., 165±3°C, 165±2°C, or 165±1°C). In some embodiments, the glycolate salt is characterized by a differential scanning calorimetry trace including a peak from about 162°C to about 164°C. In some embodiments, the glycolate salt is characterized by a differential scanning calorimetry trace comprising a peak at about 163°C to about 165°C.

[0218] In some embodiments of the glycolate salt, at least one, at least two, at least three, or all of the following (a)-(d) are true: (a) The glycolate is a hemiglycolate; (b) The glycolate salt is in crystalline form; (c) Glycolate salts (i) a peak at 14.1±0.2 degrees 2θ; (ii) peaks at 14.1±0.2 degrees and 19.4±0.2 degrees 2θ; (iii) peaks at 14.1±0.2, 19.4±0.2, and 20.1±0.2 degrees 2θ; or (iv) having an XRPD pattern including peaks at 5.4±0.2, 9.6±0.2, 13.0±0.2, 14.1±0.2, 15.5±0.2, 19.4±0.2, 20.1±0.2, and 22.4±0.2 degrees 2θ; and (d) The glycolate salt exhibits a differential scanning calorimetry trace containing a peak between about 162°C and about 165°C. In some embodiments, (a) and (b) apply. In some embodiments, (a), (b), and (c) apply. In some embodiments, (a), (b), (c), and (d) apply. In some embodiments, (c) and (d) apply. In some embodiments, (c)(i) and (d) apply. In some embodiments, (c)(ii) and (d) apply. In some embodiments, (c)(iii) and (d) apply. In some embodiments, (c)(iv) and (d) apply.

[0219] HER2 HER2 (human epidermal growth factor receptor 2), also known as Neu, ErbB2, CD340 (cluster of differentiation 340), and p185, is an epidermal growth factor receptor found in cells. The HER2 gene is found on human chromosome 17. The HER2 protein consists of four membrane-bound receptor tyrosine kinases. Signal transduction pathways activated by the HER2 protein include mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K / Akt), phospholipase Cγ, protein kinase C (PKC), and signal transducer and activator of transcription (STAT).

[0220] As used herein, the term "HER2" is also known as ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2), or Erbb2, or neu, p185, or CD34 (cluster of differentiation 34), and is the human epidermal growth factor receptor 2 tyrosine kinase protein encoded by the HER2 gene (also known as erbb2, or neu, or HER2 / neu) on chromosome 17. As used herein, the term "HER2" refers to either i) the nucleic acid sequence encoding the HER2 protein, or ii) the protein.

[0221] As used herein, the term "HER2-amplified" or "HER2-amplified" cancer or cells refers to cancer or cells characterized by amplification of the HER2 gene, which can be easily assessed by methods known to those skilled in the art, such as commercially available in situ hybridization (ISH) tests or tests that can be performed by methods known to those skilled in the art. It is a term commonly used and understood in the field. For purposes of this application, a HER2-amplified cancer or cell is one in which: a) the cancer or cell exhibits at least 3, 4, 5, or 6 copies (e.g., 6 copies) of the gene encoding the HER2 protein per interphase nucleus, as detected by a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer (e.g., according to ASCO / CAP guidelines, such as the 2007, 2013, or 2018 guidelines); b) the cancer or cell exhibits at least 1.8, 2.0, or 2.5 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein relative to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus, as detected by a dual-probe ISH test performed on a sample derived from the cancer. c) cancers or cells (i) exhibit a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8, 2.0, or 2.2, and (ii) exhibit at least 3, 4, 5, or 6 copies of the gene encoding HER2 protein per interphase nucleus constituting the sample, as detected by a dual-probe ISH test performed on the cancer-derived sample (e.g., according to the ASCO / CAP guidelines, e.g., the 2007, 2013, or 2018 guidelines). In some cases, HER2-amplified cancers are defined according to the criteria set forth in the 2007, 2013, or 2018 ASCO / CAP guidelines, or other widely accepted criteria for the cancer (e.g., a particular cancer).

[0222] HER2 amplification has been identified in various types of cancer, including, but not limited to, breast cancer, colon cancer, endometrial cancer, cervical cancer, urothelial cancer, lung cancer (including non-small cell lung cancer), ovarian cancer, gastric cancer, esophagogastric junction (GEJ) cancer, head and neck cancer, biliary tract cancer, prostate cancer, and pancreatic adenocarcinoma. HER2 amplification is present in approximately 18% to 25% of breast cancers. HER2 amplification is also present in approximately 30% of GEJ cancers and approximately 20% of gastric cancers.

[0223] HER2-amplified tumors are characterized by an aggressive phenotype (e.g., increased cell proliferation, increased cell survival, increased cell motility, and increased cell adhesion), increased metastasis, increased recurrence, shorter disease-free survival, and reduced overall survival.

[0224] In some embodiments, HER2 gene amplification can be detected and / or assessed via in situ hybridization (ISH) techniques, such as chromogenic in situ hybridization (CISH), silver-enhanced in situ hybridization (SISH), or fluorescent in situ hybridization (FISH), or similar methods performed on samples from cancer. In some embodiments, the ISH technique used is single-probe ISH, which identifies the number of HER2 gene copies on chromosome 17. In some embodiments, the ISH technique used is dual-probe ISH, in which the HER2 gene copy number is quantified in relation to the number of centromere 17 (CEP17) gene copies per nucleus. In some embodiments, HER2 protein expression is detected via immunohistochemistry (IHC) or similar methods. In some embodiments, the cancer is metastatic, and ISH testing is performed on samples from metastatic sites.

[0225] In some embodiments, the cancer has been determined to exhibit at least 3, 4, 5, or 6 copies (e.g., 6 copies) of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus, as detected by single-probe in situ hybridization (ISH) testing (e.g., according to ASCO / CAP guidelines, such as the 2007, 2013, or 2018 guidelines) performed on a sample from the cancer. In some embodiments, the cancer has been determined to exhibit a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8, 2.0, or 2.2, as detected by dual-probe ISH testing (e.g., according to ASCO / CAP guidelines, such as the 2007, 2013, or 2018 guidelines) performed on a sample from the cancer. In some embodiments, the cancer has been determined to exhibit (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8, 2.0, or 2.2, and (b) at least 3, 4, 5, or 6 copies of the gene encoding the HER2 protein per interphase nucleus comprising the sample, as detected by a dual-probe ISH test performed on the sample from the cancer (e.g., ASCO / CAP guidelines (such as the 2007, 2013, or 2018 guidelines)).

[0226] In some embodiments, the cancer comprises overexpression of the HER2 protein, which increases expression of the HER2 tyrosine kinase receptor on the cell membrane, leading to increased homo- or heterodimerization of HER2 with other family members, including HER1 / EGFR, HER3, and HER4, resulting in increased activation of HER2 signaling, resulting in increased cell cycle progression and cell proliferation, leading to cancer.

[0227] As used herein, the term "HER2-overexpressed" or "HER2-overexpressed" cancer or cells refers to cancer or cells characterized by overexpression of the HER2 protein, which can be easily assessed by methods known to those skilled in the art, such as immunohistochemistry (IHC) tests that are commercially available or can be performed by methods known to those skilled in the art. It is a term commonly used and understood in the field. For purposes of this application, HER2-overexpressed cancer or cells encompasses cancer or cells exhibiting at least 10% of cancer cells that are 2+ or 3+ positive per immunohistochemistry (IHC) test performed on a sample derived from the cancer (e.g., ASCO / CAP guidelines, 2007, 2013, or 2018 guidelines, etc.). In some cases, HER2-overexpressed cancer is defined according to the criteria set forth in the 2007, 2013, or 2018 ASCO / CAP guidelines, or other widely accepted criteria for the cancer (e.g., a particular cancer).

[0228] In some embodiments, a 3+ positive IHC score is associated with a test result showing a uniform, dark, and circumferential (wire mesh) pattern in at least 10% of the tumor cells, while a 2+ positive test result is associated with weak to moderate complete membrane staining in at least 10% of the tumor cells.

[0229] In some embodiments, when examined using one or more of (i)-(iv): (i) a single-probe in situ hybridization (ISH) test performed on a sample derived from a cancer shows at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (ii) a dual-probe ISH test performed on a sample derived from a cancer shows a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8; (iii) a dual-probe ISH test performed on a sample derived from a cancer shows (a) a ratio of at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus; (b) a ratio of at least 2.0 between the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein and the number of chromosome 17 centromeres (CEP17) per interphase nucleus, and (b) at least 4 copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (iv) an immunohistochemistry (IHC) test performed on the cancer-derived sample shows at least 10% 3+ positive cancer cells; or (v) (a) an immunohistochemistry (IHC) test performed on the cancer-derived sample shows at least 10% 2+ positive cancer cells, and (b) a single probe in situ hybridization (ISH) test performed on the cancer-derived sample is determined to be positive.

[0230] As used herein, the term "HER2-positive" cancers or cells encompasses both HER2-amplified cancers or cells and cancers or cells that overexpress HER2.

[0231] In some embodiments, the cancers described herein involve both amplification of the gene encoding HER2 and overexpression of the HER2 protein.

[0232] In some embodiments, the cancers described herein involve amplification of the gene encoding HER2, but do not involve overexpression of HER2.

[0233] In some embodiments, the cancers described herein involve overexpression of HER2 but do not involve amplification of the gene encoding HER2.

[0234] Method of preparation In some embodiments, provided is a method for preparing a malonate salt of Compound I, comprising: (1) forming a mixture of Compound I and malonic acid in a solvent; and (2) removing the solvent from step (1) to obtain the malonate salt. In some embodiments, the molar ratio of malonic acid to Compound I is about 1:1. In some embodiments, the molar ratio of malonic acid to Compound I is about 2:1. In some embodiments, the solvent in step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methylpyrrolidinone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ammonia, or acetic acid). In some embodiments, the solvent in step (1) comprises an aprotic solvent. In some embodiments, the solvent in step (1) comprises acetone. In some embodiments, the solvent in step (1) comprises a protic solvent. In some embodiments, the mixture in step (1) is stirred at 23±3° C. In some embodiments, the mixture in step (1) is stirred at a temperature of about 1° C. to about 50° C. In some embodiments, removing the solvent comprises vacuum drying. In some embodiments, step (2) further comprises centrifugation or vacuum filtration.

[0235] In some embodiments, provided is a method for preparing a glycolic acid salt of Compound I, comprising: (1) forming a mixture of Compound I and glycolic acid in a solvent; and (2) removing the solvent from step (1) to obtain the glycolic acid salt. In some embodiments, the molar ratio of glycolic acid to Compound I is about 1:1. In some embodiments, the molar ratio of glycolic acid to Compound I is about 2:1. In some embodiments, the solvent in step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methylpyrrolidinone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ammonia, or acetic acid). In some embodiments, the solvent in step (1) comprises an aprotic solvent. In some embodiments, the solvent in step (1) comprises acetone. In some embodiments, the solvent in step (1) comprises a protic solvent. In some embodiments, the mixture in step (1) is stirred at 23±3° C. In some embodiments, the mixture in step (1) is stirred at a temperature of about 1° C. to about 50° C. In some embodiments, removing the solvent comprises vacuum drying. In some embodiments, step (2) further comprises centrifugation or vacuum filtration.

