Method for treating gastrointestinal stromal tumor by using repatinib

Abstract

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

Description

[0001] Cross-references

[0002] This application claims priority to U.S. Provisional Application No. 63 / 435,137 filed on December 23, 2022, U.S. Provisional Application No. 63 / 478,736 filed on January 6, 2023, U.S. Provisional Application No. 63 / 481,093 filed on January 23, 2023, U.S. Provisional Application No. 63 / 493,821 filed on April 3, 2023, U.S. Provisional Application No. 63 / 505,720 filed on June 2, 2023, and U.S. Provisional Application No. 63 / 515,898 filed on July 27, 2023, the contents of each of which are incorporated herein by reference. Background Art

[0003] Gastrointestinal stromal tumors (GISTs) account for less than 1% of all gastrointestinal (GI) tumors but remain the most common GIST and soft tissue sarcoma. They can arise anywhere in the GI tract but are most commonly found in the stomach (60%) or small intestine (30%), and less commonly in the rectum, colon, or mesentery. Approximately 3,300 to 6,000 new GISTs are diagnosed annually in the United States. The vast majority of cases are sporadic, with older age being a known risk factor. Mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA) are found in over 80% of all primary GISTs. Mutations in the neurofibromatosis type 1 (NF1) gene and the succinate dehydrogenase (SDH) complex (SDHC) gene, as well as methylation variants in the SDHC promoter, are considered carcinogenic for GIST in the absence of activating KIT or PDGFRA mutations and are associated with familial and hereditary syndromes (NF1 and Carney-Stratakis syndrome).

[0004] Despite wide variability in tumor size, location, and histologic subtype (spindle cell, epithelioid, or mixed), approximately 85% of GISTs harbor oncogenic mutations in one of two receptor tyrosine kinases (TKs), KIT or PDGFRA. Constitutive activation of either of these TKs plays a crucial role in GIST. Early characterization of the GIST mutational status, both in the localized and metastatic setting, is crucial for distinguishing mutations that are resistant to imatinib (such as some primary KIT exon 17 mutations or PDGFRA D842V) or those that require higher doses of imatinib. Patients with GIST Tgist lacking KIT or PDGFRA mutations are generally ineffective against imatinib and are often incompatible with standard treatment algorithms. However, other mutations can also be present in these patients, with SDH deficiency, often associated with Carney or Carney-Stratakis syndromes, representing the largest subgroup. Other subtypes harbor mutations in NF1 (often associated with neurofibromatosis type I) or in BRAF or KRAS. Recently, sporadic cases of GIST-like tumors harboring NTRK translocations have further expanded the range of molecular subtypes.

[0005] In the pre-tyrosine kinase inhibitor (TKI) era, GIST (often classified as gastric leiomyosarcomas or leiomyoblastomas) was treated as a subtype of unknown sarcoma and lacked effective systemic therapies. However, since a deeper understanding of the molecular pathogenesis and driver roles of the KIT and PDGFRA proto-oncogenes, the treatment of both localized and metastatic disease has evolved. Surgery is now the treatment of localized and resectable tumors and remains the mainstay of curative therapy for localized disease. High-risk GIST is often treated with imatinib as an adjuvant after resection, while low-risk GIST requires surgery alone. Intermediate-risk GIST is managed on a case-by-case basis. In the advanced / metastatic setting, imatinib 400 mg once daily is approved, with dose escalation up to 800 mg as the disease progresses, and has been shown to produce significant disease control. For patients who are resistant to imatinib, sunitinib is used as the second-line therapy, and for patients who are resistant to or intolerant to sunitinib, regorafenib is used as the third-line therapy.

[0006] At diagnosis, 80% of GISTs harbor mutations in the KIT gene, most commonly in exon 11 and less commonly in exon 9. Both mechanisms result in ligand-independent receptor activation, leading to uncontrolled cell growth and transformation. Primary mutations influence disabling mutations within the JM region, shifting the equilibrium toward the development of type I active, or KIT-activated, conformations and away from type II inactive, or KIT-inactivated, conformations. Exon 11 is the most common primary mutation in GIST (approximately 70% of cases), and treatment with imatinib in both the adjuvant and metastatic setting yields significant benefit, with nearly 90% achieving 2-year relapse-free survival in the adjuvant setting and a median event-free survival of nearly 2 years in the metastatic setting. Primary mutations in exon 9 (in treatment-naive patients) affect the extracellular domain of KIT, mimicking the conformational changes induced by ligand binding and triggering homodimerization of the KIT receptor. This dimerization leads to the activation of specific signaling pathways within the cell and can contribute to cancer cell proliferation, survival, and resistance. Although less common than exon 11 mutations (accounting for only 10% to 15% of newly diagnosed cases), exon 9 mutations are most commonly found in GISTs arising in the small intestine. The efficacy of imatinib in either the adjuvant or metastatic setting is less pronounced than in the case of exon 11 mutations.

