KIT as a Therapeutic Target in Metastatic Melanoma

Abstract

Context Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease. Objective To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations. Design, Setting, and Patients A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites. Intervention Imatinib mesylate, 400 mg orally twice daily. Main Outcome Measures Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response. Results Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval [CI], 2%–30%), with a median time to progression of 12 weeks (interquartile range [IQR], 6–18 weeks; 95% CI, 11–18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P=.05), indicating positive selection for the mutated allele. Conclusions Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance.

Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10-06)

“…Patients with melanomas harboring KIT mutations have a high probability of responding to nilotinib but usually with short duration of response compared with KIT-mutant GIST. Nilotinib compares similarly with previous trials with imatinib in terms of response rate and median PFS in melanoma [15,16]; however, the data do not allow the conclusion that the exon 17 (I817L) mutation or other mutations should preferably be treated with nilotinib. Single-mutant exon 17 mutations may respond to imatinib, and no preclinical evidence shows that these mutants are really resistant.…”

“…Of the 2 patients with exon 11 V559A mutation, 1 showed partial response for 38 weeks and 1 showed stable disease for 16 weeks with nilotinib.V559A and N822I double KIT mutant melanoma has been shown to have some degree of response to imatinib [25]; therefore, our phase II trial demonstrated that nilotinib can induce durable responses in V559A KIT-mutated melanoma. Currently, four primary double KIT mutations in melanoma have been identified in the literature: N566D (exon 11)/K642E (exon 13) [13], N463S (exon 9)/N655S (exon 13) [15], K642E (exon 13)/ N822I (exon 17) [26], and V559A (exon 11)/N822I (exon 17) [25]. In our patient cohort, 1 patient had V560D (exon11)/ V654A(exon13) ( Table 3) and had stable disease for .42weeks on nilotinib.…”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Beyond BRAF, data from phase II trials indicate a possibility of clinical responsiveness to KIT inhibitors in the KIT-mutant melanoma population [33][34][35] . Otherwise, testing for NRAS or NF1 mutations is largely a matter of identifying patients who might be candidates for clinical trials.…”

Treatment of advanced melanoma - A changing landscape

“…24 Although infrequent, c-KIT mutations can be found in acral and mucosal melanomas; in several case reports, a rapid, but transient response was achieved with imatinib mesylate, a small molecule inhibitor of KIT and other tyrosine kinases. 25,26 These observations were confirmed in subsequent prospective, non-comparative phase 2 studies, in which imatinib resulted in response rates of approximately 20%, despite relatively short PFS intervals ranging from 2.8 to 3.7 months. 27,28 Taken together, although the benefit of targeted approaches in patients with melanoma harboring non-BRAF mutations has been limited, these results serve as a proof of concept for future molecularlydriven treatment strategies.…”