Methods for treating gastrointestinal stromal tumors with ripretinib

Abstract

The present disclosure relates to a method of treating gastrointestinal stromal tumors in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of ripretinib or a pharmaceutically acceptable salt thereof.

Description

[Background technology]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 435,137, filed December 23, 2022, U.S. Provisional Patent Application No. 63 / 478,736, filed January 6, 2023, U.S. Provisional Patent Application No. 63 / 481,093, filed January 23, 2023, U.S. Provisional Patent Application No. 63 / 493,821, filed April 3, 2023, U.S. Provisional Patent Application No. 63 / 505,720, filed June 2, 2023, and U.S. Provisional Patent Application No. 63 / 515,898, filed July 27, 2023, the contents of each of which are incorporated herein by reference.

[0002] Gastrointestinal stromal tumors (GISTs) represent less than 1% of all gastrointestinal (GI) tumors but are the most common mesenchymal tumors and soft tissue sarcomas of the GI tract. They can occur anywhere along the GI tract, most commonly in the stomach (60%) or small intestine (30%), and less commonly in the rectum, colon, and mesentery. Approximately 3,300–6,000 new cases of GIST are diagnosed each year in the United States. The majority of cases are sporadic, and older age is a recognized risk factor. Mutations in KIT and platelet-derived growth factor receptor-alpha (PDGFRA) have been found in more than 80% of all primary GISTs. Alterations in the neurofibromatosis type 1 gene (NF1) and succinate dehydrogenase (SDH) complex (SDHC) genes, as well as changes in SDHC promoter methylation, have been reported as oncogenic drivers in GISTs without activating mutations in KIT or PDGFRA and are associated with familial and hereditary syndromes (NF1 and Carney-Stratakis syndrome).

[0003] Despite variations in tumor size, location, and histologic subtype (spindle cell, epithelioid, and mixed), approximately 85% of all GISTs share oncogenic mutations in one of two receptor tyrosine kinases (TKs): KIT or PDGFRA. Constitutive activation of either of these TKs plays a central role in GIST carcinogenesis. Early characterization of the mutational status of GISTs, both localized and metastatic, is important for identifying imatinib-resistant mutations (e.g., some primary KIT exon 17 mutations or PDGFRA D842V) or mutations requiring high doses of imatinib. Patients with GISTs lacking KIT or PDGFRA mutations typically do not respond to imatinib, and standard treatment algorithms are often not applicable. However, other mutations may be present in these patients. The largest group is SDH deficiency, which is often associated with Carney syndrome or Carney-Stratakis syndrome. Other subtypes harbor mutations in NF1 (usually associated with neurofibromatosis type 1) or mutations in BRAF or KRAS. More recently, speculative cases of GIST-like tumors harboring NTRK translocations have further expanded the spectrum of molecular subtypes.

[0004] In the pre-tyrosine kinase inhibitor (TKI) era, GIST (often classified as gastric leiomyosarcoma or leiomyoblastoma) was treated in clinical trials with uncertain sarcoma subtypes and lacked effective systematic therapies. However, improved understanding of the molecular pathogenesis and inductive role of the proto-oncogenes KIT and PDGFRA has transformed treatment for both localized and metastatic disease. Localized, resectable tumors are treated surgically, and surgery remains the mainstay of curative therapy for localized disease. Resected high-risk GIST is often treated with adjuvant imatinib, whereas low-risk GIST is managed with surgery alone. Intermediate-risk GIST is managed on a case-by-case basis. For advanced / metastatic disease, a daily dose of 400 mg of imatinib is approved, with dose escalation to 800 mg at progression, which has shown dramatic results in disease control. Imatinib-refractory patients are treated with sunitinib as second-line therapy, and for sunitinib resistance or intolerance, regorafenib as third-line therapy.

[0005] At diagnosis, 80% of GISTs harbor KIT gene mutations, usually in exon 11, and less commonly in exon 9. Both mechanisms result in ligand-independent receptor activation, leading to uncontrolled cell proliferation and transformation. Primary mutations affect the JM domain, resulting in a shift in equilibrium toward the type I active, or on-state, conformation of KIT and away from the type II inactive, or off-state, conformation. Primary exon 11 mutations are the most common in GISTs (approximately 70% of cases) and induce remarkable responses to treatment with imatinib in both adjuvant and metastatic settings, achieving a 2-year recurrence-free survival of approximately 90% in the adjuvant setting and a median event-free survival of just under 2 years in the metastatic setting. Primary mutations in exon 9 (in treatment-naive patients) affect the extracellular domain of KIT, mimicking the conformational change induced by ligand binding and inducing homodimerization of the KIT receptor. This dimerization leads to the activation of specific intracellular signaling pathways, which may contribute to cancer cell proliferation, survival, and resistance. Although less common than exon 11 mutations, exon 9 mutations (10%–15% of newly diagnosed cases) are the most common in GISTs arising from the small intestine. Unlike exon 11 mutations, they are less responsive to imatinib, both in adjuvant and metastatic settings.

[0006] Although outcomes have improved significantly compared with the era before mutation-defining / TKI therapy, not all patients respond to imatinib, and most GIST patients eventually develop resistance to imatinib. The primary cause of this is the development of secondary mutations in KIT. Resistance-causing secondary mutations typically occur in the catalytic domain of the kinase: 1) in the switch pocket, often in exons 13 and 14 of KIT or exons 14 and 15 of PDGFRA, which sterically disrupt drug binding or conformationally activate KIT; and 2) in the activation loop switch, encoded by exons 17 and 18 of KIT and PDGFRA. Activation loop mutations act by shifting the kinase to an activated type I or on-state conformation, which is inaccessible to any approved type II TKI. Although rare in primary GIST (1%-2% of newly diagnosed cases), mutations in exons 13, 14, and 17 are often responsible for acquired imatinib resistance. Exon 17 mutations alone account for 50% of cases of acquired resistance to imatinib and later to sunitinib. There is a need for TKIs that can inhibit clinically relevant KIT and PDGFRA mutations. Summary of the Invention

[0007] The present disclosure provides a method of treating gastrointestinal stromal tumors in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of ripretinib or a pharmaceutically acceptable salt thereof.