[0007] While this represents a significant improvement compared to the pre-mutation-driven / TKI therapy era, not all patients benefit from imatinib, and the majority of GIST patients eventually develop resistance to imatinib, most commonly due to secondary mutations in KIT. Secondary resistance mutations typically occur within the kinase's catalytic domain: 1) in the exchange groove, typically within KIT exons 13 and 14, or PDGFRA exons 14 and 15, which sterically disrupt drug binding or conformational activation of KIT; or 2) in the activation loop switch, encoded by KIT exons 17 and 18 and PDGFRA exon 18. Activation loop mutations convert the kinase to an active type I, or primed, conformation that is refractory to binding by any approved type II TKI. Although uncommon in primary GIST (accounting for only 1% to 2% of newly diagnosed cases), exon 13, 14, and 17 mutations are commonly associated with acquired imatinib resistance, with exon 17 mutations alone accounting for nearly 50% of cases of acquired imatinib resistance and subsequent sunitinib resistance. TKIs that inhibit clinically relevant KIT and PDGFRA mutations are needed. Summary of the Invention

[0008] In one embodiment, the present invention provides a method for treating gastrointestinal stromal tumors in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ripretinib or a pharmaceutically acceptable salt thereof.

[0009] In one embodiment, disclosed herein is a method of treating a patient suffering from 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 150 mg of a compound represented by:

[0010]

[0011] It is administered once a day or twice a day, and prior to administration of the compound, the patient has progressed on imatinib or is intolerant to imatinib; and compared to patients who have KIT exon 17 and / or KIT exon 18 mutations and / or KIT exon 11 mutations, suffer from advanced gastrointestinal stromal tumors, have progressed on imatinib or are intolerant to imatinib, and are subsequently administered 50 mg of sunitinib once a day, the patients after administration of the compound achieved significantly longer progression-free survival as determined by mRECIST 1.1 and significantly longer overall survival.

[0012] In another embodiment, described herein is a method of treating a patient suffering from advanced gastrointestinal stromal tumor, the patient having a KIT exon 17 and / or KIT exon 18 mutation, not having a KIT exon 13 and / or 14 mutation, and not having a KIT exon 9 mutation, and wherein the patient has progressed on or is intolerant to imatinib, comprising administering to the patient 150 mg of a compound represented by:

[0013]

[0014] It is administered once a day or twice a day.

[0015] In another embodiment, described herein is a method of treating a patient suffering from advanced gastrointestinal stromal tumor, wherein the patient has progressed on or is intolerant to imatinib, and wherein the patient's circulating tumor DNA has a KIT exon 17 and / or KIT exon 18 mutation and does not have a KIT exon 9 mutation, comprising administering to the patient 150 mg of a compound represented by:

[0016]

[0017] It is administered once a day or twice a day.

[0018] 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 on or is intolerant to imatinib, the method comprising: selecting a patient having circulating tumor DNA KIT exon 17 and / or KIT exon 18 mutations and absence of one or more of KIT exon 9, 13, and 14 mutations to obtain a selected patient; administering to the selected patient 150 mg of a compound represented by:

[0019]

[0020] It is administered once a day or twice a day; or if the patient is not a selected patient, one or more different kinase inhibitors are administered to the patient. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Flowchart describing the evaluability of ctDNA samples for the randomized population of patients with advanced GIST who had received imatinib as first line treatment as described in Example 1.

[0022] Figure 2 Flowchart describing the detection of KIT or PDGFRA exonic mutations by ctDNA testing as described in Example 1.

[0023] Figure 3 To describe the PFS according to IRR in patients with GIST harboring KIT mutations at exon 11 and exons 17 / 18 after treatment with ripretinib or sunitinib.

[0024] Figure 4 To describe the PFS according to IRR in patients with GIST harboring KIT mutations in exon 17 / 18 after treatment with ripretinib or sunitinib.

[0025] Figure 5 Graph depicting the GIST interim analysis of overall survival from patients who have been administered ripretinib or sunitinib and who display KIT mutations at exon 11 and exons 17 / 18 (Interim Analysis 1).

[0026] Figure 6 Figure depicts an extended GIST interim analysis (Interim Analysis 2) of overall survival from patients who have been administered ripretinib or sunitinib and who display KIT mutations at exon 11 and exons 17 / 18.

[0027] Figure 7 Graph depicting the GIST interim analysis of overall survival from patients who have been administered ripretinib or sunitinib and who display KIT mutations in exon 17 / 18 (Interim Analysis 1).

[0028] Figure 8 Graph depicting an extended GIST interim analysis (Interim Analysis 2) of overall survival from patients who have been administered ripretinib or sunitinib and who display KIT mutations in exon 17 / 18.

[0029] Figure 9 Forest plot depicting progression-free survival (PFS) of GIST patients according to KIT mutation status relative to baseline ctDNA.

[0030] Figure 10 Forest plot depicting progression-free survival (PFS) of GIST patients according to KIT exon 11 mutation subgroups relative to baseline ctDNA.

[0031] Figure 11 Forest plot depicting the overall response rate (ORR) of GIST patients according to KIT mutation status relative to baseline ctDNA.

[0032] Figure 12 Forest plot depicting the overall response rate (ORR) of GIST patients according to KIT exon 11 mutation subgroups relative to baseline ctDNA.

[0033] Figure 13 Forest plot depicting overall survival (OS) of GIST patients according to KIT mutation status relative to baseline ctDNA during the extended interim analysis (Interim Analysis 2).

[0034] Figure 14 Forest plot depicting overall survival (OS) of GIST patients according to KIT exon 11 mutation subgroups relative to baseline ctDNA during the extended interim analysis (Interim Analysis 2).

[0035] Figure 15 Shown is a comparison of ORR between sunitinib-treated patients and ripretinib-treated patients in the population with KIT exon 11 and KIT exon 17 / 18 mutations at data cutoff 1 as described in Example 1.

