Currently, interferon is the only approved adjuvant treatment for melanoma but it is unsatisfactory in several respects and intensive search for alternatives is ongoing. Among such options is Gleevec.
Results of Phase II trials of Gleevec in metastatic disease have not been very impressive. One trial involving 26 patients did not produce any clinical responses, but the course of treatment was limited in most patients by drug toxicity. Data on expression of known drug targets in tumors was not reported. A second trial from was limited to 21 patients with biopsies demonstrating expression of relevant PTK in over 25% of tumor cells.2 A near complete response was seen in one patient with the strongest expression of c-kit, but the remaining 20 patients experienced progressive disease over 6–12 wk. I was not able to find any trials exploringg Gleevec in adjuvant setting.
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.
At the time of presentation, 15 patients had been treated on protocol with Gleevec 400 mg twice a day. 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.
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.
This study is a preliminary indication that Gleevec may work best for patients with specific melanoma mutations. However, it is only a preliminary indication and requires confirmation in prospective clinical trials.
Douglas Grossman Imatinib Mesylate for Melanoma: Will a New Target be Revealed?Journal of Investigative Dermatology (2004) 123, xi–xiii
Eton O, Billings L, Kim K, et al: Phase II trial of imatinib mesylate (STI-571) in metastatic melanoma. Proc Am Soc Clin Oncol 23:713, 2004.
Wyman K, Atkins M, Hubbard F, et al: A phase II trial of imatinib mesylate at 800 mg daily in metastatic melanoma: Lack of clinical efficacy with significant toxicity. Proc Am Soc Clin Oncol 22:713, 2003.
Kevin Kalinsky, Frank G Haluska Novel inhibitors in the treatment of metastatic melanoma
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