[0008] In an embodiment, disclosed herein is a method of treating a patient afflicted with an advanced gastrointestinal stromal tumor, wherein the patient has a) a KIT exon 17 and / or KIT exon 18 mutation, and / or b) a KIT exon 11 mutation, the method comprising administering to the patient, in one day or twice daily, 150 mg of a compound represented by: [ka] Prior to administration of the compound, the patient has progressed to or is intolerant to imatinib, and in this case, with administration of the compound, the patient achieves significantly longer progression-free survival as determined by mRECIST 1.1 and significantly longer overall survival compared to patients with advanced gastrointestinal stromal tumors harboring KIT exon 17 and / or KIT exon 18 mutations and / or KIT exon 11 mutations who have progressed to or are intolerant to imatinib and who are subsequently administered 50 mg of sunitinib once daily.

[0009] In another embodiment, described herein is a method of treating a patient suffering from advanced gastrointestinal stromal tumor, the patient having a mutation in KIT exon 17 and / or KIT exon 18, not having a mutation in KIT exon 13 and / or 14, and not having a mutation in KIT exon 9, wherein the patient has progressed to or is intolerant to imatinib, and the method comprises administering to the patient: [ka] The method includes administering 150 mg of a compound represented by the formula:

[0010]

[0013] In another embodiment, described herein is a method of treating a patient suffering from advanced gastrointestinal stromal tumor, wherein the patient has progressed to or is intolerant to imatinib, and the patient's circulating tumor DNA has a mutation in KIT exon 17 and / or KIT exon 18, but does not have a mutation in KIT exon 9, and the method comprises administering to the patient: [ka] The method includes administering 150 mg of a compound represented by the formula:

[0011]

[0013] In another embodiment, described herein is a method of treating advanced gastrointestinal stromal tumor in a patient in need thereof, wherein the patient has progressed to or is intolerant to imatinib, the method comprising: selecting patients who have a mutation in KIT exon 17 and / or KIT exon 18 in circulating tumor DNA, but do not have one or more of KIT exon 9, 13, and 14 mutations, to obtain a selected patient; administering in one day or twice daily to the selected patient 150 mg of a compound represented by: [ka] Or, if the patient is not a selected patient, administering one or more different kinase inhibitors to the patient. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows a flow chart for the evaluability of ctDNA samples performed in a randomized patient population with advanced GIST who received imatinib as first-line treatment, as described in Example 1. [Figure 2] FIG. 2 shows a flow chart for detecting exon mutations in KIT or PDGFRA by ctDNA testing, as described in Example 1. [Figure 3] Figure 3 shows PFS by IRR in GIST patients with KIT mutations in exon 11 and exons 17 / 18 upon treatment with ripretinib or sunitinib. [Figure 4] Figure 4 shows PFS by IRR in GIST patients with KIT mutations in exons 17 / 18 upon treatment with ripretinib or sunitinib. [Figure 5] Figure 5 shows plots from the GIST interim analysis (Interim Analysis 1) of overall survival for patients with KIT mutations in exon 11 and exons 17 / 18 who received ripretinib or sunitinib. [Figure 6]Figure 6 shows plots from the extended GIST interim analysis (Interim Analysis 2) of overall survival for patients with KIT mutations in exon 11 and exons 17 / 18 who received ripretinib or sunitinib. [Figure 7] Figure 7 shows plots from the GIST interim analysis (Interim Analysis 1) of overall survival in patients with KIT mutations in exons 17 / 18 who received ripretinib or sunitinib. [Figure 8] Figure 8 shows plots from the extended GIST interim analysis (Interim Analysis 2) of overall survival for patients with KIT mutations in exons 17 / 18 who received ripretinib or sunitinib. [Figure 9] Figure 9 shows a forest plot of progression-free survival (PFS) of GIST patients by KIT mutation status from baseline ctDNA. [Figure 10] FIG. 10 shows a forest plot of progression-free survival (PFS) of GIST patients by KIT exon 11 mutation subgroup from baseline ctDNA. [Figure 11] FIG. 11 shows a forest plot of overall response rate (ORR) in GIST patients by KIT mutation status from baseline ctDNA. [Figure 12] FIG. 12 shows a forest plot of overall response rate (ORR) of GIST patients by KIT exon 11 mutation subgroup from baseline ctDNA. [Figure 13] FIG. 13 shows a forest plot of overall survival (OS) of GIST patients by KIT mutation status from baseline ctDNA during the extended interim analysis (Interim Analysis 2). [Figure 14] FIG. 14 shows a forest plot of overall survival (OS) of GIST patients by KIT exon 11 mutation subgroup from baseline ctDNA during the extended interim analysis (interim analysis 2). [Figure 15]Figure 15 shows a comparison of ORR at data cut 1 described in Example 1 between sunitinib-treated and ripretinib-treated patients in the population with KIT exon 11 and KIT exon 17 / 18 mutations. [Figure 16] Figure 16 shows a Kaplan-Meier plot of progression-free survival (PFS) for patients in the bridging study of the study of Example 1. Patients were determined to have mutations in exon 11, and exon 17 or exon 18 of KIT per tumor tissue ITT population. [Figure 17] Figure 17 shows Kaplan-Meier analysis of PFS (A) and OS (B) for patients, comparing ctDNA-ND with ctDNA-D, as described in Example 4. [Figure 18] Figure 18 shows the ORR of patients, comparing ctDNA-ND with ctDNA-D, as described in Example 4. [Figure 19] FIG. 19 shows a Kaplan-Meier analysis of PFS for patients treated with ripretinib or sunitinib in the ctDNA-ND population (A) and the ctDNA-D population (B), as described in Example 4. [Figure 20] FIG. 20 shows a forest plot of PFS by KIT mutation status as determined by local pathology report at the time of randomization, as described in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0013] The features and other details of the present disclosure will now be described in more detail.Specific terms used in this specification, examples and appended claims are summarized here.These definitions should be read in light of the rest of this disclosure as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0014] definition As used herein, "ripretinib" is a compound represented by the following structure: [ka] Ripretinib is also referred to herein as the compound of formula (I).