[0036] Figure 16 Shown is a Kaplan-Meier plot of progression-free survival (PFS) for patients in the bridging study of the study of Example 1, in which patients were identified as having mutations in KIT exon 11 and exon 17 or exon 18 by tumor tissue ITT population.

[0037] Figure 17 Kaplan-Meier analysis of PFS (A) and OS (B) for patients with ctDNA-ND versus ctDNA-D as described in Example 4 is shown.

[0038] Figure 18 The ORR for patients with ctDNA-ND versus ctDNA-D as described in Example 4 is shown.

[0039] Figure 19 Kaplan-Meier analysis of PFS of patients treated with ripretinib or sunitinib in ctDNA-ND (A) and ctDNA-D (B) populations as described in Example 4 is shown.

[0040] Figure 20 Forest plot showing PFS by KIT mutation status as determined by local pathology report at the time of randomization as described in Example 4. DETAILED DESCRIPTION

[0041] The features and other details of the present disclosure will now be described more clearly. Specific terms used in this specification, examples, and claims are collected here. These definitions should be read in light of the remainder of this disclosure and 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.

[0042] definition

[0043] As used herein, "ripretinib" is a compound represented by the following structure:

[0044]

[0045] Ripretinib is also referred to herein as the compound of formula (I).

[0046] As used herein, "sunitinib" is a compound represented by the following structure:

[0047]

[0048] As used herein, "imatinib" is a compound represented by the following structure:

[0049]

[0050] As used herein, "regorafenib" is a compound represented by the following structure:

[0051]

[0052] "Individual," "patient," or "subject" are used interchangeably herein and include any animal, including mammals, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and humans. The compounds described herein can be administered not only to mammals such as humans, but also to other mammals, such as animals in need of veterinary treatment, for example, livestock (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated by the methods described herein is preferably a mammal in need of treatment for a condition described herein, such as a human.

[0053] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts having acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are basic in nature are capable of forming 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, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)).

[0054] As used herein, "treating" includes any effect that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, modulation, or elimination.

[0055] A "therapeutically effective amount" includes an amount of a compound of the invention that will elicit the biological or medical response of a tissue, system, animal, or human being that is being sought by a researcher, veterinarian, medical doctor, 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 an amount required to achieve the desired therapeutic and / or preventive effect, such as an amount that prevents or reduces symptoms associated with a condition.

[0056] As used herein, "KIT" also refers to KIT proto-oncogene, c-Kit, KIT, Kit, c-kit, c-kit, or CD117.

[0057] The compounds described herein (e.g., Ripretinib) can be formulated as pharmaceutical compositions using pharmaceutically acceptable carriers and administered by a variety of routes. In some embodiments, such compositions are administered orally. In some embodiments, compositions formulated for oral administration are provided in the form of lozenges. In some embodiments, such compositions are used for parenteral (by injection) administration. In some embodiments, such compositions are used for transdermal administration. In some embodiments, such compositions are topically administered. In some embodiments, such compositions are administered intravenously (IV). In some embodiments, such compositions are administered intramuscularly (IM). Such pharmaceutical compositions and methods for their preparation are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro et al., 19th edition, Mack Publishing Co., 1995).

[0058] As used herein, "exon 13 / 14" refers to i) exon 13 and exon 14 or ii) exon 13 or exon 14.

[0059] As used herein, "exon 17 / 18" refers to i) exon 17 and exon 18 or ii) exon 17 or exon 18.

[0060] Treatment

[0061] In one embodiment, described herein is a method of treating a patient suffering from 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, comprising administering to the patient 150 mg of a compound represented by:

[0062]

[0063] It is administered once a day or twice a day, and wherein prior to administration of the compound, the patient has progressed on imatinib or is intolerant to imatinib; and wherein the patient after administration of the compound achieves significantly longer progression-free survival as determined by mRECIST 1.1 and significantly longer overall survival compared to patients who have KIT exon 17 and / or KIT exon 18 mutations and / or KIT exon 11 mutations, suffer from advanced gastrointestinal stromal tumors, have progressed on imatinib or are intolerant to imatinib, and are subsequently administered 50 mg of sunitinib once daily.

[0064] In some embodiments, the patient has a) the KIT exon 17 and / or the KIT exon 18 mutation and / or b) the KIT exon 11 mutation in circulating tumor DNA. In some embodiments, the patient administered the compound does not have KIT exon 9, or does not have KIT exon 13 or 14 mutations in circulating tumor DNA. In some embodiments, the patient administered the compound does not have KIT exon 9 and does not have KIT exon 13 or 14 mutations in circulating tumor DNA. In some embodiments, 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. In some embodiments, the method comprises administering 150 mg of the compound to the patient once or twice daily for at least 40 days. In some embodiments, the method comprises administering 150 mg of the compound to the patient once daily.

[0065] In another embodiment, described herein is a method of treating a patient suffering from advanced gastrointestinal stromal tumor, the patient having a KIT exon 17 and / or KIT exon 18 mutation, not having a KIT exon 13 and / or 14 mutation, and not having a KIT exon 9 mutation, and wherein the patient has progressed on or is intolerant to imatinib, comprising administering to the patient 150 mg of a compound represented by:

[0066]

[0067] It is administered once a day or twice a day.

[0068] In some embodiments, the patient has a KIT exon 17 and / or KIT exon 18 mutation in circulating tumor DNA, does not have a KIT exon 13 and / or 14 mutation, and does not have a KIT exon 9 mutation. In some embodiments, the patient's circulating tumor DNA also has a KIT exon 11 mutation. In some embodiments, the method comprises administering 150 mg of the compound to the patient once daily.

