Reference Detail

Ref Type

Journal Article

PMID

(28327988)

Authors

Guo J, Carvajal RD, Dummer R, Hauschild A, Daud A, Bastian BC, Markovic SN, Queirolo P, Arance A, Berking C, Camargo V, Herchenhorn D, Petrella TM, Schadendorf D, Sharfman W, Testori A, Novick S, Hertle S, Nourry C, Chen Q, Hodi FS

Title

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology	28	6	2017 Jun 01	1380-1387	Ann Oncol

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Abstract Text

The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment.Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors.ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib.Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.ClinicalTrials.gov, NCT01028222.

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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	K642Q	missense	unknown	KIT K642Q lies within the protein kinase domain (exon 13) of the Kit protein (UniProt.org). K642Q has been identified in sequencing studies (PMID: 28327988), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).
KIT	W557C	missense	unknown	KIT W557C lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). W557C has been identified in the scientific literature (PMID: 28327988), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT V559A	melanoma	predicted - sensitive	Nilotinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41), including a melanoma patient harboring KIT V559A demonstrating a partial response and progression-free survival of 19.4 months and overall survival of 32.9 months (PMID: 28327988).	28327988
KIT exon13	melanoma	sensitive	Nilotinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41), which included a partial response in 7.7% (1/13) of melanoma patients harboring KIT exon 13 mutations (PMID: 28327988).	28327988
KIT exon11	melanoma	sensitive	Nilotinib	Phase II	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41), which included a partial response of 38.5% (10/26) and a progression free survival of 5.4 months in melanoma patients harboring KIT exon 11 mutations (PMID: 28327988).	28327988
KIT W557R KIT L576P	melanoma	predicted - sensitive	Nilotinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41) including a melanoma patient co-harboring KIT L576P and KIT W557R demonstrating a partial response and a progression free survival of 5.3 months and overall survival of 14.7 months when treated with Tasigna (nilotinib) (PMID: 28327988).	28327988
KIT mutant	melanoma	sensitive	Nilotinib	Phase II	Actionable	In a Phase II trial, Tasigna (nilotinib) treatment in patients with melanoma harboring KIT mutations resulted in an overall response rate of 26.2% (11/42), which included 11 patients with a partial response, a median duration of response of 7.1 months, and an overall survival of 18 months (PMID: 28327988; NCT01028222).	28327988
KIT K642E	melanoma	predicted - sensitive	Nilotinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41) including a melanoma patient harboring KIT K642E demonstrating a partial response and a progression free survival of 5.8 months and overall survival of 18.6 months (PMID: 28327988).	28327988
KIT V559D	melanoma	predicted - sensitive	Nilotinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41) including a melanoma patient harboring KIT V559D demonstrating a partial response and progression free survival of 28.3 months and overall survival of 28.3 months (PMID: 28327988).	28327988
KIT V560D	melanoma	predicted - sensitive	Nilotinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41) including a melanoma patient harboring KIT V560D demonstrating a partial response and progression free survival of 8.6 months and overall survival of 23.5 months (PMID: 28327988).	28327988
KIT L576P	melanoma	predicted - sensitive	Nilotinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41) including three melanoma patients harboring KIT L576P demonstrating a partial response (PMID: 28327988).	28327988
KIT W557R	melanoma	predicted - sensitive	Nilotinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tasigna (nilotinib) resulted in an overall response rate of 26.2% (11/41) including a melanoma patient harboring KIT W557R demonstrating a partial response and progression free survival of 35.4 months and overall survival of 35.4 months (PMID: 28327988).	28327988

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