[0015] As used herein, "sunitinib" is a compound represented by the following structure: [ka]

[0016] As used herein, "imatinib" is the compound represented by the following structure: [ka]

[0017] As used herein, "regorafenib" is a compound represented by the following structure: [ka]

[0018] The terms "individual," "patient," or "subject" are used interchangeably herein and include any animal, including mammals, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans. The compounds described herein can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the methods described herein is preferably a mammal (e.g., a human) in whom treatment of a disorder described herein is desired.

[0019] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in a compound used in the composition. Compounds included in the present composition that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0020] As used herein, "treating" includes any effect, eg, attenuation, reduction, modulation, or elimination, that results in the improvement of a condition, disease, disorder, or the like.

[0021] "Therapeutically effective amount" includes the amount of a compound of interest that induces the biological or medical response of a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician. The compounds described herein, such as ripretinib, are administered in a therapeutically effective amount to treat the conditions described herein, such as gastrointestinal stromal tumors. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect, such as an amount that results in the prevention or reduction of symptoms associated with the condition.

[0022] As used herein, "KIT" also refers to the KIT proto-oncogene, c-Kit, KIT, Kit, c-kit, c-kit, or CD117.

[0023] The compounds described herein, such as ripretinib, can be formulated into pharmaceutical compositions using pharmaceutically acceptable carriers and administered by a variety of routes. In some embodiments, such compositions are for oral administration. In some embodiments, compositions formulated for oral administration are provided as tablets. In some embodiments, such compositions are for parenteral administration (by injection). In some embodiments, such compositions are for transdermal administration. In some embodiments, such compositions are for topical administration. In some embodiments, such compositions are for intravenous (IV) administration. In some embodiments, such compositions are for intramuscular (IM) administration. Such pharmaceutical compositions and processes for their preparation are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro et al., eds., 19th ed., Mack Publishing Co., 1995).

[0024] As used herein, "exon 13 / 14" refers to i) exon 13 and exon 14, or ii) exon 13 or exon 14.

[0025] As used herein, "exon 17 / 18" refers to i) exon 17 and exon 18, or ii) exon 17 or exon 18.

[0026] Treatment method In certain embodiments, described herein are methods of treating a patient afflicted with an advanced gastrointestinal stromal tumor, wherein the patient has a) a KIT exon 17 and / or KIT exon 18 mutation, and / or b) a KIT exon 11 mutation, the method comprising administering to the patient, in one day or twice daily, 150 mg of a compound represented by: [ka] Prior to administration of the compound, the patient has progressed to or is intolerant to imatinib, and in this case, with administration of the compound, the patient achieves significantly longer progression-free survival as determined by mRECIST 1.1 and significantly longer overall survival compared to patients with advanced gastrointestinal stromal tumors harboring KIT exon 17 and / or KIT exon 18 mutations and / or KIT exon 11 mutations who have progressed to or are intolerant to imatinib and who are subsequently administered 50 mg of sunitinib once daily.

[0027] In some embodiments, the patient has a) a mutation in KIT exon 17 and / or KIT exon 18, and / or b) a mutation in KIT exon 11 in circulating tumor DNA. In some embodiments, the patient receiving the compound does not have a mutation in KIT exon 9 or a mutation in KIT exon 13 or 14 in circulating tumor DNA. In some embodiments, the patient receiving the compound does not have a mutation in KIT exon 9 and does not have a mutation in KIT exon 13 or 14 in circulating tumor DNA. In some embodiments, the patient receiving the compound has a progression-free survival of at least about 14 months, compared to a progression-free survival of about 1.5 months for patients receiving sunitinib. In some embodiments, the method includes administering 150 mg of the compound to the patient once or twice daily for at least 40 days. In some embodiments, the method includes administering 150 mg of the compound to the patient once daily.

[0028] In another embodiment, described herein is a method of treating a patient suffering from advanced gastrointestinal stromal tumor, the patient having a mutation in KIT exon 17 and / or KIT exon 18, not having a mutation in KIT exon 13 and / or 14, and not having a mutation in KIT exon 9, wherein the patient has progressed to or is intolerant to imatinib, and the method comprises administering to the patient: [ka] The method includes administering 150 mg of a compound represented by the formula:

[0029] In some embodiments, the patient has a mutation in KIT exon 17 and / or KIT exon 18, no mutation in KIT exon 13 and / or 14, and no mutation in KIT exon 9 in circulating tumor DNA. In some embodiments, the patient's circulating tumor DNA also has a mutation in KIT exon 11. In some embodiments, the method comprises administering 150 mg of the compound to the patient daily.