[0069] In another embodiment, described herein is a method of treating a patient suffering from advanced gastrointestinal stromal tumor, wherein the patient has progressed on or is intolerant to imatinib, and wherein the patient's circulating tumor DNA has a KIT exon 17 and / or KIT exon 18 mutation and does not have a KIT exon 9 mutation, comprising administering to the patient 150 mg of a compound represented by:

[0070]

[0071] It is administered once a day or twice a day.

[0072] In some embodiments, the method comprises administering 150 mg of the compound to the patient once daily.

[0073] 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 on or is intolerant to imatinib, the method comprising: selecting a patient with circulating tumor DNA KIT exon 17 and / or KIT exon 18 mutations and without one or more of KIT exon 9, 13, and 14 mutations to obtain a selected patient; administering to the selected patient 150 mg of a compound represented by:

[0074]

[0075] It is administered once a day or twice a day; or if the patient is not a selected patient, one or more different kinase inhibitors are administered to the patient.

[0076] 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.

[0077] 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, it comprises administering 50 mg of sunitinib to the patient once daily. In some embodiments, if the patient is not a selected patient and has further progressed at least after administration of sunitinib, it further comprises administering 150 mg of the compound to the patient once daily or twice daily. In some embodiments, the method comprises administering 150 mg of the compound to the selected patient once daily.

[0078] In some embodiments, the efficacy of ripretinib is determined by assessing the patient's progression-free survival (PFS) after independent radiological assessment using the Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, the efficacy of ripretinib is determined by assessing the patient's progression-free survival (PFS) after independent radiological assessment using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). In some embodiments, the efficacy of ripretinib is determined by assessing the patient's objective response rate (ORR), time to tumor progression (TTP), or overall survival (OS) after independent radiological assessment using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). In some embodiments, the efficacy of ripretinib is determined by investigator-assessed PFS. In some embodiments, the efficacy of ripretinib is determined by the patient's quality of life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC-QLQ-C30) and EuroQol 5-Dimensions 5-Level (EQ-5D-5L) questionnaires. In some embodiments, the efficacy of ripretinib is determined by the patient's disease control rate. In some embodiments, the therapeutic effect of ripretinib is determined by the duration of the patient's response. In some embodiments, the therapeutic efficacy of ripretinib can be assessed within one month of administering ripretinib (e.g., at 1, 15, or 29 days). In some embodiments, the therapeutic efficacy of ripretinib is assessed within three months of administering ripretinib (e.g., at 43, 71, or 85 days). In some embodiments, the therapeutic efficacy of ripretinib can be assessed after three months of administering ripretinib.

[0079] After at least one month, two months (e.g., 42 days or more) of treatment with ripretinib, the patient can have a progression-free survival as measured using mRECIST v1.1. As another example, the patient can have a progression-free survival of at least 5 or 6 months after at least 4 weeks of daily administration of ripretinib, and / or significantly reduce the risk of disease progression or death by 85%, for example, after at least 4 weeks of daily administration of ripretinib, compared to placebo.

[0080] In some embodiments, wherein the patient has at least one measurable tumor lesion according to modified RECIST version 1.1 within 21 days prior to the first dose of ripretinib. In some embodiments, the patient has a non-nodular tumor lesion greater than or equal to 1.0 cm in the long axis, or greater than or equal to twice the thickness of the tumor in the long axis, within 21 days prior to the first dose of ripretinib.

[0081] Dosage adjustment

[0082] Due to the adverse events experienced by patients, the ripretinib administration method described herein can be adjusted by dose. In some embodiments, dose adjustment is to interrupt the dose. In some embodiments, dose adjustment is to permanently discontinue the dose. In some embodiments, dose adjustment is to reduce the dose. In some embodiments, a 150mg dose of ripretinib (e.g., three tablets, each containing 50mg ripretinib) is administered to the patient once a day, reduced to 100mg (e.g., two tablets, each containing 50mg ripretinib) administered once a day. In some embodiments, a 150mg dose of ripretinib (e.g., three tablets, each containing 50mg ripretinib) is administered to the patient once a day, reduced to 50mg (e.g., one tablet containing 50mg ripretinib) administered once a day. In some embodiments, adverse reactions are selected from the group consisting of: hand-foot skin reaction (e.g., palmar-plantar erythrodysesthesia syndrome), hypertension, arthralgia, and myalgia.

[0083] In some embodiments, adverse events are graded (e.g., baseline, grade 1, grade 2, grade 3, or grade 4) according to the National Cancer Institute's Universal Adverse Event Terminology Criteria Version 5.0. In some embodiments, dosage adjustment is the interruption dose (e.g., interruption dose continues for at least 7 days) due to grade 2 adverse events. In some embodiments, if the adverse event is reduced to grade 1 or baseline within the first period (e.g., within 7 days), the dosage is continued with the same dosage level before the interruption. In some embodiments, if the adverse event is reduced to grade 1 or baseline after the first period (e.g., after 7 days), the dosage is continued with the dosage level less before the interruption dose. In some embodiments, if the adverse event is reduced to grade 1 or baseline after the first period, but still maintains grade 1 or baseline adverse events after the second period (e.g., after 28 days), the reduced dosage level is returned to the dosage level before the interruption dose. In some embodiments, dosage adjustment is the interruption dose (e.g., interruption dose continues for at least 7 days, up to 28 days) due to grade 3 adverse events. In some embodiments, administration continues with the reduced level after the dose interruption. In some embodiments, the dose adjustment is due to permanent discontinuation of dosing due to a Grade 4 adverse event (e.g., Grade 4 hypertension).