[0236] composition Also provided herein are compositions containing a salt described herein, such as a malonate or glycolate salt of Compound I. In some embodiments, the composition contains a malonate salt of Compound I. In some embodiments, the composition contains a glycolate salt of Compound I. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a sterile composition.

[0237] In some embodiments, provided are compositions containing a malonate salt of Compound I. In some embodiments, the compositions are substantially free of other salts and non-salt forms of Compound I. In some embodiments, the compositions are substantially free of amorphous or non-crystalline forms of Compound I.

[0238] In some embodiments of a composition containing a malonate salt of Compound I, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is malonate salt. In some embodiments of a composition containing a malonate salt of Compound I, at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of Compound I in the composition is present as the malonate salt.

[0239] In some embodiments, provided are compositions containing the glycolic acid salt of Compound I. In some embodiments, the compositions are substantially free of other salts and non-salt forms of Compound I. In some embodiments, the compositions are substantially free of amorphous or non-crystalline forms of Compound I.

[0240] In some embodiments of a composition containing the glycolic acid salt of Compound I, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is glycolic acid salt. In some embodiments of a composition containing a glycolic acid salt of Compound I, at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of Compound I in the composition is present as the glycolic acid salt.

[0241] Treatment methods In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a salt or pharmaceutical composition provided herein. In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a therapeutically effective amount of a salt or pharmaceutical composition described herein. In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a malonate salt of Compound I, or a pharmaceutical composition comprising a malonate salt of Compound I and a pharmaceutically acceptable carrier. In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a glycolic acid salt of Compound I, or a pharmaceutical composition comprising a glycolic acid salt of Compound I and a pharmaceutically acceptable carrier.

[0242] Also provided herein is the use of a salt or composition provided herein in the manufacture of a medicament for treating cancer in a subject. In some embodiments, provided herein is a salt or composition provided herein for use in a method of treating cancer. In some embodiments, provided herein is the use of a salt or composition provided herein for treating cancer.

[0243] In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a malonate salt of Compound I, a glycolate salt of Compound I, a pharmaceutical composition comprising a malonate salt of Compound I, or a pharmaceutical composition comprising a glycolate salt of Compound I. In some embodiments, provided are methods of treating cancer (e.g., metastatic cancer) in an individual in need of treatment, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer comprises a mutation in epidermal growth factor receptor (EGFR), or one or more wild-type or mutant kinases selected from ERBB2 (HER2) and ERBB4. In some embodiments, the cancer comprises one or more mutations selected from the group consisting of EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, EGFR exon 20 ins ASV, and an ERBB2 mutation that is EGFR exon 20 ins YVMA. In some embodiments, the cancer comprises a mutation that is EGFR Del19 / T790M. In some embodiments, the cancer comprises a mutation that is EGFR L858R / T790M. In some embodiments, the cancer comprises a mutation that is EGFR L858R. In some embodiments, the cancer comprises a mutation that is EGFR exon 20 ins NPH. In some embodiments, the cancer comprises a mutation that is EGFR exon 20 ins SVD. In some embodiments, the cancer comprises a mutation that is EGFR exon 20 ins FQEA. In some embodiments, the cancer comprises a mutation in EGFR exon 20 ins H. In some embodiments, the cancer comprises a mutation in EGFR exon 20 ins ASV. In some embodiments, the cancer comprises a mutation in ERBB2 in Her2 exon 20 ins YVMA. In some embodiments, the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, gastric cancer, and colorectal cancer.

[0244] In some embodiments, the cancer is selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullary carcinoma, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal cancer, kidney cancer, The cancer is selected from the group consisting of cardiac cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain tumor, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. In some embodiments, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer. In some embodiments, the cancer is metastatic brain cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer.

[0245] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer is non-small cell lung cancer and the cancer has been determined to contain one or more mutations selected from (a) an EGFR exon 20 insertion mutation, (b) a HER2 exon 20 insertion mutation, and (c) HER2 amplification or overexpression. In some embodiments, the cancer has been determined to contain one or more EGFR exon 20 insertion mutations. In some embodiments, the cancer has been determined to contain one or more HER2 exon 20 insertion mutations. In some embodiments, the cancer has been determined to contain HER2 amplification or overexpression. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0246] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer is non-small cell lung cancer, and the cancer has been determined to contain one or more mutations selected from (a) an EGFR exon 20 insertion mutation, and (b) a HER2 exon 20 insertion mutation. In some embodiments, the non-small cell lung cancer has been determined to contain one or more EGFR exon 20 insertion mutations. In some embodiments, the non-small cell lung cancer has been determined to contain one or more HER2 exon 20 insertion mutations. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0247] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer has been determined to contain one or more mutations selected from (a) an EGFR exon 20 insertion mutation, (b) a HER2 exon 20 insertion mutation, and (c) HER2 amplification or overexpression using an FDA-approved test. In some embodiments, the cancer has been determined to contain one or more EGFR exon 20 insertion mutations using an FDA-approved test. In some embodiments, the cancer has been determined to contain one or more HER2 exon 20 insertion mutations using an FDA-approved test. In some embodiments, the cancer has been determined to contain HER2 amplification or overexpression using an FDA-approved test. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0248] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer is non-small cell lung cancer, and the cancer has been determined to contain one or more mutations selected from (a) an EGFR exon 20 insertion mutation, (b) a HER2 exon 20 insertion mutation, and (c) HER2 amplification or overexpression using an FDA-approved test. In some embodiments, the cancer has been determined to contain one or more EGFR exon 20 insertion mutations using an FDA-approved test. In some embodiments, the cancer has been determined to contain one or more HER2 exon 20 insertion mutations using an FDA-approved test. In some embodiments, the non-small cell lung cancer has been determined to contain HER2 amplification or overexpression using an FDA-approved test. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0249] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer has been determined in the individual to contain one or more mutations selected from (a) an EGFR exon 20 insertion mutation, and (b) a HER2 exon 20 insertion mutation by use of any nucleic acid-based diagnostic test. In some embodiments, the cancer has been determined to contain one or more EGFR exon 20 insertion mutations by use of any nucleic acid-based diagnostic test. In some embodiments, the cancer has been determined to contain one or more HER2 exon 20 insertion mutations by use of any nucleic acid-based diagnostic test. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0250] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer in the individual is non-small cell lung cancer, and the cancer has been determined to contain one or more mutations selected from (a) an EGFR exon 20 insertion mutation and (b) a HER2 exon 20 insertion mutation using any nucleic acid-based diagnostic test. In some embodiments, the non-small cell lung cancer has been determined to contain one or more EGFR exon 20 insertion mutations using any nucleic acid-based diagnostic test. In some embodiments, the non-small cell lung cancer has been determined to contain one or more HER2 exon 20 insertion mutations using any nucleic acid-based diagnostic test. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0251] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more EGFR exon 20 insertion mutations or one or more HER2 exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed during or after platinum-based chemotherapy. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more EGFR exon 20 insertion mutations, and the cancer has progressed during or after platinum-based chemotherapy. In some embodiments, the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more HER2 exon 20 insertion mutations, and the cancer has progressed during or after platinum-based chemotherapy. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0252] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer containing one or more EGFR exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed during or after platinum-based chemotherapy. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0253] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer containing one or more HER2 exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed during or after platinum-based chemotherapy. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0254] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more EGFR exon 20 insertion mutations or one or more HER2 exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed after a prior EGFR exon 20 insertion therapy or a HER2 exon 20 insertion therapy. In some embodiments, the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more EGFR exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed after a prior EGFR exon 20 insertion therapy. In some embodiments, the cancer in the individual is locally advanced or metastatic non-small cell lung cancer with one or more HER2 exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed after a prior HER2 exon 20 insertion therapy. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0255] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer containing one or more EGFR exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed after prior EGFR exon 20 insertion mutation therapy. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0256] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer in the individual is locally advanced or metastatic non-small cell lung cancer containing one or more HER2 exon 20 insertion mutations as detected by an FDA-approved test, and the cancer has progressed after prior HER2 exon 20 insertion mutation therapy. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0257] Provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer in the individual has been determined to contain HER2 amplification or overexpression by use of immunohistochemistry (IHC) or in situ hybridization (ISH) testing. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0258] In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises overexpression of the human epidermal growth factor receptor 2 (HER2) protein.

[0259] In some variations of any of the embodiments described herein, the cancer is locally advanced. In some embodiments, the cancer is unresectable. In some variations, the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some variations, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some variations, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some variations, when examined using a dual-probe ISH test performed on a sample from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample. In some variations, the cancer exhibits at least 10% 2+ or 3+ positive cancer cells when examined using an immunohistochemistry (IHC) test performed on a sample from the cancer.In some variations, (a) the cancer, when examined using an immunohistochemistry (IHC) test performed on a sample from the cancer, exhibits at least 10% 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some variations, the cancer is selected from the group consisting of metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations (e.g., any of the mutations described herein) in the epidermal growth factor receptor (EGFR) protein. In some variations, the cancer does not comprise a mutation in the epidermal growth factor receptor (EGFR) protein. In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations (e.g., any of the mutations described herein) in the HER2 protein. In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the HER2 protein, wherein the one or more (e.g., 1, 2, or 3) mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variations, the cancer does not comprise any mutations in the HER2 protein. In some variations, the cancer does not comprise overexpression of HER2. In some variations, the cancer does not comprise amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein. In some variations, the cancer does not comprise one or more mutations in the HER2 protein. In some variations, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some variations, the cancer does not contain one or more exon 20 insertion mutations in the HER2 protein selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778insGCP.In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein, p.G780_P781dupGSP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein, p.G778_S779insCPG. In some variations, the cancer does not contain a mutation in the HER2 protein, L775S. In some variations, the cancer does not contain a mutation in the HER2 protein, G776C. In some variations, the cancer does not contain any mutations in the HER2 protein. In some variations, the cancer contains a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not contain a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein at histidine 1047. In some variations, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein selected from H1047L and H1047R. In some variations, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof. In some variations, the method further comprises administering one or more additional anti-cancer agents (e.g., any of the anti-cancer agents described herein) to an individual in need thereof. In some variations, the one or more additional anti-cancer agents comprise a HER2 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise a HER2-immunotargeting bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T cells (CTLs). In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells.In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anti-cancer agents comprise an epidermal growth factor receptor (EGFR) inhibitor. In some variations, the one or more additional anti-cancer agents comprise a poly-ADP-ribose polymerase (PARP) inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PD-1 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PD-L1 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PI3K inhibitor. In some variations, the one or more additional anti-cancer agents comprise a chemotherapeutic agent. In some variations, the individual is human.

[0260] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) overexpression of the human epidermal growth factor receptor 2 (HER2) protein.

[0261] In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I, as described herein, or a pharmaceutical composition comprising a salt of Compound I, as described herein, wherein prior to administering the salt of Compound I, or a pharmaceutically acceptable salt thereof, the cancer is characterized in that: (i) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer reveals at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (ii) a dual-probe ISH test performed on a sample from the cancer reveals at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein relative to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus; (iii) a dual-probe ISH test performed on a sample derived from the cancer shows one or more of the following: (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 2.0, and (b) at least four copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (iv) an immunohistochemistry (IHC) test performed on a sample derived from the cancer shows at least 10% 3+ positive cancer cells; or (v) (a) an immunohistochemistry (IHC) test performed on a sample derived from the cancer shows at least 10% 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some embodiments, the cancer includes one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the cancer is locally advanced cancer. In some embodiments, the cancer is unresectable.