[0030]

[0013] In another embodiment, described herein is a method of treating a patient suffering from advanced gastrointestinal stromal tumor, wherein the patient has progressed to or is intolerant to imatinib, and the patient's circulating tumor DNA has a mutation in KIT exon 17 and / or KIT exon 18, but does not have a mutation in KIT exon 9, and the method comprises administering to the patient: [ka] The method includes administering 150 mg of a compound represented by the formula:

[0031] In some embodiments, the methods comprise administering to the patient 150 mg of the compound per day.

[0032]

[0013] In another embodiment, described herein is a method of treating advanced gastrointestinal stromal tumor in a patient in need thereof, wherein the patient has progressed to or is intolerant to imatinib, the method comprising: selecting patients who have a mutation in KIT exon 17 and / or KIT exon 18 in circulating tumor DNA, but do not have one or more of KIT exon 9, 13, and 14 mutations, to obtain a selected patient; administering in one day or twice daily to the selected patient 150 mg of a compound represented by: [ka] Or, if the patient is not a selected patient, administering one or more different kinase inhibitors to the patient.

[0033] In some embodiments, the one or more different kinase inhibitors are selected from the group consisting of sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, vatalanib, and crenolanib. In some embodiments, the one or more different kinase inhibitors are selected from the group consisting of sunitinib and regorafenib. In some embodiments, the one or more different kinase inhibitors are selected from the group consisting of sunitinib malate and regorafenib.

[0034] In some embodiments, if the patient is not a selected patient, the one or more different kinase inhibitors include sunitinib. In some embodiments, if the patient is not a selected patient, the method includes administering 50 mg of sunitinib once daily to the patient. In some embodiments, if the patient is not a selected patient and further progresses after at least sunitinib administration, the method further includes administering 150 mg of the compound to the patient in one day or twice daily. In some embodiments, the method includes administering 150 mg of the compound once daily to the selected patient.

[0035] In some embodiments, the therapeutic efficacy of ripretinib is determined by the patient's progression-free survival after independent radiological review using Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, the therapeutic efficacy of ripretinib is determined by the patient's progression-free survival after independent radiological review using modified Response Evaluation Criteria in Solid Tumors (mRECIST). In some embodiments, the therapeutic efficacy of ripretinib is determined by the patient's objective response rate (ORR), time to tumor progression (TTP), or overall survival (OS) after independent radiological review using mRECIST. In some embodiments, the therapeutic efficacy of ripretinib is determined by the patient's progression-free survival based on investigator assessment. In some embodiments, the therapeutic efficacy of ripretinib is determined by the patient's quality of life according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer 30-item (EORTC-QLQ-C30) and EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaires. In some embodiments, the therapeutic efficacy of ripretinib is determined by the disease control rate of patients. In some embodiments, the therapeutic efficacy of ripretinib is determined by the duration of response of patients. In some embodiments, the therapeutic efficacy of ripretinib is evaluated within one month (e.g., 1, 15, or 29 days) after administering ripretinib. In some embodiments, the therapeutic efficacy of ripretinib is evaluated within three months (e.g., 43, 71, or 85 days) after administering ripretinib. In some embodiments, the therapeutic efficacy of ripretinib is evaluated three months after administering ripretinib.

[0036] After at least 1 month, 2 months, e.g., 42 days or more, of treatment with ripretinib, the patient may have progression-free survival as measured using mRECIST v1.1. As another example, the patient may have progression-free survival of at least 5 or 6 months compared to placebo after at least 4 weeks of daily ripretinib administration, and / or may have a significant 85% reduction in the risk of disease progression or death after, for example, 4 weeks of daily ripretinib administration.

[0037] In some embodiments, the patient has at least one measurable tumor lesion by modified RECIST version 1.1 within 21 days prior to the first dose of ripretinib. In some embodiments, the patient has a non-lymph node tumor lesion measuring 1.0 cm or greater in its long axis or two or more slide thicknesses in its long axis within 21 days prior to the first dose of ripretinib.

[0038] Dose modification Dose adjustments may be made in the methods of administering ripretinib described herein as a result of adverse events experienced by the patient. In some embodiments, the dose adjustment is a dose interruption. In some embodiments, the dose adjustment is a permanent cessation of administration. In some embodiments, the dose adjustment is a dose reduction. In some embodiments, the dose of ripretinib administered to a patient is reduced from 150 mg once daily, e.g., three tablets each containing 50 mg of ripretinib, to 100 mg once daily, e.g., two tablets each containing 50 mg of ripretinib. In some embodiments, the dose of ripretinib administered to a patient is reduced from 150 mg once daily, e.g., three tablets each containing 50 mg of ripretinib, to 50 mg once daily, e.g., one tablet containing 50 mg of ripretinib. In some embodiments, the adverse reaction is selected from the group consisting of palmar-plantar erythrodysesthesia syndrome, hypertension, arthralgia, and myalgia.

[0039] In some embodiments, adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (e.g., baseline, Grade 1, Grade 2, Grade 3, or Grade 4). In some embodiments, the dose modification is a dose interruption (e.g., a dose interruption for at least 7 days) as a result of a Grade 2 adverse event. In some embodiments, if the adverse event declines to Grade 1 or baseline within a first time period (e.g., within 7 days), dosing is resumed at the same dose level before dose interruption. In some embodiments, if the adverse event declines to Grade 1 or baseline after a first time period (e.g., after 7 days), dosing is resumed at the reduced dose level before dose interruption. In some embodiments, if the adverse event declines to Grade 1 or baseline after a first time period but remains as a Grade 1 or baseline adverse event after a second time period (e.g., after 28 days), the reduced dose level is re-escalated to the dose level before dose interruption. In some embodiments, the dose modification is a dose interruption (e.g., a dose interruption for at least 7 days and up to 28 days) as a result of a Grade 3 adverse event. In some embodiments, dosing is continued at a reduced level after the dose interruption. In some embodiments, the dose modification is a permanent cessation of dosing as a result of a Grade 4 adverse event (e.g., Grade 4 hypertension).

