Imatinib Is Yet Another Option in Advanced Melanoma

Nick Mulcahy

August 13, 2013

Clinicians now have another treatment option for patients with advanced melanoma.

The targeted therapy imatinib (Gleevec, Novartis Pharmaceuticals Corporation) has shown efficacy in an uncommon molecular subset of the skin cancer — patients with KIT-mutant melanoma.

Imatinib, which revolutionized the treatment of chronic myelogenous leukemia, has now been included in the National Comprehensive Cancer Network Clinical Practice Guidelines for Melanoma, observes Richard D. Carvajal, MD, of the Memorial Sloan-Kettering Cancer Center, New York City.

In an editorial published online August 12 in the Journal of Clinical Oncology, Dr. Carvajal also says that "further work is required to enhance our ability to identify patients with true driving alterations of KIT and optimize patient selection."

These alterations are typically mutually exclusive of the more common BRAF and NRAS mutations in melanoma, he also points out.

Dr. Carvajal's new essay was occasioned by the completion and publishing of a multicenter phase II trial of imatinib in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene.

In their new phase II trial, Stephen Hodi, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, and colleagues screened tumor samples from 213 patients with melanomas arising from acral, mucosal, or chronically sun-damaged sites for the presence of KIT mutations or amplification.

They identified 50 cases with KIT alterations and treated 25 patients with KIT-mutant or -amplified melanoma with imatinib.

Of 24 evaluable patients, 7 achieved a partial response to therapy, with 5 patients' responses confirmed on subsequent imaging studies, for an overall confirmed response rate (RR) of 21%.

These new study results, which were published August 5 in the Journal of Clinical Oncology, reinforce earlier findings on imatinib in this setting.

In a study led by Dr. Carvajal, imatinib provided a confirmed RR of 16%, with responses durable for longer than 1 year (JAMA 2011;305:2327-2334). And in another study, there was an observed RR of 23.3% (J Clin Oncol 2011;29:2904-2909).

Taken together, the 3 trials demonstrate that imatinib works in patients with KIT-mutant melanoma.

The 3 trials also prove the value of molecularly based patient selection in melanoma drug treatment trials, says Dr. Carvajal.

Imatinib had been a flop in 3 other, earlier phase II melanoma trials. But in each of these prior negative trials, imatinib was used in molecularly unselected melanoma patients. The trials were initiated before the identification of KIT mutations in this disease. The results were very poor: only 1 radiographic response was observed in 62 patients treated across the 3 trials.

Imatinib is not the first targeted therapy to show promise in KIT-mutated melanoma. "Significant" radiographic responses in KIT-mutant melanoma have also been reported with other targeted inhibitors of KIT, including sorafenib, dasatinib, sunitinib, and nilotinib, says Dr. Carvajal. It appears that responses to all of the various targeted therapies occur in tumors harboring exon 11 and 13 KIT mutations, he also notes. However, more research is needed to firmly establish this finding and to optimize patient selection, he points out.

For now, patients with KIT-mutated advanced melanoma may be considered for treatment with imatinib, Dr. Carvajal concludes.

Dr. Carvajal reports being a consultant to Novartis.

J Clin Oncol. Published August 5 and August 12, 2013. Full article, Editorial

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