[0262] In some variations of any of the embodiments described herein, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample prior to administering a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some variations, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some variations, when examined using a dual-probe ISH test performed on a sample derived from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample. In some variations, the cancer exhibits at least 10% 2+ or 3+ positive cancer cells when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer. In some variations, (a) when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some variations, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein (e.g., any of the mutations described herein). In some variations, the cancer does not comprise a mutation in the epidermal growth factor receptor (EGFR) protein. In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the HER2 protein (e.g., any of the mutations described herein). In some variations, the cancer does not comprise overexpression of HER2. In some variations, the cancer does not comprise any mutations in the HER2 protein. In some variations, the cancer does not comprise an amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein. In some variations, the cancer does not comprise one or more mutations in the HER2 protein. In some variations, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some variations, the cancer does not contain one or more exon 20 insertion mutations in the HER2 protein selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some variations, the cancer does not contain a mutation in the HER2 protein that is L775S. In some variations, the cancer does not contain a mutation in the HER2 protein that is G776C. In some variations, the cancer comprises a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein.In some variations, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein at histidine 1047. In some variations, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein selected from H1047L and H1047R. In some variations, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof. In some variations, the method further comprises administering one or more additional anti-cancer agents (e.g., any of the anti-cancer agents described herein) to an individual in need thereof. In some variations, the one or more additional anti-cancer agents comprise a HER2 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise a HER2-immunotargeting bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T cells (CTLs). In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anti-cancer agents comprise an epidermal growth factor receptor (EGFR) inhibitor. In some variations, the one or more additional anti-cancer agents comprise a poly-ADP-ribose polymerase (PARP) inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PD-1 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PD-L1 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PI3K inhibitor. In some variations, the one or more additional anti-cancer agents comprise a chemotherapeutic agent. In some variations, the individual is human.

[0263] In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein a single-probe in situ hybridization (ISH) test performed on a sample from the cancer indicates at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and a single-probe in situ hybridization (ISH) test performed on a sample from the cancer indicates at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein, and wherein a single-probe in situ hybridization (ISH) test performed on a sample from the cancer shows at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample, prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein a dual-probe ISH test performed on a sample from the cancer shows a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises central nervous system (CNS) metastases, and a dual-probe ISH test performed on a sample from the cancer shows a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein, and wherein a dual-probe ISH test performed on a sample from the cancer shows a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein a dual-probe ISH test performed on a sample from the cancer shows, prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 2.0, and (b) at least 4 copies of genes encoding human epidermal growth factor receptor 2 (HER2) proteins per interphase nucleus comprising the sample. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein a dual-probe ISH test performed on a sample from the cancer shows, prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 2.0, and (b) at least 4 copies of genes encoding human epidermal growth factor receptor 2 (HER2) proteins per interphase nucleus comprising the sample.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein, and wherein a dual-probe ISH test performed on a sample from the cancer shows, prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 2.0, and (b) at least 4 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of 3+ positive cancer cells prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of 3+ positive cancer cells prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein, and wherein immunohistochemistry (IHC) testing performed on a sample from the cancer shows at least 10% of 3+ positive cancer cells prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of cancer cells that are 2+ positive, and (b) a single in situ hybridization (ISH) test performed on a sample from the cancer determines a positive result. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% 2+ positive cancer cells, and (b) a single in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein, wherein prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (i) an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% 2+ positive cancer cells, and (ii) a single in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive.

[0264] In some variations of any of the embodiments described herein, the cancer is locally advanced cancer. In some embodiments, the cancer is unresectable. In some variations, the cancer includes one or more central nervous system (CNS) metastases (e.g., brain metastases). In some variations, the cancer is selected from the group consisting of metastatic brain tumors, breast cancer, and non-small cell lung cancer.

[0265] In some variations of any of the embodiments described herein, the cancer is a metastatic solid tumor. In some variations, the cancer is a metastatic solid tumor and is unresectable. In some variations, the cancer is a metastatic solid tumor and includes one or more central nervous system (CNS) metastases (e.g., brain metastases). In some variations, the cancer is a metastatic solid tumor and is selected from the group consisting of metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some variations, the cancer is a metastatic solid tumor including brain tumor. In some variations, the cancer is a metastatic solid tumor including metastatic breast cancer. In some variations, the cancer is a metastatic solid tumor including breast cancer. In some variations, the cancer is a metastatic solid tumor including non-small cell lung cancer. In some embodiments, the cancer is metastatic non-small cell lung cancer. In some variations, the cancer is metastatic non-small cell lung cancer, wherein the cancer includes central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0266] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual a salt or pharmaceutical composition described herein, wherein the cancer in the individual comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the CNS metastases developed in the individual after prior therapy comprising an EGFR or HER2 inhibitor. In some embodiments, the prior therapy comprises an EGFR inhibitor. In some embodiments, the prior therapy comprises an EGFR exon 20 mutation inhibitor. In some embodiments, the prior therapy comprises a HER2 inhibitor. In some embodiments, the prior therapy comprises a HER2 exon 20 mutation inhibitor. In some embodiments, administering to the individual a salt or pharmaceutical composition provided herein successfully treats one or more central nervous system (CNS) metastases (e.g., brain metastases).

[0267] In some variations of any of the embodiments described herein, the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, gastric cancer, and colorectal cancer.

[0268] In some variations of any of the embodiments described herein, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein. In some variations, the one or more mutations in the EGFR protein are G309A, G309E, S310F, R678Q, R678Q, and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759 EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR del19, EGFR L858R / C797S, EGFR del19 / C797S, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, and EGFR exon 20 ins ASV. In some variations, the cancer comprises one or more mutations selected from the group consisting of G309A, G309E, S310F, R678Q, R678Q, and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR del19, EGFR L858R / C797S, EGFR del19 / C797S, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, and EGFR exon 20 ins ASV. In some variations, the cancer does not include any of the EGFR mutations listed above. In some variations, the cancer does not include any mutations in the epidermal growth factor receptor (EGFR) protein.

[0269] In some variations of any of the embodiments described herein, the cancer does not contain an EGFR T790M mutation. In some variations of any of the embodiments described herein, the cancer has been determined to not contain an EGFR T790M mutation using an FDA-approved test. In some variations of any of the embodiments described herein, the cancer is non-small cell lung cancer and has been determined to not contain an EGFR T790M mutation using an FDA-approved test. In some variations of any of the embodiments described herein, the cancer is non-small cell lung cancer with central nervous system (CNS) metastases (e.g., brain metastases) and has been determined to not contain an EGFR T790M mutation using an FDA-approved test. In some variations of any of the embodiments described herein, the cancer is metastatic non-small cell lung cancer with central nervous system (CNS) metastases (e.g., brain metastases) and has been determined to not contain an EGFR T790M mutation using an FDA-approved test. In some variations of any of the embodiments described herein, the cancer is breast cancer with central nervous system (CNS) metastases (e.g., brain metastases) and is determined to not contain an EGFR T790M mutation by using an FDA-approved test. In some variations of any of the embodiments described herein, the cancer is metastatic breast cancer with central nervous system (CNS) metastases (e.g., brain metastases) and is determined to not contain an EGFR T790M mutation by using an FDA-approved test. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0270] In some variations of any of the embodiments described herein, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the HER2 protein, wherein the one or more (e.g., 1, 2, or 3) mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variations, the cancer does not comprise any mutations in the HER2 protein. In some variations, the cancer does not comprise one or more mutations in the HER2 protein. In some variations, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some variations, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some variations, the cancer does not contain a mutation in the HER2 protein that is L775S. In some variations, the cancer does not contain a mutation in the HER2 protein that is G776C.

[0271] In some variations of any of the embodiments described herein, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof.

[0272] In some variations of any of the embodiments described herein, the individual has not undergone one or more prior therapies for the treatment of cancer prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein.

[0273] In some variations of any of the embodiments described herein, the individual has not received prior therapy for the treatment of cancer with an EGFR exon 20 mutation inhibitor before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the cancer has been determined to contain one or more EGFR exon 20 mutations, and the individual has not received prior therapy for the treatment of cancer with an EGFR exon 20 mutation inhibitor before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein. In some embodiments, the cancer is non-small cell lung cancer determined to contain one or more EGFR exon 20 mutations, and the individual has not received prior therapy for the treatment of cancer with an EGFR exon 20 mutation inhibitor before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein. In some embodiments, the cancer is metastatic non-small cell lung cancer determined to contain one or more EGFR exon 20 mutations, and the individual has not received prior therapy for the treatment of the cancer with an EGFR exon 20 mutation inhibitor before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the cancer is non-small cell lung cancer with central nervous system (CNS) metastases (e.g., brain metastases) determined to contain one or more EGFR exon 20 mutations, and the individual has not received prior therapy for the treatment of the cancer with an EGFR exon 20 mutation inhibitor before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0274] In some variations of any of the embodiments described herein, the cancer is non-small cell lung cancer, and the individual has not received prior therapy for the treatment of the cancer with an EGFR exon 20 mutation inhibitor prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0275] In some variations of any of the embodiments described herein, the individual has not been treated with an EGFR exon 20 mutation inhibitor before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the cancer has been determined to contain one or more EGFR exon 20 mutations, and the individual has not been treated with an EGFR exon 20 mutation inhibitor before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the cancer is non-small cell lung cancer determined to contain one or more EGFR exon 20 mutations, and the individual has not been treated with an EGFR exon 20 mutation inhibitor before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the cancer is metastatic non-small cell lung cancer determined to contain one or more EGFR exon 20 mutations, and the individual has not been treated with an EGFR exon 20 mutation inhibitor before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the cancer is non-small cell lung cancer with central nervous system (CNS) metastases (e.g., brain metastases) determined to contain one or more EGFR exon 20 mutations, and the individual has not been treated with an EGFR exon 20 mutation inhibitor prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0276] In some variations of any of the embodiments described herein, the cancer is non-small cell lung cancer, and the individual has not been treated with an EGFR exon 20 mutation inhibitor prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the cancer has been determined to contain one or more HER2 exon 20 mutations, and the individual has not been treated with a HER2 exon 20 mutation inhibitor prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the cancer is non-small cell lung cancer determined to contain one or more HER2 exon 20 mutations, and the individual has not been treated with a HER2 exon 20 mutation inhibitor prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the cancer is metastatic non-small cell lung cancer determined to contain one or more HER2 exon 20 mutations, and the individual has not been treated with a HER2 exon 20 mutation inhibitor prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein. In some embodiments, the cancer is non-small cell lung cancer with central nervous system (CNS) metastases (e.g., brain metastases) determined to contain one or more HER2 exon 20 mutations, and the individual has not been treated with a HER2 exon 20 mutation inhibitor prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0277] In some variations of any of the embodiments described herein, before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein, the individual has undergone one or more prior therapies for the treatment of cancer. In some variations, the one or more prior therapies include one or more anti-HER2-based regimens. In some variations, one or more anti-HER2-based regimens were administered to the individual in a metastatic state. In some variations, before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, the individual has failed one or more prior therapies.