[0040] The patient may be administered additional treatment in response to an adverse event or to prevent the occurrence of an adverse event. In some embodiments, a patient suffering from an adverse dermatological reaction, e.g., a palmar-plantar erythrodysesthesia syndrome, is administered a topical composition (e.g., an emollient) to treat the adverse dermatological reaction. In some embodiments, the patient is administered a topical composition (e.g., an emollient) based on the severity of the adverse dermatological reaction, e.g., a Grade 2, Grade 3 adverse dermatological reaction, e.g., a Grade 1, Grade 2, or Grade 3 palmar-plantar erythrodysesthesia syndrome, e.g., a Grade 1, Grade 2, or Grade 3 palmar-plantar erythrodysesthesia syndrome. In some embodiments, the topical composition (e.g., an emollient) is administered to the patient during a dose interruption of ripretinib. In some embodiments, the topical composition (e.g., an emollient) is administered to the patient contemporaneously with a dose of ripretinib, e.g., a reduced dose of ripretinib.

[0041] The patient may also be administered an additional treatment before or during administration of ripretinib in accordance with the methods described herein to prevent or ameliorate adverse events. In some embodiments, the patient is administered a topical composition (e.g., an emollient) before and / or during administration of ripretinib to prevent or ameliorate the development of adverse dermatological reactions, e.g., hand-foot skin reactions, e.g., palmar-plantar erythrodysesthesia syndrome. [Example]

[0042] Example 1. Mutational heterogeneity of imatinib resistance and comparative efficacy of ripretinib and sunitinib in patients with gastrointestinal stromal tumors: ctDNA analysis of a multicenter, international, randomized, open-label phase 3 trial. This was a multicenter, international, randomized, open-label, phase 3 study enrolling adult patients with advanced gastrointestinal stromal tumors (GISTs) who had progressed to or were previously intolerant to imatinib. Patients were randomized 1:1 to receive ripretinib 150 mg once daily (QD) or sunitinib 50 mg once daily (QD) (4 weeks on / 2 weeks off). Baseline peripheral whole blood samples were analyzed by Guardant360, a 74-gene circulating tumor DNA (ctDNA) next-generation sequencing (NGS)-based assay. A flowchart of the evaluability of ctDNA samples is shown in Figure 1. A scheme for the implementation of ctDNA testing to detect exonic mutations at baseline is shown in Figure 2.

[0043] Of the 453 patients in the overall intent-to-treat (ITT) population, baseline ctDNA analysis was performed in 362 patients for whom evaluable samples were available. ctDNA was detected in 280 samples, and KIT mutations were detected in 213 patients. Primary KIT mutations were detected in exon 11 in 157 patients and in exon 9 in 36 patients. Common resistance mutations in KIT were in exons 17 / 18 in 89 patients and exons 13 / 14 in 81 patients. Among patients with a primary KIT exon 11 mutation, 52 patients had mutations in exons 17 or 18 only, 41 patients had mutations in exons 13 or 14 only, and 22 patients had mutations in both exons 13 / 14 and 17 / 18. Patients with primary mutations in KIT exon 11 only and secondary mutations in exons 17 or 18 only had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with QINLOCK compared with sunitinib (Table 1). Efficacy in patients with detectable ctDNA in KIT exon 11 and in the intention-to-treat population was consistent with the primary analysis based on tumor data used for randomization. Safety profiles of subgroups were consistent with the primary analysis. [Table 1]

[0044] Top-line results Figure 3 shows a PFS plot by independent radiologic review (IRR) for GIST patients with KIT mutations in exon 11 and exons 17 / 18, excluding mutations in KIT exons 9, 13, and / or 14. In this figure, the median PFS for patients receiving ripretinib was 14.2 months, whereas the median PFS for patients receiving sunitinib was 1.5 months. Figure 4 shows a PFS plot by IRR for GIST patients with KIT mutations in exons 17 / 18, excluding mutations in KIT exons 9, 13, and / or 14. In this figure, the median PFS for patients receiving ripretinib was 13.8 months, whereas the median PFS for patients receiving sunitinib was 2.8 months.

[0045] Figure 5 shows an interim analysis of overall survival (OS) for GIST patients with KIT exon 11 and exon 17 / 18 mutations, excluding mutations in KIT exons 9, 13, and / or 14. In this figure, the median OS for patients treated with ripretinib was not estimable (NE), whereas the median OS for patients treated with sunitinib was 16.9 months. Figure 6 shows an extended interim analysis of overall survival (OS) for GIST patients with KIT exon 11 and exon 17 / 18 mutations, excluding mutations in KIT exons 9, 13, and / or 14. In this figure, the median OS for patients treated with ripretinib was not estimable (NE), whereas the median OS for patients treated with sunitinib was 17.5 months. Figure 7 shows an interim analysis of overall survival (OS) in GIST patients with KIT exon 17 / 18 mutations, excluding mutations in KIT exons 9, 13, and / or 14. In this figure, the median OS for patients receiving ripretinib was not evaluable (NE), whereas the median OS for patients receiving sunitinib was 17.0 months. Figure 8 shows an extended interim analysis of overall survival (OS) in GIST patients with KIT exon 17 / 18 mutations, excluding mutations in KIT exons 9, 13, and / or 14. In this figure, the median OS for patients receiving ripretinib was not evaluable (NE), whereas the median OS for patients receiving sunitinib was 17.5 months.