[0084] In order to deal with adverse events or prevent adverse events from occurring, additional treatment can be implemented to the patient. In some embodiments, a topical composition (e.g., emollient) is applied to a patient suffering from an adverse dermatological reaction (e.g., hand-foot skin reaction, e.g., palmoplantar erythrodysesthesia syndrome) to treat the adverse dermatological reaction. In some embodiments, based on the severity of the adverse dermatological reaction, such as grade 2, grade 3 adverse dermatological reactions, such as grade 1, grade 2, or grade 3 hand-foot skin reaction, such as grade 1, grade 2, or grade 3 palmoplantar erythrodysesthesia syndrome, a topical composition (e.g., emollient) is applied to the patient. In some embodiments, a topical composition (e.g., emollient) is applied to the patient during the dose interruption of ripretinib. In some embodiments, a topical composition (e.g., emollient) and a certain dose of ripretinib are applied to the patient simultaneously, such as a reduced dose of ripretinib.

[0085] To prevent or mitigate adverse events, additional treatments may also be administered according to the methods described herein before or during the administration of ripretinib to the patient. In some embodiments, a topical composition (e.g., an emollient) is administered to the patient before and / or during the administration of ripretinib to avoid or mitigate the onset of adverse dermatological reactions (e.g., hand-foot skin reactions, such as palmoplantar erythrodysesthesia syndrome).

[0086] Example

[0087] Example 1. Mutational heterogeneity of imatinib resistance and efficacy of ripretinib relative to sunitinib in patients with gastrointestinal stromal tumors: ctDNA analysis from a multicenter, global, randomized, open-label, phase 3 study.

[0088] This multicenter, global, randomized, open-label, Phase 3 study enrolled adult patients with advanced gastrointestinal stromal tumor (GIST) who had progressed on or were intolerant to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg once daily (QD) (4 weeks on / 2 weeks off). Baseline peripheral whole blood was analyzed using Guardant360, a 74-gene circulating tumor DNA (ctDNA) next-generation sequencing (NGS)-based assay. A flow chart of the evaluability of ctDNA samples is shown in Figure 1 The algorithm for performing ctDNA testing to detect exonic mutations at baseline is shown in Figure 2 middle.

[0089] Of the 453 patients in the entire intent-to-treat population (ITT), baseline ctDNA analysis was performed in 362 patients with evaluable samples available. ctDNA was detected in 280 samples and KIT mutations were detected in 213 patients. Primary mutations in KIT were detected in exon 11 in 157 patients and exon 9 in 36 patients. Common resistance mutations in KIT were present in exons 17 / 18 in 89 patients and exons 13 / 14 in 81 patients. Of the patients with primary KIT exon 11 mutations, 52 patients had mutations only in exons 17 or 18, 41 had mutations only in exons 13 or 14, and 22 patients had mutations in both exons 13 or 14 and exons 17 or 18. Patients with only KIT exon 11 primary mutations and only exon 17 or 18 secondary mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with QINLOCK compared to sunitinib (Table 1). Efficacy in patients with detectable ctDNA in KIT exon 11 and in the ITT population was consistent with the primary analysis based on tumor data used for randomization. The subgroup safety profile was consistent with the primary analysis.

[0090] Table 1. Summary of efficacy results of ctDNA analysis in patients with mutations only in KIT exons 11 and 17 or 18

[0091]

[0092] Notes: (1) Data cutoff 1; (2) Data cutoff 2.

[0093] Top-line results

[0094] PFS according to independent radiological review (IRR) for GIST patients with KIT mutations at exon 11 and exons 17 / 18 (excluding mutations in KIT exons 9, 13, and / or 14) is shown in Figure 2. Figure 3 In the 2016 study, patients receiving ripretinib showed a median PFS of 14.2 months, while patients receiving sunitinib showed a median PFS of 1.5 months. The PFS of GIST patients according to IRR for patients with KIT mutations in exons 17 / 18 (excluding mutations in KIT exons 9, 13, and / or 14) is shown in Figure 2. Figure 4 Among them, patients who received ripretinib showed a median PFS of 13.8 months, while those who received sunitinib showed a median PFS of 2.8 months.

[0095] Figure 5An interim analysis of overall survival (OS) in patients with GIST harboring mutations in KIT exon 11 and exons 17 / 18 (excluding mutations in KIT exons 9, 13, and / or 14) is shown, with patients treated with ripretinib showing a median OS of not estimable (NE) and those treated with sunitinib showing a median OS of 16.9 months. Figure 6 An extended interim analysis of overall survival (OS) in patients with GIST harboring mutations in KIT exon 11 and exons 17 / 18 (excluding mutations in KIT exons 9, 13, and / or 14) was shown, with patients treated with ripretinib showing a median OS of not estimable (NE) and those treated with sunitinib showing a median OS of 17.5 months. Figure 7 An interim analysis of overall survival (OS) in patients with GIST harboring mutations in KIT exons 17 / 18 (excluding mutations in KIT exons 9, 13, and / or 14) is shown, with patients treated with ripretinib showing a median OS of not evaluable (NE) and those treated with sunitinib showing a median OS of 17.0 months. Figure 8 Shown is an extended interim analysis of overall survival (OS) in patients with GIST harboring mutations in KIT exons 17 / 18 (excluding mutations in KIT exons 9, 13, and / or 14), where patients treated with ripretinib showed a median OS of not evaluable (NE), while patients treated with sunitinib showed a median OS of 17.5 months.

