Gleevec shows promise as targeted melanoma treatment

Gleevec is approved in the United States for the treatment of cancers with mutations in the KIT oncogene, Philadelphia chromosome positive chronic myelogenous leukemia and KIT+ GIST (gastrointestinal stromal tumors). Although a fractional percentage of melanoma patients have KIT mutations, prior studies looking at Gleevec therapy for metastatic melanoma, not requiring specific genetic sequence mutations for trial entry, were uniformly unsuccessful.

 

A new, ongoing, Phase II trial of Gleevec therapy for metastatic melanoma patients was recently presented by Dr. Carvajal at Sloan Kettering at ASCO 2009 as an interim update of results. This trial required all patients to have genetic sequencing of their tumors and limited enrollment to patients with specific mutations in KIT (at exons 9, 11, 13, 17 or 18) and/or amplification of KIT. About 21% of screened patients were eligible for enrollment. The patients also had to have primary melanomas that were acral (hands or feet), mucosal (e.g. vaginal or oral), or on skin with chronic sun damage as evidenced by histopathologic examination of the biopsy.

 

At the time of presentation, 15 patients had been treated on protocol with Gleevec 400 mg twice a day. The regimen was relatively safe; some dose reductions were required for rash or gastrointestinal toxicity. Of the twelve evaluable subjects, two had complete responses, two had partial responses, six had stable disease and two had progressive disease as their best response, for a 33% (4/12) overall response rate. While this is a respectable rate of clinical responses, the real promise of this study lies in the analysis of the genetic mutations in the responders and non-responders, and what those differences imply and suggest for future investigations.

 

Both of the two complete responders had Exon 11 mutation (designated L576P) and also KIT amplification). The two partial responders had Exon 11 (same mutation) and Exon 13 mutations, respectively, without KIT amplification. All four of those patients remain on treatment; the two complete responses appear to be durable. Most of the stable disease patients had Exon 13 mutations with or without KIT amplification. The two stable disease patients had other mutations (Exon 9 or different locus in Exon 13) and no KIT amplification.

 

Although this data is very preliminary, it suggests that we may be able to prospectively identify patients with genetic (here, KIT) mutations that are susceptible to available targeted therapy. Like the BRAF data presented at the same ASCO session, these are encouraging results for a future paradigm of a personalized approach to cancer therapy, where patients’ therapy(s) would be increasingly guided by not just the tissue diagnosis but also the specific genetic abnormalities of that person’s cancer.