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. Trial Registration clinicaltrials.gov Identifier: NCT00470470.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Carvajal reported being a consultant for Novartis and receiving research support from the American Society of Clinical Oncology, National Institutes of Health, and the US Food and Drug Administration. Dr Wolchok reported being a consultant for Novartis. Dr Chapman reported being a consultant for and receiving research support for travel, accommodations, and meeting expenses from Roche-Genentech. Dr Chmielowski reported being a consultant for Celgene and Prometheus and receiving payment for lectures from Novartis and Prometheus. Dr Lutzy reported being a consultant for Bristol-Myers Squibb, receiving payment for lectures from Millennium and Bristol-Myers Squibb, and receiving research support from Memorial Sloan-Kettering Cancer Center. Dr Bastian reported being a consultant for Novartis, Abbott, sanofi-aventis, DermTech, and Genomel, having patents filed by the University of California, and receiving research support from the US Food and Drug Administration, National Institutes of Health, Melanoma Research Alliance, Canadian Institutes of Health Research, Canadian Cancer Society, European Commission, Jubilaeumsfonds of the Oesterreichische National Bank, and Deutsche Forchungsgemeinschaft. Dr Schwartz reported being a consultant for Pfizer, Tragara, and Pharmagap, and has received research support from the US Food and Drug Administration. No other authors reported any disclosures.

Figures

Figure 1. Treatment Response Over Time by Melanoma Subtype and Genetic Alteration of KIT

CSD indicates melanoma arising from chronically sun-damaged skin; NA, not applicable. The melanoma subtype, KIT mutational and amplification status, the ratio of mutant to wild-type alleles as determined by their respective electropherogram peak heights, and the RECIST (Response Evaluation Criteria in Solid Tumors) response achieved for each patient treated with imatinib mesylate is shown. Amplification was defined as a KIT-to-centromere ratio of 2.5 or more, with the pattern of amplification described as uniform (homogeneous) or mixed (heterogeneous) across the tumor specimen. The best response as determined by RECIST is identified by the color of the bar. The length of the bar represents the duration of time in weeks that each patient remained receiving therapy. a Mutations previously identified in melanoma, and gastrointestinal stroma tumors., b Tumors with mutant to wild-type allelic ratios of more than 1:1, which are those hypothesized most likely to respond to therapy with KIT inhibition. c Patients receiving treatment at the time of this report.

Figure 2. Radiographic Responses to Imatinib Mesylate

MRI indicates magnetic resonance imaging; PET, positron emission tomography. MRI and PET scans from a representative patient with vulvovaginal mucosal melanoma harboring both an exon 11 L576P mutation and amplification of KIT are shown at baseline (yellow arrows, A and C) and after 6 weeks of therapy with imatinib mesylate (yellow arrows, B and D). The arrowhead in A indicates a heterogeneous multilobulated mass distending the entire vagina and extending inferiorly to the introitus. This lesion demonstrates intense fluorodeoxyglucose uptake on PET imaging (arrowhead in C). After 6 weeks of therapy with imatinib mesylate, there was significant shrinkage in the size of this mass with interval resolution of hypermetabolic activity (arrowheads in B and D indicate baseline locations of tumor). This patient ultimately achieved a complete radiographic response to therapy at her week 12 scan. Baseline and posttreatment PET images of a second representative patient with an acral melanoma harboring an exon 11 576P mutation and amplification are shown in E and F. This patient ultimately achieved a complete radiographic and pathological response to therapy at his week 12 scan.

Figure 3. Overall Survival and Time to Progression of All 25 Patients and Those With Recurrent or Sporadic Mutations

Kaplan-Meier curves for overall survival (15 deaths) and time to progression (22 progression events) of the 25 evaluable patients are shown. The median overall survival was 10.7 months (95% confidence interval [CI], 6.5 months-not achieved) and the median time to progression was 2.8 months (95% CI, 2.5–4.0 months). Mutations repeatedly identified in melanoma or gastrointestinal stromal tumors and those associated with a mutated to wild-type allele ratio of more than 1 are those most likely to be pathogenetically relevant. The subset of patients with tumors harboring such alterations achieved an overall survival and time to progression greater than that achieved in cases without such characteristics.