[0096] Figure 9 A forest plot showing progression-free survival (PFS) of GIST patients by KIT mutation status relative to 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.

[0097] Figure 10 A forest plot showing progression-free survival (PFS) of GIST patients by KIT exon 11 mutation subgroup relative to baseline ctDNA. The plot shows that, for example, groups with mutations in only KIT exon 11 and KIT exon 17, only KIT exon 11 and KIT exon 18, any case with mutations in KIT exons 11 and 17, and any case with mutations in exon 11 and exons 17 or 18 favor ripretinib treatment. However, the plot favors sunitinib for exon 11 mutations in combination with exon 13 or exon 14 mutations.

[0098] Figure 11A forest plot showing the overall response rate (ORR) of GIST patients by KIT mutation status relative to baseline ctDNA. For example, the plot favors ripretinib treatment for KIT exon 11, 17, or 18 populations. However, the plot favors sunitinib treatment for, for example, KIT exon 9 mutations.

[0099] Figure 12 A forest plot showing the overall response rate (ORR) of GIST patients by KIT exon 11 mutation subgroup relative to baseline ctDNA. For example, the plot favors ripretinib treatment for the group with a combination of KIT exon 11 mutations and KIT exon 17 or 18 mutations, while the plot favors sunitinib treatment for, for example, a combination of KIT exon 11 mutations and KIT exon 13 alone.

[0100] Figure 13 A forest plot showing overall survival (OS) of GIST patients by KIT mutation status relative to baseline ctDNA during the extended interim analysis (interim analysis 2). For example, the plot favors ripretinib treatment for the population with KIT exon 17 and 18 mutations, but favors sunitinib treatment for, for example, KIT exon 13 and 14 mutations.

[0101] Figure 14 A forest plot showing overall survival (OS) of GIST patients by KIT exon 11 mutation subgroup relative to baseline ctDNA during the extended interim analysis (interim analysis 2). For example, the plot favors ripretinib treatment for the group with KIT exons 11 and 17 or KIT exons 11 and 18 mutations. In contrast, the plot favors sunitinib treatment for the group with, for example, KIT exons 11 and 13 mutations or KIT exons 11 and 14 mutations.

[0102] in addition, Figure 15 Shown is a comparison of the ORR between patients treated with sunitinib and patients treated with ripretinib in the population with KIT exon 11 and KIT exon 17 / 18 mutations at data cutoff 1 as described above. This comparison shows an ORR of 44.4% for ripretinib and 0% for sunitinib.

[0103] Example 2. A phase 3, randomized, multicenter, open-label study of ripretinib 150 mg QD versus sunitinib in second-line advanced GIST patients with KIT exon 11+17 / 18 mutations following treatment with imatinib.

[0104] This phase 3 clinical trial will enroll 54 patients with advanced gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib. The resulting patient population will undergo a 2:1 randomization to either ripretinib (N=36) or sunitinib (N=18), with patients randomized to sunitinib being able to cross over to ripretinib if their disease progresses. Inclusion criteria include: male or female patients 18 years of age or older; a histological diagnosis of GIST with coexisting KIT exon 11+17 / 18 mutations confirmed by central laboratory ctDNA analysis at prescreening; advanced GIST and radiological progression on imatinib therapy that was discontinued 10 days or more before the first dose of study drug; patients must have at least one measurable lesion according to mRECIST v1.1 within 21 days before the first dose of study drug; and an Eastern Cooperative Oncology Group performance status (ECOGPS) of 2 or greater. Exclusion criteria included: coexisting KIT exon 11+17 and / or 18 mutations that could not be confirmed by central laboratory ctDNA analysis; a 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 line of therapy other than imatinib for advanced GIST (imatinib-containing combination therapy in the first-line setting was not permitted); any prior or concurrent malignancy whose treatment could interfere with the safety or efficacy assessments of this study; and known active metastases to the central nervous system.

[0105] Patients receiving ripretinib will receive 150 mg QD, and patients receiving sunitinib will receive 50 mg QD by receiving 4 weeks of sunitinib treatment and 2 weeks of no sunitinib treatment. 150 mg QD of ripretinib (3 × 50 mg tablets) will be administered continuously in repeated 42-day cycles, while 50 mg QD of sunitinib (4 × 12.5 mg capsules) will be administered in 42-day cycles, wherein sunitinib will be administered continuously for 4 weeks and interrupted for 2 weeks. Participants will visit the study site as follows: Day 1, Day 15, and Day 29 of Cycle 1; Day 1 and Day 29 of Cycle 2; and Day 1 only of Cycle 3 and all other subsequent cycles. Both treatments will continue until disease progression, unacceptable toxicity, or withdrawal of patient study consent. The primary endpoint will be progression-free survival (PFS) using independent radiological review (IRR) of mRECIST. Key secondary endpoints included objective response rate (ORR) and overall survival (OS) using mRECIST for IRR.