[0046] Figure 9 shows a forest plot of progression-free survival (PFS) in GIST patients by KIT mutation status from baseline ctDNA. The plot shows that mutations in KIT exons 17 and 18 favor ripretinib treatment, while mutations in KIT exons 9, 13, and 14 favor sunitinib.

[0047] Figure 10 shows a forest plot of progression-free survival (PFS) for GIST patients by KIT exon 11 mutation subgroup from baseline ctDNA. The plot shows that, for example, the subgroup with mutations in only KIT exon 11 and KIT exon 17, the subgroup with mutations in only KIT exon 11 and KIT exon 18, cases with mutations in KIT exons 11 and 17, and cases with mutations in exon 11 and exon 17 or 18 are favored by ripretinib treatment. However, the plot also shows that exon 11 mutations combined with exon 13 or exon 14 mutations are favored by sunitinib.

[0048] Figure 11 shows a forest plot of overall response rates (ORR) for GIST patients by KIT mutation status from baseline ctDNA. For example, the plot favors ripretinib treatment for patients with KIT exon 11, 17, or 18. However, the plot favors sunitinib treatment for patients with KIT exon 9 mutations.

[0049] Figure 12 shows a forest plot of overall response rates (ORR) for GIST patients by KIT exon 11 mutation subgroup from baseline ctDNA. For example, the plot shows that the population with KIT exon 11 mutations combined with KIT exon 17 or 18 mutations favors ripretinib treatment, while the plot shows that KIT exon 11 mutations combined with KIT exon 13 alone favors sunitinib treatment.

[0050] Figure 13 shows a forest plot of overall survival (OS) of GIST patients by KIT mutation status from baseline ctDNA during the extended interim analysis (Interim Analysis 2). For example, the plot shows that the population with KIT exon 17 and 18 mutations favors ripretinib treatment, while the plot shows that the population with KIT exon 13 and 14 mutations favors sunitinib treatment.

[0051] Figure 14 shows a forest plot of overall survival (OS) for GIST patients by KIT exon 11 mutation subgroup from baseline ctDNA during the extended interim analysis (Interim Analysis 2). For example, the plot favors ripretinib treatment for the subgroup with KIT exon 11 and 17 mutations or KIT exon 11 and 18 mutations. In contrast, the plot favors sunitinib treatment for the subgroup with KIT exon 11 and 13 mutations or KIT exon 11 and 14 mutations.

[0052] Additionally, Figure 15 shows a comparison of ORR at data cut 1 described above between sunitinib-treated and ripretinib-treated patients in the population with KIT exon 11 and KIT exon 17 / 18 mutations. The comparison shows an ORR of 44.4% for ripretinib, while the ORR for sunitinib is 0%.

[0053] Example 2. A randomized, multicenter, open-label phase 3 study comparing ripretinib 150 mg QD with sunitinib in second-line advanced GIST patients with KIT exon 11+17 / 18 mutations after treatment with imatinib. This phase 3 clinical trial included 54 patients with advanced gastrointestinal stromal tumors (GISTs) previously treated with imatinib. The resulting patient population was randomized 2:1 to either the ripretinib (N=36) or sunitinib (N=18) treatment groups. Patients randomized to the sunitinib group could cross over to the ripretinib group after progressive disease. Inclusion criteria included: male or female patients aged 18 years or older; a histological diagnosis of GIST with co-occurring KIT exon 11 + 17 / 18 mutations confirmed by central laboratory ctDNA analysis at prescreening; advanced GISTs with radiological progression on imatinib therapy, discontinued ≥10 days before receiving the first dose of study drug; patients must have at least one measurable lesion per mRECIST v1.1 within 21 days prior to receiving the first dose of study drug; and an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≥2. Exclusion criteria included: no co-occurring KIT exon 11 + 17 and / or 18 mutations confirmed by central laboratory ctDNA analysis; history of KIT exon 9 mutation or detection of KIT exon 9, 13, or 14 mutations by central laboratory ctDNA analysis; treatment with any other treatment option in addition to imatinib for advanced GIST (imatinib-containing combination therapy in the first-line set was not permitted); any previous or concurrent malignancy where treatment may interfere with the safety or efficacy evaluation of this study; known active metastases of the central nervous system.

[0054] Patients receiving ripretinib will receive 150 mg QD, while patients receiving sunitinib will receive 50 mg QD sunitinib for four weeks followed by two weeks without sunitinib. Ripretinib 150 mg QD (3 x 50 mg tablets) will be administered continuously in a repeating 42-day cycle. Meanwhile, sunitinib 50 mg QD (4 x 12.5 mg capsules) will be administered in a 42-day cycle, with sunitinib administered continuously for four weeks followed by a two-week break. Participants will visit the investigational site as follows: Days 1, 15, and 29 of Cycle 1; Days 1 and 29 of Cycle 2; and Day 1 only for Cycle 3 and all subsequent cycles. Both treatments will progress until disease progression, unacceptable toxicity, or patient withdrawal of study consent. The primary endpoint is progression-free survival (PFS) by independent radiological review (IRR) using mRECIST. Key secondary endpoints include objective response rate (ORR) by IRR using mRECIST and overall survival (OS).