[0278] In some variations of any of the embodiments described herein, prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of cancer. In some embodiments, the cancer has been determined to contain one or more EGFR exon 20 mutations, and prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of cancer. In some embodiments, the cancer is non-small cell lung cancer determined to contain one or more EGFR exon 20 mutations, and prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of cancer. In some embodiments, the cancer is metastatic non-small cell lung cancer determined to contain one or more EGFR exon 20 mutations, and prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer. In some embodiments, the cancer is non-small cell lung cancer with central nervous system (CNS) metastases (e.g., brain metastases) determined to contain one or more EGFR exon 20 mutations, and prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0279] In some variations of any of the embodiments described herein, the cancer is non-small cell lung cancer, and prior to administering to the individual a pharmaceutical composition comprising a salt of compound I described herein or a salt of a compound described herein, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer.

[0280] In some variations of any of the embodiments described herein, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of cancer prior to administration of the salt or pharmaceutical composition to the individual, and the individual is further administered a bispecific EGF receptor-directed and MET receptor-directed antibody. In some embodiments, the cancer has been determined to contain one or more EGFR exon 20 mutations, and the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of cancer prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein to the individual, and the individual is further administered a bispecific EGF receptor-directed and MET receptor-directed antibody. In some embodiments, the cancer is non-small cell lung cancer determined to contain one or more EGFR exon 20 mutations, and the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of cancer prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein to the individual, and the individual is further administered a bispecific EGF receptor-directed and MET receptor-directed antibody. In some embodiments, the cancer is metastatic non-small cell lung cancer determined to contain one or more EGFR exon 20 mutations, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, and the individual is further administered a bispecific EGF receptor-directed and MET receptor-directed antibody. In some embodiments, the cancer is non-small cell lung cancer with central nervous system (CNS) metastases (e.g., brain metastases) determined to contain one or more EGFR exon 20 mutations, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, and the individual is further administered a bispecific EGF receptor-directed and MET receptor-directed antibody.In some embodiments, the bispecific EGF receptor-directed and MET receptor-directed antibody is amivantamab. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0281] In some variations of any of the embodiments described herein, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of cancer prior to administration of the salt or pharmaceutical composition to the individual, and the individual is further administered a bispecific EGF receptor-directed and MET receptor-directed antibody. In some embodiments, the bispecific EGF receptor-directed and MET receptor-directed antibody is amivantamab. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0282] In some variations of any of the embodiments described herein, (a) the cancer is non-small cell lung cancer; and (b) prior to administration of the salt or pharmaceutical composition to the individual, the individual has received one or more prior EGFR exon 20 mutation inhibitor therapies for the treatment of the cancer, and the individual is further administered amivantamab. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0283] In some variations of any of the embodiments described herein, the individual has undergone one or more prior therapies for the treatment of cancer prior to administration of the salt or pharmaceutical composition to the individual, wherein the one or more prior therapies include an EGFR exon 20 mutation inhibitor and a bispecific EGF receptor-directed and MET receptor-directed antibody. In some embodiments, the bispecific EGF receptor-directed and MET receptor-directed antibody is amivantamab. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0284] In some variations of any of the embodiments described herein, the cancer is non-small cell lung cancer and the individual has received one or more prior therapies for the treatment of the cancer prior to administration of the salt or pharmaceutical composition to the individual, wherein the one or more prior therapies include an EGFR exon 20 mutation inhibitor and a bispecific EGF receptor-directed and MET receptor-directed antibody. In some embodiments, the bispecific EGF receptor-directed and MET receptor-directed antibody is amivantamab. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0285] In some variations of any of the embodiments described herein, the individual has undergone one or more prior therapies for the treatment of cancer prior to administration of the salt or pharmaceutical composition to the individual, wherein the one or more prior therapies include an EGFR exon 20 mutation inhibitor and amivantamab. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0286] In some variations of any of the embodiments described herein, the cancer is non-small cell lung cancer and the individual has received one or more prior therapies for the treatment of the cancer prior to administration of the salt or pharmaceutical composition to the individual, wherein the one or more prior therapies include an EGFR exon 20 mutation inhibitor and amivantamab. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0287] In some variations of any of the embodiments described herein, the individual has undergone one or more prior therapies for the treatment of cancer prior to administration of the salt or pharmaceutical composition to the individual, wherein the one or more prior therapies include chemotherapy. In some embodiments, the one or more prior therapies including chemotherapy include platinum-based chemotherapy. In some embodiments, the one or more prior therapies including chemotherapy do not include platinum-based chemotherapy. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0288] In some variations of any of the embodiments described herein, the individual has failed one or more prior therapies prior to administration of the salt or pharmaceutical composition to the individual, wherein the one or more prior therapies are selected from (a) a bispecific EGF receptor-directed and MET receptor-directed antibody, and (b) chemotherapy. In some embodiments, the EGF receptor-directed and MET receptor-directed antibody is amivantamab. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0289] In some variations of any of the embodiments described herein, the cancer does not involve overexpression of HER2.

[0290] In some variations of any of the embodiments described herein, the cancer does not include amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein.

[0291] In some variations of any of the embodiments described herein, the method further includes identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer.

[0292] In some variations of any of the embodiments described herein, the cancer does not comprise a mutation in a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein (e.g., one or more mutations at histidine 1047 or cysteine ​​420, e.g., H1047L, H1047R, or C420R).

[0293] In some variations of any of the embodiments described herein, the method further comprises administering to the individual in need thereof one or more additional anti-cancer agents (e.g., any of the anti-cancer agents described herein) or a second therapy (e.g., radiation therapy). In some variations, the one or more additional anti-cancer agents comprise a HER2 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise a HER2-immunotargeting bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T cells (CTLs). In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anti-cancer agents comprise an epidermal growth factor receptor (EGFR) inhibitor. In some variations, the one or more additional anticancer agents comprise a poly-ADP-ribose polymerase (PARP) inhibitor. In some variations, the one or more additional anticancer agents comprise a PD-1 inhibitor. In some variations, the one or more additional anticancer agents comprise a PD-L1 inhibitor. In some variations, the one or more additional anticancer agents comprise a PI3K inhibitor. In some variations, the one or more additional anticancer agents comprise a chemotherapeutic agent.

[0294] In some variations of any of the embodiments described herein, the method further comprises administering to the individual in need thereof one or more additional anti-cancer agents, wherein the one or more additional anti-cancer agents comprise a bispecific EGF receptor-directed and MET receptor-directed antibody. In some embodiments, the bispecific EGF receptor-directed and MET receptor-directed antibody is amivantamab.

[0295] In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises overexpression of HER2. In some embodiments, the cancer sample exhibits HER2 expression of 3+ when examined using an immunohistochemistry (IHC) test. In some embodiments, the present application provides methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the present application provides a method of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises amplification of the gene encoding the HER2 protein. In some embodiments, the cancer comprises overexpression of the HER2 protein. In some embodiments, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein.In some embodiments, the one or more mutations in the EGFR protein are G309A, G309E, S310F, R678Q, R678Q and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759 EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR del19, EGFR L858R / C797S, EGFR del19 / C797S, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, and EGFR exon 20 ins ASV. In some embodiments, the one or more mutations comprise a G309A mutation. In some embodiments, the one or more mutations comprise a G309E mutation. In some embodiments, the one or more mutations comprise a S310F mutation. In some embodiments, the one or more mutations comprise a R678Q mutation. In some embodiments, the one or more mutations comprise a R678Q mutation and a L755W mutation. In some embodiments, the one or more mutations comprise a L755S mutation. In some embodiments, the one or more mutations comprise a L755W mutation. In some embodiments, the one or more mutations comprise a I767M mutation. In some embodiments, the one or more mutations comprise a D769H mutation. In some embodiments, the one or more mutations comprise a D769Y mutation. In some embodiments, the one or more mutations comprise a V777L mutation. In some embodiments, the one or more mutations comprise a Y835F mutation. In some embodiments, the one or more mutations comprise a V842I mutation. In some embodiments, the one or more mutations comprise a R896C mutation. In some embodiments, the one or more mutations comprise a G1201V mutation. In some embodiments, the one or more mutations comprise a del.755-759 EGFR Del19 / T790M mutation. In some embodiments, the one or more mutations comprise an EGFR L858R / T790M mutation. In some embodiments, the one or more mutations comprise an EGFR L858R mutation. In some embodiments, the one or more mutations comprise an EGFR del 19 mutation.In some embodiments, the one or more mutations comprise an EGFR L858R / C797S mutation. In some embodiments, the one or more mutations comprise an EGFR del19 / C797S mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins NPH mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins SVD mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins FQEA mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins H mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins ASV mutation. In some embodiments, the cancer does not comprise any of the EGFR mutations listed above. In some embodiments, the cancer does not comprise any mutations in the epidermal growth factor receptor (EGFR) protein. In some embodiments, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus constituting the sample prior to administering a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2).In some embodiments, when examined using a dual-probe ISH test performed on a sample derived from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample. In some embodiments, when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ or 3+ positive cancer cells. In some embodiments, (a) when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some embodiments, the cancer is selected from the group consisting of metastatic brain tumors, breast cancer, and non-small cell lung cancer. In some embodiments, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof. In some embodiments, the individual has not received one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the individual has received one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the one or more prior therapies include one or more anti-HER2-based regimens. In some embodiments, one or more anti-HER2-based regimens have been administered to the individual in a metastatic state. In some embodiments, the individual has failed one or more prior therapies before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein.In some embodiments, the method further includes identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer. In some embodiments, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer. In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is unresectable.

[0296] In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises overexpression of HER2. In some embodiments, the cancer sample exhibits HER2 expression of 3+ when examined using an immunohistochemistry (IHC) test. In some embodiments, the present application provides methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the present application provides a method of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, the cancer comprises amplification of a gene encoding a HER2 protein. In some embodiments, the cancer comprises overexpression of a HER2 protein. In some embodiments, the cancer comprises one or more (e.g., one, two, or three) mutations in a HER2 protein, wherein the one or more (e.g., one, two, or three) mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some embodiments, the one or more mutations comprise a p.A775_G776insYVMA mutation. In some embodiments, the one or more mutations comprise a p.778insGCP mutation. In some embodiments, the one or more mutations comprise a p.G780_P781dupGSP mutation.In some embodiments, the one or more mutations include a G778_S779insCPG mutation. In some embodiments, the cancer does not include any of the HER2 mutations described above. In some embodiments, the cancer does not include any mutations in the HER2 protein. In some embodiments, according to any one of the methods described herein, the cancer does not include one or more mutations in the HER2 protein. In some embodiments, according to any one of the methods described herein, the cancer does not include one or more exon 20 insertion mutations in the HER2 protein. In some embodiments, according to any one of the methods described herein, the cancer does not include one or more exon 20 insertion mutations in the HER2 protein selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some embodiments, according to any one of the methods described herein, the cancer does not include an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some embodiments of any one of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some embodiments of any one of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some embodiments of any one of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some embodiments of any one of the methods described herein, the cancer does not comprise a mutation in the HER2 protein that is L775S. In some embodiments of any one of the methods described herein, the cancer does not comprise a mutation in the HER2 protein that is G776C.In some embodiments, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus constituting the sample prior to administering a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some embodiments, when examined using a dual-probe ISH test performed on a sample derived from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample. In some embodiments, when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ or 3+ positive cancer cells. In some embodiments, (a) when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some embodiments, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.In some embodiments, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof. In some embodiments, the individual has not received one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the individual has received one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the one or more prior therapies include one or more anti-HER2-based regimens. In some embodiments, one or more anti-HER2-based regimens were administered to the individual in a metastatic state. In some embodiments, the individual has failed one or more prior therapies before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein. In some embodiments, the method further includes identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer. In some embodiments, the cancer is selected from the group consisting of metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is unresectable.