[0106] Other secondary endpoints included summary measures from the EORTC-QLQ-C30, NCI-PRO-CTCAE items (question numbers 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 until documented progressive disease (PD) based on mRECIST IRR; disease control rate (DCR) based on mRECIST IRR at weeks 6, 12, 18, and 24, defined as complete response (CR), partial response (PR), and PR at weeks 12, 18, and 24. The proportion of participants with a confirmed response (PR) or stable disease (SD); investigator-assessed PFS by mRECIST, defined as the time from randomization until documented PD by investigator-assessed mRECIST or death attributable to any cause, whichever comes first; duration of response (DOR) for participants who achieved a confirmed CR or PR, defined as the interval from the time the measurement criteria were initially met for a confirmed CR or confirmed PR (whichever was documented first) to the first objectively documented date of PD or death, whichever comes first; and TTR, defined as the time from the date of randomization until the first confirmed CR or PR assessment by mRECIST.

[0107] Safety endpoints included 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 study drug; and changes from baseline in ECOGPs, vital signs, ECGs, dermatologic examinations, and clinical laboratory parameters.

[0108] Exploratory endpoints included the pharmacokinetics (PK) of ripretinib, including C max 、T max 、T 1 / 2 and AUC; PFS2, defined as the time from randomization until PD on the next line of treatment as determined by the investigator or death from any cause, whichever comes first; second PFS, defined as the date of the first dose of the next line of treatment until PD based on investigator assessment or death from any cause, whichever comes first; participant visit to complete the Healthcare Utilization Questionnaire (HCUQ); baseline levels and changes in selected plasma biomarkers; and association of genetic variants with differences in PK, pharmacodynamics, efficacy, tolerability, and / or safety among the populations.

[0109] Ripretinib interruption and adjustment due to toxicity

[0110] Ripretinib may be interrupted or a first dose reduction from 150 mg once daily to 100 mg once daily or a second dose reduction to 50 mg once daily may be performed. These dose interruptions or reductions were at the investigator's discretion due to adverse events and according to the criteria for ripretinib interruption or reduction in Table 2 (dermatologic toxicity, arthralgia, and myalgia), Table 3 (left ventricular systolic dysfunction), Table 4 (hypertension), and Table 5 (treatment-related adverse events other than dermatologic toxicity, arthralgia / myalgia, left ventricular systolic dysfunction, and hypertension). The severity of adverse events that do not appear in 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.

[0111] If ripretinib is interrupted and subsequently restarted, participants should remain on their original cycle schedule. If any participant requires a ripretinib dose lower than 50 mg once daily, or if a participant has had their dose reduced and has progressive disease as assessed by independent radiological review (IRR), the participant must discontinue ripretinib and must undergo an end-of-treatment (EOT) visit, safety follow-up, and survival follow-up.

[0112] Table 2. Ripretinib Dose Modifications for Dermatologic Toxicity, Arthralgia, and Myalgia

[0113]

[0114] Table 3. Ripretinib dose adjustment for left ventricular systolic dysfunction

[0115] Toxicity level Administration Guide Any Level 3 or Level 4 Permanently discontinue ripretinib

[0116] Table 4. Ripretinib dose adjustment and management in hypertension

[0117]

[0118]

[0119] BP: blood pressure

[0120] aRipretinib dose escalation was permitted at the investigator's discretion if BP remained controlled for at least 28 days.

[0121] Table 5. Ripretinib Dose Modifications for Treatment-Related Adverse Events Other Than Dermatologic Toxicity, Arthralgia / Myalgia, Left Ventricular Systolic Dysfunction, and Hypertension

[0122]

[0123]

[0124] CPK: creatine phosphokinase.

[0125] aDose adjustment rules for laboratory adverse events will be based on local laboratory results.

[0126] Table 6. Severity grading scale

[0127]

[0128] ADL: Activities of Daily Living

[0129] If the adverse event returns to Grade 1 or baseline, the ripretinib dose may be re-escalated. Efforts must be made to re-decrease the dose to the dose level at which the adverse event occurred. If the dose level is reduced to the first dose reduction level and the adverse event returns to Grade 1 or baseline, the participant may restart at the starting dose level. If a participant undergoes two sequential dose reductions and the adverse event returns to Grade 1 or baseline at the second dose reduction level, the participant may restart at the first dose reduction level and must remain at this dose level for one cycle without interruption before escalating to the starting dose level.

[0130] If the adverse event leading to ripretinib dose modification does not recover to Grade 1 or baseline within 1 cycle (42 days), ripretinib must be discontinued unless the investigator considers the event to be clinically insignificant, in which case the participant may be restarted at a reduced dose level after consultation with the trial sponsor.

[0131] Example 3. Results of a bridging study of second-line ripretinib in the treatment of GIST.

[0132] The results of a bridging study of the second line administration of 150 mg of ripretinib once daily in Chinese patients with gastrointestinal stromal tumor (GIST) were obtained for the study in Example 1 above, compared to 50 mg of sunitinib once daily. In this study, 21 patients were identified as having mutations at KIT exon 11 and exon 17 / 18 by the tumor tissue ITT population. Progression-free survival (PFS) was determined by independent radiological review using mRECIST. As Figure 16 A Kaplan-Meier plot of PFS is provided. The data show that the median PFS in the sunitinib treatment group was 6.7 months, while PFS in the ripretinib treatment group was not achieved (NE: not evaluable).

[0133] Example 4. Outcomes for patients with advanced gastrointestinal stromal tumors with no detectable baseline ctDNA in a clinical study with ripretinib.