[0055] Other secondary endpoints included summary measures from the EORTC-QLQ-C30, NCI-PRO-CTCAE items (questions 15 "Constipation," 16 "Diarrhea," 30 "Hand-Foot Syndrome," and 53a and b "Fatigue"), and EQ-5D-5L; time to progression (TTP) based on mRECIST IRR, defined as the time from randomization to documented progressive disease (PD) based on mRECIST IRR; disease control rates at 6, 12, 18, and 24 weeks based on mRECIST IRR, defined as the proportion of participants achieving a complete response (CR), partial response (PR), or stable disease (SD) at the specified time point based on mRECIST IRR; and investigator-performed PFS based on mRECIST. This is defined as the time from randomization to documentation of PD based on investigator assessment by mRECIST or death from any cause, whichever occurs first; duration of response (DOR) for participants who achieved confirmed CR or PR, which is defined as the time interval from when the measurement criteria for confirmed CR or confirmed PR (whichever occurred first) were first met to the objectively documented first day of PD or death, whichever occurred first; TTR is defined as the time from the date of randomization to the first assessment of confirmed CR or PR by mRECIST.

[0056] Safety endpoints include the frequency of treatment-emergent adverse events (TEAEs); the frequency of serious adverse events (SAEs); the frequency of TEAEs leading to dose reduction, interruption, or discontinuation of the study drug; and changes from baseline in ECOG PS, vital signs, ECG, skin test, and clinical laboratory parameters.

[0057] Exploratory endpoints include C max , T max , T 1 / 2These include: pharmacokinetics (PK) of ripretinib, including PK, AUC, and AUC; PFS2, defined as the time from randomization to PD on next-line therapy or death from any cause, as determined by the investigator, whichever occurs first; second PFS, defined as the time from the date of the first dose of next-line therapy to PD or death from any cause, as assessed by the investigator, whichever occurs first; interviews with participants to complete the healthcare utilization questionnaire (HCHQ); baseline levels and changes in selected plasma biomarkers; and associations of genetic variation in the population with differences in PK, pharmacology, efficacy, tolerability, and / or safety.

[0058] Ripretinib interruptions and modifications due to toxicity Ripretinib may be interrupted or reduced, with a first dose reduction from 150 mg once daily to 100 mg once daily or a second dose reduction to 50 mg once daily. These dose interruptions or reductions are at the investigator's discretion due to adverse events and follow the criteria for ripretinib interruptions or reductions in Tables 2 (skin toxicity, arthralgia and myalgia), 3 (left ventricular systolic dysfunction), 4 (hypertension), and 5 (treatment-related adverse events other than skin toxicity, arthralgia / myalgia, left ventricular systolic dysfunction, and hypertension). The severity of adverse events not listed on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v5.0 scale must be assessed according to the criteria in Table 6.

[0059] If ripretinib is discontinued and then restarted, participants will be maintained on the original cycle schedule. If any participant requires a ripretinib dose less than 50 mg once daily or if the participant has a dose reduction and progressive disease as assessed by independent radiological review (IRR), the participant must discontinue ripretinib and undergo an end-of-treatment (EOT) visit, safety follow-up, and survival follow-up. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0060] If adverse events return to Grade 1 or baseline, the ripretinib dose should be re-escalated. Efforts should be made to re-escalate the dose to the dose level at which the adverse event occurred. If the dose level is reduced to the first lower dose level and adverse events return to Grade 1 or baseline, the participant may be restarted at the starting dose level. If a participant undergoes two consecutive dose reductions and adverse events return to Grade 1 or baseline at the second lower dose level, the participant may be restarted at the first lower dose level and must remain at this dose level for one cycle without interruption before being titrated back to the starting dose level.

[0061] If an adverse event leading to a ripretinib dose modification does not return to grade 1 or baseline within one cycle (42 days), ripretinib must be discontinued, except that if the event is not deemed clinically significant by the investigator, there is the possibility of restarting the participant at a lower dose level after consultation with the sponsor.

[0062] Example 3. Results of a bridging study of ripretinib as a second-line treatment for GIST. The results of a bridging study of second-line 150 mg ripretinib administered once daily compared with 50 mg sunitinib administered once daily in patients with gastrointestinal stromal tumors (GIST) in China, related to the study in Example 1 above, were obtained. In this study, 21 patients were determined to have mutations in KIT exon 11 and exon 17 / 18 per tumor tissue ITT population. Progression-free survival (PFS) was determined by independent radiological review using mRECIST. A Kaplan-Meier plot of PFS is shown in Figure 16. The data showed that the median PFS in the sunitinib treatment group was 6.7 months, while the PFS in the ripretinib treatment group was not reached (NE: not estimable).

[0063] Example 4. Outcomes of patients with advanced gastrointestinal stromal tumors with no detectable baseline ctDNA in a clinical trial with ripretinib. The study in Example 1 above examined efficacy outcomes in patients with advanced gastrointestinal stromal tumors in which ctDNA was detected compared to patients without detectable ctDNA. ctDNA-D was defined as a sample in which at least one somatic alteration (SNV or INDEL) was detected and successfully analyzed. ctDNA was detected in 280 / 362 patients (77.3%) (ctDNA-D), while 82 / 362 patients (22.7%) had no detectable ctDNA (ctDNA-ND). Of the ctDNA-ND patients, 40 patients received ripretinib and 42 patients received sunitinib. Of the ctDNA-D patients, 135 patients received ripretinib and 145 patients received sunitinib.

[0064] Figure 17 shows Kaplan-Meier analysis of PFS (A) and OS (B) comparing patients with ctDNA-ND and ctDNA-D. Figure 18 shows ORR comparing patients with ctDNA-ND and ctDNA-D. Figure 19 shows Kaplan-Meier analysis of PFS for patients treated with ripretinib or sunitinib in the ctDNA-ND (A) and ctDNA-D (B) populations. Figure 20 shows a forest plot of PFS by KIT mutation status as determined by local pathology report at the time of randomization.