[0297] In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents or second therapies, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents or second therapies, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents or second therapies, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a pharmaceutical composition comprising a salt of Compound I as described herein or a salt of Compound I as described herein, and b) a HER2 inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a HER2 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a HER2 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more chemotherapeutic agents, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more chemotherapeutic agents, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more chemotherapeutic agents, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents, including trastuzumab and capecitabine, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents, including trastuzumab and capecitabine, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents, including trastuzumab and capecitabine, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) an EGFR inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) an EGFR inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) an EGFR inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PARP inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided is a method of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual: a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein; and b) a PARP inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PARP inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-1 inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-1 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-L1 inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-L1 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-L1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PI3K inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PI3K inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PI3K inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, provided are methods of treating gastric cancer in an individual in need of treatment, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents, including a chemotherapeutic agent or a PD-1 inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating gastric cancer in an individual in need of treatment, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents, including a chemotherapeutic agent or a PD-1 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, provided are methods of treating gastric cancer in an individual in need thereof, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein; and b) one or more additional anti-cancer agents, including a chemotherapeutic agent or a PD-1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, provided is a method of treating lung cancer (e.g., NSCLC or SCLC) in an individual in need thereof, comprising administering to the individual: a) a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein; and b) one or more additional anticancer agents selected from the group consisting of carboplatin, a taxane, pemetrexed, a PD-1 inhibitor, and a PD-L1 inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein, overexpression of the HER2 protein, or one or more mutations in the HER2 protein. In some embodiments, provided is a method of treating lung cancer (NSCLC or SCLC) in an individual in need thereof, comprising administering to the individual: a) a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein; and b) one or more additional anti-cancer agents selected from the group consisting of carboplatin, a taxane, pemetrexed, a PD-1 inhibitor, and a PD-L1 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, provided is a method of treating lung cancer (e.g., NSCLC or SCLC) in an individual in need thereof, comprising administering to the individual: a) a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein; and b) one or more additional anticancer agents selected from the group consisting of carboplatin, a taxane, pemetrexed, a PD-1 inhibitor, and a PD-L1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein, overexpression of the HER2 protein, or one or more mutations in the HER2 protein.

[0298] In some variations of any of the embodiments described herein, the cancer comprises amplification of a gene encoding a HER2 protein. In some variations, the cancer comprises overexpression of a HER2 protein. In some variations, the one or more additional anti-cancer agents comprise a HER2 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise a HER2-immunotargeting bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T cells (CTLs). In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anti-cancer agents comprise an epidermal growth factor receptor (EGFR) inhibitor. In some variations, the one or more additional anticancer agents comprise a poly-ADP-ribose polymerase (PARP) inhibitor. In some variations, the one or more additional anticancer agents comprise a PD-1 inhibitor. In some variations, the one or more additional anticancer agents comprise a PD-L1 inhibitor. In some variations, the one or more additional anticancer agents comprise a PI3K inhibitor. In some variations, the one or more additional anticancer agents comprise a chemotherapeutic agent. In some variations, the one or more additional anticancer agents are selected from antibody-drug conjugates.In some variations, the one or more additional anticancer agents are trastuzumab, trastuzumab and hyaluronidase, capecitabine, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, margetuximab, trastuzumab emtansine, trastuzumab deruxtecan, ZW49 (Zymeworks), A166 (Klaus Pharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, nekitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, bevacizumab Selected from the group consisting of riparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemipilimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189. In some variations, the second therapy is radiation. In some variations, the one or more chemotherapeutic agents are selected from the group consisting of doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxiplatin, and eribulin. In some variations, the EGFR inhibitor is selected from the group consisting of erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, lapatinib, dacomitinib, necitumumab, vandetanib, afatinib, brigatinib, and nicotinib.In some variations, the PARP inhibitor is selected from the group consisting of niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, and E7016. In some variations, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tirelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514. In some variations, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189. In some variations, the PI3K inhibitor is selected from the group consisting of taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, buparlisib (BKM120), duvelisib, (IPI-145), copanlisib (BAY80-6946), PX-866, dactolisib, CUDC-907, boctalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597. In some variations, the additional anticancer agent comprises a chemotherapeutic agent. In some variations, the chemotherapeutic agent is selected from the group consisting of doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxiplatin, and eribulin. In some variations, the additional anticancer agent comprises a PD-1 inhibitor.In some variations, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tirelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514. In some variations, the cancer comprises one or more mutations in the HER2 protein. In some variations, the one or more additional anticancer agents comprise carboplatin. In some variations, the one or more additional anticancer agents comprise a taxane. In some variations, the one or more additional anticancer agents comprise pemetrexed. In some variations, the one or more additional anticancer agents comprise a PD-1 inhibitor. In some variations, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tirelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514. In some variations, the one or more additional anticancer agents comprise a PD-L1 inhibitor. In some variations, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189. In some variations, the cancer, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.In some variations, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some variations, when examined using a dual-probe ISH test performed on a sample from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample. In some variations, the cancer exhibits at least 10% 2+ or 3+ positive cancer cells when examined using an immunohistochemistry (IHC) test performed on a sample from the cancer. In some variations, (a) the cancer exhibits at least 10% 2+ positive cancer cells when examined using an immunohistochemistry (IHC) test performed on a sample from the cancer, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some variations, the cancer is selected from the group consisting of metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some variations, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof. In some variations, the individual has not undergone one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some variations, the individual has undergone one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some variations, the one or more prior therapies include one or more anti-HER2-based regimens.In some variations, one or more anti-HER2-based regimens have been administered to the individual in a metastatic state. In some variations, the individual has failed one or more prior therapies before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some variations, the method further includes identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer. In some variations, the cancer is selected from the group consisting of metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some variations, the cancer is locally advanced or metastatic. In some variations, the cancer is unresectable.

[0299] In some embodiments, there is provided a use of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein for the manufacture of a medicament for treating an individual with cancer, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, there is provided a use of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein for the treatment of a human with cancer, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is unresectable. In some embodiments, the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, there is provided a use of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein for the treatment of a human with cancer, wherein the cancer comprises one or more central nervous system (CNS) metastases. In some embodiments, there is provided a use of a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, for the manufacture of a medicament for treating cancer in an individual, wherein the cancer comprises one or more central nervous system (CNS) metastases. In some embodiments, the cancer further comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises amplification of the gene encoding the HER2 protein. In some embodiments, the cancer comprises overexpression of the HER2 protein. In some embodiments, the cancer does not comprise overexpression of HER2. In some embodiments, the cancer does not comprise amplification of the gene encoding the HER2 protein.In some embodiments, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus constituting the sample prior to administering a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some embodiments, when examined using a dual-probe ISH test performed on a sample derived from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample. In some embodiments, when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ or 3+ positive cancer cells. In some embodiments, (a) when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some embodiments, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.In some embodiments, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein (e.g., any of the mutations described herein). In some embodiments, the cancer does not comprise a mutation in the epidermal growth factor receptor (EGFR) protein. In some embodiments, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the HER2 protein (e.g., any of the mutations described herein). In some embodiments, the cancer does not comprise one or more mutations in the HER2 protein. In some embodiments, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some embodiments, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some embodiments, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some embodiments, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some embodiments, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some embodiments, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778_S779insGCP. In some embodiments, the cancer does not contain a mutation in the HER2 protein that is L775S. In some embodiments, the cancer does not contain a mutation in the HER2 protein that is L776C. In some embodiments, the cancer does not contain any mutations in the HER2 protein. In some embodiments, the cancer contains a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some embodiments, the cancer does not contain a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein.In some embodiments, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein at histidine 1047. In some embodiments, the cancer does not comprise a mutation selected from H1047L and H1047R in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some embodiments, the individual has not undergone one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the individual has undergone one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the one or more prior therapies include one or more anti-HER2-based regimens (e.g., in a metastatic setting). In some embodiments, the individual has failed one or more prior therapies before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein. In some embodiments, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to the individual in need thereof. In some variations, the method further comprises administering to the individual in need thereof one or more additional anti-cancer agents (e.g., any of the anti-cancer agents described herein). In some embodiments, the one or more additional anti-cancer agents comprise one or more agents selected from a HER2 inhibitor, a HER2-CD3 bispecific antibody, a HER2 immunotargeting bispecific antibody, an anti-HER2 chimeric antigen receptor (CAR) T cell, an anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocyte (CTL), an anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cell, an anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cell, an epidermal growth factor receptor (EGFR) inhibitor, a poly-ADP-ribose polymerase (PARP) inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and a chemotherapeutic agent.In some embodiments, the one or more additional anti-cancer agents are selected from antibody-drug conjugates (e.g., trastuzumab emtansine or trastuzumab deruxtecan). In some embodiments, the one or more additional anti-cancer agents comprise trastuzumab and capecitabine. In some embodiments, the drugs are used in combination with radiation. In some embodiments, the method further comprises identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer. In some embodiments, the individual is human.

[0300] In some embodiments, the individual has undergone one or more (e.g., one, two, or three) prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the individual has failed one or more (e.g., one, two, or three) prior therapies before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.

[0301] In some embodiments, the one or more prior therapies exhibit inhibitory activity against cancers that comprise a T790M mutation in the epidermal growth factor receptor (EGFR) protein. In some embodiments, the one or more prior therapies exhibit inhibitory activity against cancers that comprise a T790M mutation in the epidermal growth factor receptor (EGFR) protein include osimertinib.

[0302] In some embodiments, the individual has been administered osimertinib prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, at the time the individual is administered a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, the administration of osimertinib has been completed for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0303] In some embodiments, the one or more prior therapies include one or more standard of care treatments for the cancer.

[0304] In some embodiments, the individual has not undergone one or more (e.g., 1, 2, or 3) prior therapies for the treatment of cancer prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein.

[0305] In some embodiments, the individual is a mammal, hi some embodiments, the individual is a human.

[0306] Second drug or therapy In some embodiments, the methods further comprise administering to the individual in need thereof one or more additional anti-cancer agents or second therapies.

[0307] In some embodiments, the one or more additional anti-cancer agents comprise one or more agents selected from the group consisting of a HER2 inhibitor, a HER2-CD3 bispecific antibody, a HER2 immunotargeting bispecific antibody, an anti-HER2 chimeric antigen receptor (CAR) T cell, an anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocyte (CTL), an anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cell, an anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cell, an epidermal growth factor receptor (EGFR) inhibitor, a poly-ADP-ribose polymerase (PARP) inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and a chemotherapeutic agent.

