Imatinib Active in Melanomas with KIT Mutation but Not KIT Amplification Alone
Mutations and amplifications in the KIT oncogene have been identified in mucosal and acral melanomas and in melanomas arising on chronically sun-damaged skin. In a multicenter phase II study reported in the Journal of Clinical Oncology, F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, and colleagues assessed the effects of imatinib (Gleevec) treatment in patients with melanomas with KIT mutations or amplifications. Responses were observed in patients with KIT mutation but not when KIT amplification alone was present.
Study Details
In the study, 24 evaluable patients with mucosal (n = 17), acral (n = 6), or chronically sun-damaged (n=1) unresectable stage III or IV melanoma with KIT mutations or amplifications were treated with imatinib 400 mg once or (in the absence of initial response) twice daily. Of the 24 patients, 8 (33%) had tumors with KIT mutations, 11 (46%) had KIT amplifications, and 5 (21%) had both. Patients had a median age of 65 years and most were female (75%), had M1c disease (63%), and ECOG performance status of 0 (71%). All patients had undergone cancer-directed surgery, with seven (29%) receiving radiation treatment, six (25%) chemotherapy, and seven (29%) both.
Responses in Patients with KIT Mutation
Median follow-up was 10.6 months (range 3.7–27.1 months). Response (all partial responses) was observed in seven patients, for a best overall response rate of 29% (confirmed response in 21%). Stable disease was observed in 5 patients (21%) and progressive disease in 12 (50%). Best overall response rate was significantly greater than the hypothesized null value of 5% (P < .001).
The relationship between best overall response and mutational status was significant (overall P = .003), with all responses occurring in patients with KIT-mutated tumors: Response occurred in 7 (54%) of 13 patients with KIT-mutated tumors vs 0 (0%) of 11 with amplifications only (P = .006). Responses were observed only in patients with mucosal primary tumors (41% vs 0% of those with acral or chronically sun-damaged melanoma).
The overall disease control rate was 50%, reflecting a higher rate among patients with mutations than among those with amplification alone (77% vs 18%).
For all patients, median time to progression was 3.7 months and median overall survival was 12.5 months. There were no significant differences in rates of progression or survival by mutation status or melanoma site.
Potential Effect of NRAS Mutation, KIT Copy Number Gain
Four patients had pretreatment NRAS mutations, including two with KIT mutations and two with KIT amplification, and all had progressive disease as best response. Biopsy at the time of progression in two patients with initial response showed the same KIT mutations as prior to treatment with no additional KIT mutations; however, one patient also showed amplification of KIT after treatment.
The most common adverse events were nausea, fatigue, anemia, hyperglycemia, and vomiting. Grade 3 adverse events occurred in 29% of patients, and grade 4 adverse events occurred in 12.5%.
The investigators concluded, “Melanomas that arise on mucosal, acral, or chronically sun-damaged skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.”
For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
