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Ref Type Journal Article
PMID (35753087)
Authors Janku F, Bauer S, Shoumariyeh K, Jones RL, Spreafico A, Jennings J, Psoinos C, Meade J, Ruiz-Soto R, Chi P
Title Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma.
Journal ESMO open
Vol 7
Issue 4
Date 2022 Jun 23
URL
Abstract Text Ripretinib, a broad-spectrum KIT and platelet-derived growth factor receptor A switch-control tyrosine kinase inhibitor, is approved for the treatment of adult patients with advanced gastrointestinal stromal tumor as ≥ fourth-line therapy. We present the efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma enrolled in the expansion phase of the ripretinib phase I study.Patients with KIT-altered metastatic melanoma were enrolled and treated with ripretinib at the recommended phase II dose of 150 mg once daily in 28-day cycles. Investigator-assessed responses according to Response Evaluation Criteria In Solid Tumors version 1.1 were carried out on day 1 of cycles 3, 5, 7, every three cycles thereafter, and at a final study visit.A total of 26 patients with KIT-altered metastatic melanoma (25 with KIT mutations, 1 with KIT-amplification) were enrolled. Patients had received prior immunotherapy (n = 23, 88%) and KIT inhibitor therapy (n = 9, 35%). Confirmed objective response rate (ORR) was 23% [95% confidence interval (CI) 9%-44%; one complete and five partial responses] with a median duration of response of 9.1 months (range, 6.9-31.3 months). Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months). Patients without prior KIT inhibitor therapy had a higher ORR and longer mPFS (n = 17, ORR 29%, mPFS 10.2 months) than those who had received prior KIT inhibitor treatment (n = 9, ORR 11%, mPFS 2.9 months). The most common treatment-related treatment-emergent adverse events (TEAEs) of any grade in ≥15% of patients were increased lipase, alopecia, actinic keratosis, myalgia, arthralgia, decreased appetite, fatigue, hyperkeratosis, nausea, and palmar-plantar erythrodysesthesia syndrome. There were no grade ≥4 treatment-related TEAEs.In this phase I study, ripretinib demonstrated encouraging efficacy and a well-tolerated safety profile in patients with KIT-altered metastatic melanoma, suggesting ripretinib may have a clinically meaningful role in treating these patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT D579G missense unknown KIT D579G lies within the cytoplasmic domain of the Kit protein (UniProt.org). D579G has been identified in the scientific literature (PMID: 35753087), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Sep 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V560D KIT D579G KIT D816N melanoma predicted - sensitive Ripretinib Case Reports/Case Series Actionable In a Phase I trial, Qinlock (ripretinib) treatment resulted in a partial response in a patient with metastatic melanoma harboring KIT D579G, V560D, and D816N (PMID: 35753087; NCT02571036). 35753087
KIT L576P melanoma predicted - sensitive Ripretinib Case Reports/Case Series Actionable In a Phase I trial, Qinlock (ripretinib) treatment resulted in a partial response in 3 of 4 patients with metastatic melanoma harboring KIT L576P (PMID: 35753087; NCT02571036). 35753087
KIT D820Y melanoma predicted - sensitive Ripretinib Case Reports/Case Series Actionable In a Phase I trial, Qinlock (ripretinib) treatment resulted in a complete response in a patient with metastatic melanoma harboring KIT D820Y (PMID: 35753087; NCT02571036). 35753087
KIT Y823D melanoma predicted - sensitive Ripretinib Case Reports/Case Series Actionable In a Phase I trial, Qinlock (ripretinib) treatment resulted in a complete response in a patient with metastatic melanoma harboring KIT Y823D (PMID: 35753087; NCT02571036). 35753087
KIT mutant melanoma predicted - sensitive Ripretinib Phase I Actionable In a Phase I trial, Qinlock (ripretinib) treatment demonstrated manageable safety and preliminary efficacy in patients with KIT-mutated melanoma, and led to an objective response rate of 23% (6/26, 1 complete and 5 partial responses), a median progression-free survival of 7.3 months, and a median duration of response of 9.1 months (PMID: 35753087; NCT02571036). 35753087