[0308] Exemplary HER2 inhibitors include trastuzumab, trastuzumab and hyaluronidase, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, margetuximab, trastuzumab emtansine, trastuzumab deruxtecan, ZW49 (Zymeworks), A166 (Klaus16pharma), ), ARX788 (Ambrx), RC48-ADC (RemeGen), bic-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189.

[0309] Exemplary EGFR inhibitors include, but are not limited to, erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, lapatinib, dacomitinib, necitumumab, vandetanib, afatinib, brigatinib, and nicotinib.

[0310] Exemplary PARP inhibitors include, but are not limited to, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, and E7016.

[0311] Exemplary anti-PD-1 antibodies include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tirelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514.

[0312] Exemplary PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0313] Exemplary CTLA-4 inhibitors include ipilimumab and tremelimumab.

[0314] In some embodiments, the one or more additional anticancer agents are bevacizumab, trastuzumab, trastuzumab and hyaluronidase, capecitabine, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, margetuximab, trastuzumab emtansine, trastuzumab deruxtecan, ZW49 (Zymeworks), A166 (Klaus Pharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, nekitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, bevacizumab Selected from the group consisting of riparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemipilimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0315] In some embodiments, the one or more additional anti-cancer agents are selected from antibody-drug conjugates, hi some embodiments, the antibody-drug conjugates are selected from the group consisting of trastuzumab emtansine and trastuzumab deruxtecan.

[0316] In some embodiments, the one or more additional anti-cancer agents comprise one or more chemotherapeutic agents, hi some embodiments, the one or more chemotherapeutic agents are selected from the group consisting of doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxiplatin, and eribulin.

[0317] In some embodiments, the one or more additional anti-cancer agents comprise trastuzumab and capecitabine.

[0318] In some embodiments, the one or more additional anticancer agents comprise a PI3K inhibitor. Exemplary PI3K inhibitors include, but are not limited to, taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, buparlisib (BKM120), duvelisib, (IPI-145), copanlisib (BAY80-6946), PX-866, dactolisib, CUDC-907, boctalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597.

[0319] In some embodiments, the one or more additional anticancer agents are erlotinib, gefitinib, afatanib, bevacizumab, trastuzumab, trastuzumab and hyaluronidase, capecitabine, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, margetuximab, trastuzumab emtansine, trastuzumab deruxtecan, ZW49 (Zymeworks), A166 (Klaus Pharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, poziotinib, pyrotinib, mobocertinib (TAK-788), BDTX-189, osimertinib, cetuximab, panitumumab, nekitumumab, vandetanib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, semipilimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0320] In some embodiments, the one or more anticancer agents are selected from the group consisting of osimertinib, erlotinib, gefitinib, and afatinib.

[0321] In some embodiments, one or more anticancer agents comprises osimertinib.

[0322] In some embodiments, one or more anti-cancer agents comprises erlotinib.

[0323] In some embodiments, one or more anti-cancer agents comprises gefitinib.

[0324] In some embodiments, one or more anticancer agents comprises afatinib.

[0325] In some embodiments, the method further comprises treating the individual in need thereof with radiation.

[0326] Administration and Methods of Administration The amount of a salt of Compound I described herein administered to an individual (e.g., a human) can vary depending on the particular composition, method of administration, and the particular cancer being treated. The amount should be sufficient to produce a desired response, such as a therapeutic response to cancer. In some embodiments, the amount of a salt of Compound I described herein is below a level that induces toxicological effects (e.g., effects above clinically acceptable toxicity levels), or is at a level at which potential side effects can be controlled or tolerated when a salt of Compound I described herein is administered to an individual.

[0327] In some embodiments, the salt of Compound I described herein is administered systemically to a subject. In some embodiments, the salt of Compound I described herein is administered parenterally to a subject. In some embodiments, the salt of Compound I described herein is administered locally (i.e., topically) to a subject. In some embodiments, the salt of Compound I described herein is administered orally, intravenously, intraarterially, intraperitoneally, intravesicularly, subcutaneously, intrathecally, intrapulmonary, intramuscularly, intratracheally, intracerebrally, intraocularly, transdermally, or by inhalation. In some embodiments, the salt of Compound I described herein is administered orally to a subject. In some embodiments, the salt of Compound I described herein is administered orally to a subject, while one or more additional agents may be administered to the subject by other routes, including intravenously, intraarterially, intraperitoneally, intravesicularly, subcutaneously, intrathecally, intrapulmonary, intramuscularly, intratracheally, intracerebrally, intraocularly, transdermally, or by inhalation. For example, in some embodiments, the salt of Compound I described herein is administered orally to a subject, while one or more additional agents are administered intravenously to a subject. In some embodiments, the salts of Compound I described herein are administered orally to an individual. In some embodiments, the salts of Compound I described herein are administered parenterally to an individual. In some embodiments, the salts of Compound I described herein are administered intravenously to an individual. In some embodiments, the salts of Compound I described herein are administered subcutaneously to an individual. In some embodiments, the salts of Compound I described herein are administered intracerebrally to an individual.

[0328] In some embodiments, a salt of Compound I described herein and a second agent or therapy are administered to an individual simultaneously. In some embodiments, a salt of Compound I described herein and a second agent or therapy are administered to an individual simultaneously. In some embodiments, a salt of Compound I described herein and a second agent or therapy are administered to an individual sequentially.

[0329] In some embodiments, a dosage of about 1 mg / kg to about 100 mg / kg of a salt of Compound I described herein is administered to an individual, such as a human (e.g., about 1 mg / kg to about 75 mg / kg, about 2 mg / kg to about 75 mg / kg, about 3 mg / kg to about 75 mg / kg, about 4 mg / kg to about 75 mg / kg, about 5 mg / kg to about 75 mg / kg, about 1 mg / kg to about 50 mg / kg, about 2 mg / kg to about 50 mg / kg, about 3 mg / kg to about 50 mg / kg, about 4 mg / kg to about 50 mg / kg, about 5 mg / kg to about 50 mg / kg, about 1 mg / kg to about 40 mg / kg, about 2 mg / kg to about 40 mg / kg, about 3 mg / kg to about 40 mg / kg, about 4 mg / kg~40mg / kg, 5mg / kg~40mg / kg, 1mg / kg~30mg / kg, 2mg / kg~30mg / kg, 3mg / kg~30mg / kg, 4mg / kg~30mg / kg, 5mg / kg~30mg / kg, 6mg / kg~80mg / kg, 10mg / kg~80mg / kg g, about 15 mg / kg to about 80 mg / kg, about 20 mg / kg to about 80 mg / kg, about 25 mg / kg to about 80 mg / kg, about 30 mg / kg to about 80 mg / kg, about 35 mg / kg to about 80 mg / kg, about 40 mg / kg to about 80 mg / kg, about 45 mg / kg to about 80 mg / kg, or about 50 mg / kg to about 80 mg / kg). In some embodiments, a salt of Compound I described herein is administered to an individual (e.g., a human) once or twice daily, optionally orally or parenterally. For oral administration, an exemplary daily dose of a salt of Compound I described herein is about 0.001 to about 1000 mg / kg body weight, with treatment repeated at appropriate intervals.

[0330] Additionally, the salts of Compound I described herein can be administered according to the methods disclosed herein in amounts of about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 10 mg to about 500 mg, or about 25 mg to about 500 mg, or about 50 to about 500 mg, or about 100 mg to about 500 mg, or about 10 mg to about 750 mg, or about 10 mg to about 700 mg, or about 10 mg to about 650 mg, or about 10 mg to about 600 mg, or about 10 mg It may be administered in an amount of from about 10 mg to about 575 mg, or from about 10 mg to about 550 mg, or from about 10 mg to about 500 mg, or from about 10 mg to about 450 mg, or from about 10 mg to about 400 mg, or from about 10 mg to about 350 mg, or from about 10 mg to about 300 mg, or from about 10 mg to about 275 mg, or from about 10 mg to about 250 mg, or from about 10 mg to about 200 mg, or from about 10 mg to about 150 mg, or from about 10 mg to about 100 mg, or from about 10 mg to about 75 mg, or from about 10 mg to about 50 mg, or from about 10 mg to about 25 mg.

[0331] Additionally, the salts of Compound I described herein may be administered once daily (QD) in accordance with the methods disclosed herein. Compound I may be administered as a salt in an amount that provides about 6 mg QD, about 12 mg QD, about 20 mg QD, about 30 mg QD, about 45 mg QD, about 60 mg QD, about 75 mg QD, about 90 mg QD, or about 105 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount that provides about 6 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount that provides about 12 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount that provides about 20 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount that provides about 30 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount to provide about 45 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount to provide about 60 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount to provide about 75 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount to provide about 90 mg QD of Compound I free base. In one embodiment, Compound I may be administered as a salt in an amount to provide about 105 mg QD of Compound I free base.

[0332] In another embodiment, Compound I may be administered as a salt in an amount to provide an amount of Compound I free base of about 110 mg QD, or about 115 mg QD, or about 120 mg QD, or about 125 mg QD, or about 130 mg QD, or about 135 mg QD, or about 140 mg QD, or about 145 mg QD, or about 150 mg QD, or about 155 mg QD, or about 160 mg QD, or about 165 mg QD, or about 170 mg QD, or about 180 mg QD, or about 190 mg QD, or about 200 mg QD. In some embodiments, Compound I is administered in the form of a malonate salt in an amount that provides about 110 mg QD, or about 115 mg QD, or about 120 mg QD, or about 125 mg QD, or about 130 mg QD, or about 135 mg QD, or about 140 mg QD, or about 145 mg QD, or about 150 mg QD, or about 155 mg QD, or about 160 mg QD, or about 165 mg QD, or about 170 mg QD, or about 180 mg QD, or about 190 mg QD, or about 200 mg QD of the free base of Compound I. In some embodiments, the salt of Compound I is administered in the form of a pharmaceutically acceptable composition. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the salt of Compound I is a glycolate salt.

