Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
ESMO open	7	4	2022 Jun 23	100520	ESMO Open

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, Apr 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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 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 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