[0134] In the study of Example 1 above, the efficacy results of patients with advanced gastrointestinal stromal tumors in which ctDNA was detected were compared with those in patients in whom ctDNA was not detected, where ctDNA-D was defined as a sample that was successfully analyzed to detect at least one subject's cell variation (SNV or INDEL). ctDNA was detected in 280 / 362 patients (77.3%) (ctDNA-D), while ctDNA was not detected in 82 / 362 patients (22.7%) (ctDNA-ND). Among patients with ctDNA-ND, 40 patients received ripretinib, while 42 received sunitinib. Among patients with ctDNA-D, 135 patients received ripretinib, and 145 received sunitinib.

[0135] Figure 17 Kaplan-Meier analysis of PFS (A) and OS (B) for patients with ctDNA-ND versus ctDNA-D is shown. Figure 18 Shown are the ORRs for patients with ctDNA-ND relative to ctDNA-D. Figure 19 Kaplan-Meier analysis of PFS is shown for patients treated with ripretinib or sunitinib in the ctDNA-ND (A) and ctDNA-D (B) populations. Figure 20 Forest plot showing PFS according to KIT mutation status as determined by local pathology report at the time of randomization.

[0136] Example 5. Multiple treatment comparisons across mutation subgroups.

[0137] Cox proportional hazards analyses of PFS and OS were performed to examine the interaction between treatment group and mutation subgroup with or without adjustment for baseline characteristics in the study of Example 1.

[0138] For PFS, a Cox model with interaction effects was used, and a Bonferroni adjustment was applied. Interaction analysis between treatment group and mutation subgroup for PFS showed that the hazard ratio (HR) values ​​were different between subgroups. Before and after the Bonferroni correction was performed, the treatment effect was nominally significant in the KIT exon 11+13 / 14 and KIT exon 11+17 / 18 populations. This 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 to men, regardless of treatment or mutation subgroup. An overview of the results is presented in Table 2 below. The results are robust when taking into account multiple treatment comparisons across mutation subgroups.

[0139] Table 2.

[0140]

[0141]

[0142] Abbreviations: CI, confidence interval; DF, degrees of freedom; HR, hazard ratio; PDGFRA, platelet-derived growth factor receptor α; PFS, progression-free survival.

[0143] For OS, a Cox model with interaction effect was used, and a Bonferroni adjustment was applied. Interaction analysis between treatment group and mutation subgroup for OS showed that the hazard ratio (HR) values ​​were different between the subgroups. Before and after performing the Bonferroni correction, the treatment effect was nominally significant in the KIT exon 11+17 / 18 population, but not in the KIT exon 11+13 / 14 population. This analysis also showed nominal significance after adjustment for age, sex, and race. Women showed a trend toward a lower risk of death compared to men, and there was a trend toward a higher risk of death in older patients, regardless of treatment or mutation subgroup. An overview of the results is presented in Table 3 below. The results are robust when taking into account multiple treatment comparisons across mutation subgroups.

[0144] Table 3.

[0145]

[0146]

[0147] Abbreviations: CI, confidence interval; DF, degrees of freedom; HR, hazard ratio; PDGFRA, platelet-derived growth factor receptor α; PFS, progression-free survival.

Claims

1. A method of treating a patient suffering from an advanced gastrointestinal stromal tumor, wherein the patient has a) a KIT exon 17 and / or KIT exon 18 mutation and b) a KIT exon 11 mutation, the method comprising: The patient is administered 150 mg of the compound represented by: It is administered once a day or twice a day, and wherein prior to administration of the compound, the patient has progressed on or is intolerant to imatinib; and Compared with patients with KIT exon 17 and / or KIT exon 18 mutations and KIT exon 11 mutations, who had advanced gastrointestinal stromal tumors, had progressed on imatinib or were intolerant to imatinib, and were subsequently treated with 50 mg of sunitinib once daily, patients who were administered the compound achieved significantly longer progression-free survival as determined by mRECIST 1.1 and significantly longer overall survival.

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

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

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

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

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

8. A method of treating a patient suffering from advanced gastrointestinal stromal tumor, said patient having a KIT exon 17 and / or KIT exon 18 mutation, not having a KIT exon 13 and / or 14 mutation, and not having a KIT exon 9 mutation, and wherein said patient has progressed on or is intolerant to imatinib, said method comprising administering to said patient 150 mg of a compound represented by: It is administered once a day or twice a day.

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

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

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

12. A method of treating a patient suffering from advanced gastrointestinal stromal tumor, wherein the patient has progressed on or is intolerant to imatinib, and wherein the patient's circulating tumor DNA has KIT exon 17 and / or KIT exon 18 mutations and does not have KIT exon 9 mutations, the method comprising administering to the patient 150 mg of a compound represented by: It is administered once a day or twice a day.

13. The method of claim 12, comprising administering 150 mg of the compound to the patient once daily.

14. A method of treating advanced gastrointestinal stromal tumors in a patient in need thereof, wherein: The patient has progressed on imatinib or is intolerant to imatinib, and the method comprises: selecting patients who have circulating tumor DNA KIT exon 17 and / or KIT exon 18 mutations and lack one or more of KIT exon 9, 13, and 14 mutations to obtain selected patients; The selected patient is administered 150 mg of the compound represented by: It is administered once or twice daily; Or if the patient is not a selected patient, administering one or more different kinase inhibitors to the patient.

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

16. The method of claim 14, wherein if the patient is not a selected patient, the method comprises administering 50 mg of sunitinib to the patient once daily.

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

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

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