[0333] In another embodiment, the individual in need thereof receives (a) greater than 10 mg but less than about 45 mg, (b) greater than about 45 mg but less than about 200 mg, (c) about 45 mg to about 60 mg, (d) about 45 mg to about 90 mg, (e) about 45 mg to about 120 mg, (f) about 45 mg to about 60 mg, (h) about 75 mg, (i) about 80 mg, (d) about 45 mg to about 90 mg, (e) about 45 mg to about 120 mg. In some embodiments, the salt of Compound I or pharmaceutical composition is administered in an amount to provide a total daily dose of Compound I selected from (a) about 45 mg, (b) about 60 mg, (c) about 75 mg, (d) about 80 mg, (e) about 90 mg, (f) about 100 mg, (g) about 120 mg, (g) about 150 mg, (h) about 175 mg, (i) about 80 mg, (j) about 90 mg, (k) about 100 mg, (l) about 120 mg, (m) about 150 mg, (n) about 175 mg, (o) about 200 mg, and (p) greater than about 120 mg and less than about 200 mg. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0334] In another embodiment, the individual in need thereof receives (a) greater than 10 mg but less than about 45 mg, (b) greater than about 45 mg but less than about 200 mg, (c) about 45 mg to about 60 mg, (d) about 45 mg to about 90 mg, (e) about 45 mg to about 120 mg, (f) about 45 mg to about 60 mg, (h) about 75 mg, (i) about 80 mg, (d) about 45 mg to about 90 mg, (e) about 45 mg to about 120 mg. (f) about 45 mg, (g) about 60 mg, (h) about 75 mg, (i) about 80 mg, (j) about 90 mg, (k) about 100 mg, (l) about 120 mg, (m) about 150 mg, (n) about 175 mg, (o) about 200 mg, and (p) about 120 mg but less than about 200 mg of Compound I. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 200 mg. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 175 mg. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 150 mg. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 140 mg. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 130 mg. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 120 mg. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 110 mg. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 100 mg. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of Compound I of greater than about 45 mg but less than about 95 mg.In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of greater than about 45 mg but less than about 90 mg of Compound I. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of greater than about 45 mg but less than about 85 mg of Compound I. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of greater than about 45 mg but less than about 80 mg of Compound I. In some embodiments, the individual in need thereof is administered malonate in an amount that provides a total daily dose of greater than about 45 mg but less than about 75 mg of Compound I.

[0335] In another embodiment, the individual in need thereof is administered a malonate salt or pharmaceutical composition of Compound I in an amount providing about 30 mg BID, about 40 mg BID, about 45 mg QD, about 50 mg BID, about 60 mg QD, about 75 mg QD, about 90 mg QD, or about 120 mg QD of Compound I. In some embodiments, the individual in need thereof is administered a malonate salt or pharmaceutical composition in an amount that is about 30 mg BID. In some embodiments, the individual in need thereof is administered a malonate salt or pharmaceutical composition in an amount that is about 40 mg BID. In some embodiments, the individual in need thereof is administered a malonate salt or pharmaceutical composition in an amount that is about 45 mg QD. In some embodiments, the individual in need thereof is administered a malonate salt or pharmaceutical composition in an amount that is about 50 mg BID. In some embodiments, the individual in need thereof is administered a malonate salt or pharmaceutical composition in an amount that is about 60 mg QD. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 75 mg QD. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 80 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 85 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 90 mg QD. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 100 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 110 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 120 mg QD. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 125 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 130 mg. In some embodiments, the individual in need thereof is administered the malonate salt or pharmaceutical composition in an amount that is about 135 mg.In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 140 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 145 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 150 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 160 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 170 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 180 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 190 mg. In some embodiments, the individual in need thereof is administered malonate or the pharmaceutical composition in an amount that is about 200 mg.

[0336] In another embodiment, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.1 nM or greater for at least 8 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 8 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt.

[0337] In another embodiment, the individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.1 nM or greater for at least 12 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered a salt or pharmaceutical composition in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 12 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0338] In another embodiment, the individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.1 nM or greater for at least 16 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered a salt or pharmaceutical composition in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 16 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0339] In another embodiment, the individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.1 nM or greater for at least 20 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered a salt or pharmaceutical composition in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 20 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0340] In another embodiment, the individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.1 nM or greater for at least 24 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered a salt or pharmaceutical composition in an amount that provides an average unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 24 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0341] In another embodiment, the individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides a Cmax of Compound I in the individual's plasma of 0.2 nM or greater after administration of the salt or pharmaceutical composition to the individual. In another embodiment, the individual in need thereof is administered a Cmax of Compound I in the individual's plasma of 0.25 nM or greater, 0.3 nM or greater, 0.35 nM or greater, 0.4 nM or greater, 0.45 nM or greater, 0.5 nM or greater, 0.55 nM or greater, 0.6 nM or greater, 0.65 nM or greater, 0.7 nM or greater, 0.75 nM or greater, 0.8 nM or greater, 0.85 nM or greater, 0.9 nM or greater, 0.95 nM or greater, 1 nM or greater, 1.25 nM or greater after administration of the salt or pharmaceutical composition to the individual. The salt or pharmaceutical composition is administered in an amount that provides a Cmax of Compound I in the plasma of the individual that is greater than or equal to 1.5 nM, greater than or equal to 1.75 nM, greater than or equal to 2 nM, greater than or equal to 2.5 nM, greater than or equal to 3 nM, greater than or equal to 3.5 nM, greater than or equal to 4 nM, greater than or equal to 4.5 nM, greater than or equal to 5 nM, greater than or equal to 5.5 nM, greater than or equal to 6 nM, greater than or equal to 6.5 nM, greater than or equal to 7 nM, greater than or equal to 7.5 nM, greater than or equal to 8 nM, greater than or equal to 8.5 nM, greater than or equal to 9 nM, greater than or equal to 9.5 nM, or greater than or equal to 10 nM. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0342] In another embodiment, an individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides a Cmax of Compound I in the individual's plasma of greater than or equal to 0.2 nM and less than or equal to 10 nM after administration of the salt or pharmaceutical composition to the individual. In another embodiment, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a Cmax of Compound I in the individual's plasma of 0.2 nM or more and 9 nM or less, or 0.2 nM or more and 8.5 nM or less, or 0.2 nM or more and 8 nM or less, or 0.2 nM or more and 7.5 nM or less, or 0.2 nM or more and 7 nM or less, or 0.2 nM or more and 6.5 nM or less, or 0.2 nM or more and 6 nM or less, or 0.2 nM or more and 5.5 nM or less, or 0.2 nM or more and 5 nM or less, or 0.2 nM or more and 4.5 nM or less, or 0.2 nM or more and 4 nM or less, or 0.2 nM or more and 3.5 nM or less, or 0.2 nM or more and 3 nM or less, or 0.2 nM or more and 2.75 nM or less, after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0343] In another embodiment, an individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides (a) a Cmax of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, and (b) a mean unbound concentration of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, in the plasma of the individual for at least 8 hours after administration of the salt or pharmaceutical composition to the individual. In another embodiment, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a Cmax of Compound I in the individual's plasma of greater than or equal to 0.2 nM and less than or equal to 9 nM, or greater than or equal to 0.2 nM and less than or equal to 8.5 nM, or greater than or equal to 0.2 nM and less than or equal to 8 nM, or greater than or equal to 0.2 nM and less than or equal to 7.5 nM, or greater than or equal to 0.2 nM and less than or equal to 7 nM, or greater than or equal to 0.2 nM and less than or equal to 6.5 nM, or greater than or equal to 0.2 nM and less than or equal to 6 nM, or greater than or equal to 0.2 nM and less than or equal to 5.5 nM, or greater than or equal to 0.2 nM and less than or equal to 5 nM, or greater than or equal to 0.2 nM and less than or equal to 4.5 nM, or greater than or equal to 0.2 nM and less than or equal to 4 nM, or greater than or equal to 0.2 nM and less than or equal to 3.5 nM, greater than or equal to 0.2 nM and less than or equal to 3 nM, or greater than or equal to 0.2 nM and less than or equal to 2.75 nM, after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a mean unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 8 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0344] In another embodiment, an individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides (a) a Cmax of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, and (b) a mean unbound concentration of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, in the plasma of the individual for at least 12 hours after administration of the salt or pharmaceutical composition to the individual. In another embodiment, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a Cmax of Compound I in the individual's plasma of greater than or equal to 0.2 nM and less than or equal to 9 nM, or greater than or equal to 0.2 nM and less than or equal to 8.5 nM, or greater than or equal to 0.2 nM and less than or equal to 8 nM, or greater than or equal to 0.2 nM and less than or equal to 7.5 nM, or greater than or equal to 0.2 nM and less than or equal to 7 nM, or greater than or equal to 0.2 nM and less than or equal to 6.5 nM, or greater than or equal to 0.2 nM and less than or equal to 6 nM, or greater than or equal to 0.2 nM and less than or equal to 5.5 nM, or greater than or equal to 0.2 nM and less than or equal to 5 nM, or greater than or equal to 0.2 nM and less than or equal to 4.5 nM, or greater than or equal to 0.2 nM and less than or equal to 4 nM, or greater than or equal to 0.2 nM and less than or equal to 3.5 nM, greater than or equal to 0.2 nM and less than or equal to 3 nM, or greater than or equal to 0.2 nM and less than or equal to 2.75 nM, after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a mean unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 12 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0345] In another embodiment, an individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides (a) a Cmax of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, and (b) a mean unbound concentration of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, in the plasma of the individual for at least 16 hours after administration of the salt or pharmaceutical composition to the individual. In another embodiment, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a Cmax of Compound I in the individual's plasma of greater than or equal to 0.2 nM and less than or equal to 9 nM, or greater than or equal to 0.2 nM and less than or equal to 8.5 nM, or greater than or equal to 0.2 nM and less than or equal to 8 nM, or greater than or equal to 0.2 nM and less than or equal to 7.5 nM, or greater than or equal to 0.2 nM and less than or equal to 7 nM, or greater than or equal to 0.2 nM and less than or equal to 6.5 nM, or greater than or equal to 0.2 nM and less than or equal to 6 nM, or greater than or equal to 0.2 nM and less than or equal to 5.5 nM, or greater than or equal to 0.2 nM and less than or equal to 5 nM, or greater than or equal to 0.2 nM and less than or equal to 4.5 nM, or greater than or equal to 0.2 nM and less than or equal to 4 nM, or greater than or equal to 0.2 nM and less than or equal to 3.5 nM, greater than or equal to 0.2 nM and less than or equal to 3 nM, or greater than or equal to 0.2 nM and less than or equal to 2.75 nM, after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a mean unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 16 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0346] In another embodiment, an individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides (a) a Cmax of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, and (b) a mean unbound concentration of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, in the plasma of the individual for at least 20 hours after administration of the salt or pharmaceutical composition to the individual. In another embodiment, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a Cmax of Compound I in the individual's plasma of greater than or equal to 0.2 nM and less than or equal to 9 nM, or greater than or equal to 0.2 nM and less than or equal to 8.5 nM, or greater than or equal to 0.2 nM and less than or equal to 8 nM, or greater than or equal to 0.2 nM and less than or equal to 7.5 nM, or greater than or equal to 0.2 nM and less than or equal to 7 nM, or greater than or equal to 0.2 nM and less than or equal to 6.5 nM, or greater than or equal to 0.2 nM and less than or equal to 6 nM, or greater than or equal to 0.2 nM and less than or equal to 5.5 nM, or greater than or equal to 0.2 nM and less than or equal to 5 nM, or greater than or equal to 0.2 nM and less than or equal to 4.5 nM, or greater than or equal to 0.2 nM and less than or equal to 4 nM, or greater than or equal to 0.2 nM and less than or equal to 3.5 nM, greater than or equal to 0.2 nM and less than or equal to 3 nM, or greater than or equal to 0.2 nM and less than or equal to 2.75 nM, after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a mean unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 20 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0347] In another embodiment, an individual in need thereof is administered a salt or pharmaceutical composition of Compound I in an amount that provides (a) a Cmax of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, and (b) a mean unbound concentration of Compound I that is greater than or equal to 0.2 nM and less than or equal to 10 nM, in the plasma of the individual for at least 24 hours after administration of the salt or pharmaceutical composition to the individual. In another embodiment, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a Cmax of Compound I in the individual's plasma of greater than or equal to 0.2 nM and less than or equal to 9 nM, or greater than or equal to 0.2 nM and less than or equal to 8.5 nM, or greater than or equal to 0.2 nM and less than or equal to 8 nM, or greater than or equal to 0.2 nM and less than or equal to 7.5 nM, or greater than or equal to 0.2 nM and less than or equal to 7 nM, or greater than or equal to 0.2 nM and less than or equal to 6.5 nM, or greater than or equal to 0.2 nM and less than or equal to 6 nM, or greater than or equal to 0.2 nM and less than or equal to 5.5 nM, or greater than or equal to 0.2 nM and less than or equal to 5 nM, or greater than or equal to 0.2 nM and less than or equal to 4.5 nM, or greater than or equal to 0.2 nM and less than or equal to 4 nM, or greater than or equal to 0.2 nM and less than or equal to 3.5 nM, greater than or equal to 0.2 nM and less than or equal to 3 nM, or greater than or equal to 0.2 nM and less than or equal to 2.75 nM, after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the individual in need thereof is administered the salt or pharmaceutical composition in an amount that provides a mean unbound concentration of Compound I in the individual's plasma that is 0.2 nM, or 0.25 nM, or 0.3 nM, or 0.35 nM, or 0.4 nM, or 0.45 nM, or 0.5 nM, or 0.55 nM, or 0.6 nM, or 0.65 nM, or 0.7 nM, 0.8 nM, or 0.9 nM, or 1 nM, or 1.25 nM, or 1.5 nM, or 1.75 nM, or 2 nM or greater for at least 24 hours after administration of the salt or pharmaceutical composition to the individual. In some embodiments, the salt of Compound I is a malonate salt. In some embodiments, the pharmaceutical composition comprises a malonate salt of Compound I. In some embodiments, the salt of Compound I is a glycolate salt. In some embodiments, the pharmaceutical composition comprises a glycolate salt of Compound I.