[0065] Example 5. Multiple treatment comparisons between mutation subgroups. Cox proportional hazards analyses for PFS and OS were performed to examine the interaction between treatment group and mutation subgroup with or without adjustment for baseline characteristics in the Example 1 study.

[0066] For PFS, a Cox model with interaction effects was used, and Bonferroni correction was applied. Interaction analysis between treatment group and mutation subgroup for PFS showed that hazard ratio (HR) values ​​differed between subgroups. The treatment effect was nominally significant in the KIT exon 11+13 / 14 and KIT exon 11+17 / 18 populations before and after Bonferroni correction. The interaction analysis also showed nominal significance after adjustment for age, sex, and race; women had a significantly lower risk of disease progression or death compared with men, regardless of treatment or mutation subgroup. A summary of the results is shown in Table 2 below. The results were robust and support the multiple treatment comparisons between mutation subgroups. [Table 7]

[0067] For OS, a Cox model with interaction effects was used, with Bonferroni correction applied. Interaction analysis between treatment group and mutation subgroup on OS showed that hazard ratio (HR) values ​​differed between subgroups. The treatment effect was nominally significant in the KIT exon 11+17 / 18 subgroup before and after Bonferroni correction, but not in the KIT exon 11+13 / 14 subgroup. This analysis also showed nominal significance after adjustment for age, sex, and race. Women tended to have a lower risk of death compared with men. There was a trend toward a higher risk of death in older patients, regardless of treatment or mutation subgroup. A summary of the results is shown in Table 3 below. The results were robust and support the multiple treatment comparisons across mutation subgroups. [Table 8]

Claims

1. 1. A method of treating a patient suffering from advanced gastrointestinal stromal tumor, wherein the patient has a) a mutation in KIT exon 17 and / or KIT exon 18, and b) a mutation in KIT exon 11; to the patient, 【Chemistry 1】 in a single day or twice daily, Prior to administration of the compound, the patient has progressed to or is intolerant to imatinib, and The method of claim 1, wherein, upon administration of the compound, the patient achieves significantly longer progression-free survival as determined by mRECIST 1.1 and significantly longer overall survival compared to patients with advanced gastrointestinal stromal tumors harboring KIT exon 17 and / or KIT exon 18 mutations and KIT exon 11 mutations who have progressed to or are intolerant to imatinib and who subsequently receive 50 mg of sunitinib once daily.

2. 2. The method of claim 1, wherein the patient has a) a mutation in the KIT exon 17 and / or the KIT exon 18, and b) a mutation in the KIT exon 11 in circulating tumor DNA.

3. 3. The method of claim 1 or 2, wherein the patient to whom the compound is administered does not have a mutation in KIT exon 9 or does not have a mutation in KIT exon 13 or 14 in circulating tumor DNA.

4. 4. The method of any one of claims 1 to 3, wherein the patient to whom the compound is administered does not have a mutation in KIT exon 9 and does not have a mutation in KIT exon 13 or 14 in circulating tumor DNA.

5. 5. The method of any one of claims 1-4, wherein the patient administered the compound has a progression free survival of at least about 14 months, compared to a progression free survival of about 1.5 months for the patient administered sunitinib.

6. 6. The method of any one of claims 1 to 5, comprising administering to the patient 150 mg of the compound once or twice daily for at least 40 days.

7. 7. The method of any one of claims 1 to 6, comprising administering 150 mg of the compound to the patient once daily.

8. 1. A method of treating a patient suffering from advanced gastrointestinal stromal tumor, wherein the patient has a mutation in KIT exon 17 and / or KIT exon 18, does not have a mutation in KIT exon 13 and / or 14, and does not have a mutation in KIT exon 9, and the patient has progressed to or is intolerant to imatinib, comprising administering to the patient: 【Chemistry 2】 in one day or twice daily.

9. 9. The method of claim 8, wherein the patient has a mutation in KIT exon 17 and / or KIT exon 18, does not have a mutation in KIT exon 13 and / or 14, and does not have a mutation in KIT exon 9 in circulating tumor DNA.

10. 10. The method of claim 8 or 9, wherein the patient's circulating tumor DNA also harbors a mutation in KIT exon 11.

11. 11. The method of any one of claims 8 to 10, comprising administering to the patient 150 mg of the compound daily.

12. 1. A method of treating a patient suffering from advanced gastrointestinal stromal tumor, wherein the patient has progressed to or is intolerant to imatinib, and the patient's circulating tumor DNA has a mutation in KIT exon 17 and / or KIT exon 18 and does not have a mutation in KIT exon 9, comprising administering to the patient: 【Transformation 3】 in one day or twice daily.

13. 13. The method of claim 12, comprising administering to the patient 150 mg of the compound in one day.

14. 1. A method of treating advanced gastrointestinal stromal tumor in a patient in need thereof, wherein the patient has progressed to or is intolerant to imatinib; selecting patients who have a mutation in KIT exon 17 and / or KIT exon 18 in circulating tumor DNA and do not have one or more of the mutations in KIT exons 9, 13, and 14 to obtain the selected patients; To the selected patient, 【Chemistry 4】 150 mg of a compound represented by the formula: or if said patient is not a selected patient, administering to said patient one or more different kinase inhibitors.

15. 15. The method of claim 14, wherein if the patient is not a selected patient, the one or more different kinase inhibitors comprise sunitinib.

16. 15. The method of claim 14, comprising administering 50 mg of sunitinib once daily to said patient if said patient is not an elective patient.

17. 17. The method of claim 15 or 16, further comprising administering to the patient 150 mg of the compound once or twice daily if the patient is not a selected patient and progresses further after at least the sunitinib administration.

18. 18. The method of any one of claims 14 to 17, comprising administering 150 mg of said compound to said selected patient once daily.

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