[0348] Additionally, the salts of Compound I described herein may be administered twice daily (BID) in accordance with the methods disclosed herein. Compound I may be administered as a salt in an amount to provide about 3 mg BID, about 6 mg BID, about 10 mg BID, about 15 mg BID, about 20 mg BID, about 25 mg BID, about 30 mg BID, about 45 mg BID, or about 50 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 3 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 6 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 10 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 15 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 20 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 25 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 30 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 45 mg BID of the free base of Compound I. In one embodiment, Compound I may be administered as a salt in an amount to provide about 50 mg BID of the free base of Compound I.

[0349] Those of skill in the art will understand that for the salts of Compound I described herein, the particular pharmaceutical formulation, dosage, and number of doses administered daily to an individual in need of such treatment are all options within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.

[0350] Dosages of the compositions described herein can be determined by any suitable method. The maximum tolerated dose (MTD) and maximum response dose (MRD) of the salts of Compound I described herein can be determined by established animal and human experimental protocols and the Examples described herein. For example, the toxicity and therapeutic effects of the salts of Compound I described herein can 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 a population) and ED50 (the dose therapeutically effective in 50% of a population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the molar ratio of LD50 to ED50. Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for human use. The dosage of such salts of Compound I described herein preferably falls within a range of circulating concentrations that includes the ED50 with minimal toxicity. Dosages may vary within this range depending on the dosage form employed and the route of administration used. Further relative dosages, expressed as a percentage of maximum response or maximum tolerated dose, are readily obtained via protocols.

[0351] In some embodiments, the amount of a salt of Compound I described herein that constitutes a formulation equivalent to such an amount will vary depending on factors such as the particular salt or form, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., age, weight, sex), but will 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 condition being treated, and the subject or host being treated.

[0352] The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from 2 to 6 weeks. In some embodiments, the length of a treatment cycle ranges from 3 to 6 weeks. In some embodiments, the length of a treatment cycle ranges from 3 to 4 weeks. In some embodiments, the length of a treatment cycle is 3 weeks (or 21 days). In some embodiments, the length of a treatment cycle is 4 weeks (or 28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts 1, 2, 3, or 4 weeks. In some embodiments, a treatment cycle lasts 3 weeks. In some embodiments, a treatment cycle lasts 4 weeks. The number of planned treatment doses within each cycle also varies depending on the agent being administered.

[0353] In one aspect, a composition comprising a salt of Compound I described herein is used to treat cancer in a subject. In one embodiment, such a composition is in a suitable dosage form. Suitable dosage forms include, for example, a liquid, a suspension, a powder for reconstitution, a tablet, a pill, a sachet, or a hard or soft gelatin capsule (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005))).

[0354] The salts of Compound I described herein may be formulated into pharmaceutical compositions, as described below, in any pharmaceutical form that would be suitable for a person skilled in the art. The pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of at least one salt of Compound I of the present disclosure and an inert, pharmaceutically acceptable carrier or diluent.

[0355] The pharmaceutical carrier employed can be either solid or liquid. Exemplary solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers include syrup, peanut oil, olive oil, water, and the like. Similarly, the compositions of the present invention may contain time-delay or sustained-release materials known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with waxes, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate, and the like. Additional additives or excipients may be added to achieve desired formulation characteristics. For example, bioavailability enhancers such as Labrasol, Gelucire, and the like, or compounding agents such as CMC (carboxymethylcellulose), PG (propylene glycol), or PEG (polyethylene glycol) may be added. Gelucir, a semi-solid vehicle that protects active ingredients from light, moisture, and oxidation, may be added, for example, when preparing capsule formulations.

[0356] When a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier can vary, but is generally about 25 mg to about 1 g. When a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial, or a non-aqueous liquid suspension. When a semi-solid carrier is used, the preparation can be in the form of a hard or soft capsule formulation. The compositions of the present invention are prepared in unit dosage forms appropriate for the mode of administration, for example, parenteral or oral administration.

[0357] To obtain a stable water-soluble dosage form, the salt of Compound I described herein may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the drug may be dissolved in a suitable cosolvent or combination of cosolvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like, at concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, the salt of Compound I described herein is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of the salt form of the active ingredient in water or a suitable aqueous vehicle such as isotonic saline or dextrose solution.

[0358] Suitable formulation depends on the selected route of administration.For injection, the salt of Compound I of the present disclosure can be formulated in aqueous solution, preferably in physiologically compatible buffer such as Hanks' solution, Ringer's solution or physiological saline buffer.For transmucosal administration, penetrants suitable for the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

[0359] For oral administration, the salts of Compound I described herein can be formulated by combining the active compound with pharmaceutically acceptable carriers known in the art. Such carriers allow the compounds of the present disclosure to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Oral pharmaceutical preparations can be obtained by using solid excipients mixed with the active ingredient (drug), optionally milling the resulting mixture, and optionally adding suitable excipients before processing the granular mixture to obtain tablets or dragee cores. Suitable excipients include sugars, including lactose, sucrose, mannitol, and sorbitol; and cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof such as sodium alginate.

[0360] The dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active ingredients.

[0361] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in a mixture with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All preparations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0362] For nasal or inhalation administration, the salt of Compound I for use according to the present disclosure may be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the salt of Compound I described herein and a suitable powder base, such as lactose or starch.

[0363] The salts of Compound I described herein may be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. The formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents.

[0364] Pharmaceutical preparations for parenteral administration include aqueous solutions of active compounds in water-soluble form.In addition, suspensions of active ingredients can be prepared as suitable oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the salt of Compound I described herein, allowing for the preparation of highly concentrated solutions.

[0365] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0366] In addition to the formulations described above, the salts of Compound I of the present disclosure may also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the salts of Compound I described herein may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as sparingly soluble salts. A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be the VPD cosolvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant polysorbate 80, and 65% w / v of polyethylene glycol 300, made up to volume with absolute ethanol. The VPD cosolvent system (VPD:5W) contains VPD diluted 1:1 with 5% dextrose in water. This cosolvent system dissolves hydrophobic compounds well and itself produces low toxicity upon systemic administration. The proportions of the cosolvent system may be varied as desired without destroying its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components may be varied; for example, other low-toxicity nonpolar surfactants may be substituted for polysorbate 80; the fraction size of the polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinylpyrrolidone; other sugars or polysaccharides may replace dextrose.

[0367] The pharmaceutical compositions may also include suitable solid- or gel-phase carriers or excipients. These carriers and excipients may significantly improve the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. Additionally, additives or excipients such as Gelucire, Capryol, Labrafil, Labrasol, Lauroglycol, Plurol, Peceol, and Transcutol may also be used.

[0368] Additionally, the pharmaceutical composition may be incorporated into a skin patch to deliver the drug directly onto the skin.

[0369] Additionally, pharmaceutically acceptable formulations used in accordance with the methods disclosed h...

Claims

1. Malonate salt of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

2. 10. The malonate salt of claim 1, wherein the malonate salt is in a crystalline form.

3. 3. The malonate salt of claim 1 or claim 2, wherein the malonate salt has a pH of about 4.5 and a solubility, calculated as the amount of the free base of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, of greater than about 2 mg / mL in aqueous solution at a temperature of about 37° C.

4. 4. The malonate salt of claim 2 or claim 3, wherein the malonate salt exhibits an XRPD pattern comprising a peak at 5.9±0.2 degrees 2θ.

5. 5. The malonate salt of any one of claims 1 to 4, wherein the malonate salt exhibits a differential scanning calorimetry trace comprising a peak at about 147°C to about 151°C.

6. A pharmaceutical composition comprising the malonate salt of any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide glycolate salt.

8. 8. The glycolate salt of claim 7, wherein the glycolate salt is in a crystalline form.

9. 9. The glycolate salt of claim 8, wherein the glycolate salt exhibits an XRPD pattern including a peak at 14.1±0.2 degrees 2θ.

10. A pharmaceutical composition comprising the glycolic acid salt of any one of claims 7 to 9 and a pharmaceutically acceptable carrier.

11. 10. A method of treating cancer in an individual in need thereof, comprising administering to the individual (a) a malonate salt of any one of claims 1 to 5, (b) a glycolate salt of any one of claims 7 to 9, (c) a pharmaceutical composition of claim 6, or (d) a pharmaceutical composition of claim 10.

12. 12. The method of claim 11, wherein the cancer comprises a mutation in epidermal growth factor receptor (EGFR) or one or more wild-type or mutant kinases selected from the group consisting of ERBB2 and ERBB4.

13. 12. The method of claim 11, wherein the cancer is non-small cell lung cancer, and the cancer is determined to contain one or more mutations selected from the group consisting of: (a) an EGFR exon 20 insertion mutation, (b) a HER2 exon 20 insertion mutation, and (c) HER2 amplification or overexpression.

14. 14. The method of any one of claims 11 to 13, wherein the cancer comprises one or more mutations selected from the group consisting of EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, EGFR exon 20 ins ASV, and an ERBB2 mutation, and the ERBB2 mutation is Her2 exon 20 ins YVMA.

15. A method for preparing the malonate salt of any one of claims 1 to 5, comprising the steps of: (1) forming a mixture of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide and malonic acid in a solvent; (2) removing the solvent from step (1) to obtain the malonate salt.

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