Melanoma Treatment

Posted by Graham McMahon • August 27th, 2010

Many melanomas contain an activating mutation in BRAF. In a study of a new agent, PLX4032, that inhibits mutated BRAF, 26 of 32 patients (81%) who received PLX4032 had a partial or complete response lasting at least 19 months.

Metastatic melanoma is an aggressive disease for which there are few effective therapies.

Clinical Pearls

What are the currently approved treatments for metastatic melanoma?

The two therapies approved by the Food and Drug Administration, high-dose interleukin-2 and dacarbazine, are each associated with response rates of only 10 to 20% and a small percentage of complete responses; neither is thought to improve overall survival. In randomized trials, the median survival among patients treated with dacarbazine was less than 8 months.

How prevalent is the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) mutation among patients with metastatic melanoma?

A search for mutations in a component of the MAP kinase pathway in a large panel of common cancers revealed that 40 to 60% of melanomas, and 7 to 8% of all cancers, carry an activating mutation in BRAF.

Morning Report Questions

Q: How effective was the oral inhibitor of BRAF, PLX4032, in treating patients with metastatic melanoma?

A: This trial demonstrated that therapy targeting tumors containing activating V600E BRAF mutations can induce clinically significant tumor regression in patients. PLX4032 induced clinically significant tumor regression in 81% of patients who had melanoma with the V600E BRAF mutation. Responses were observed at all sites of disease, including the bone, liver, and small intestine.

Q: What tumors emerged in patients treated with PLX4032?

A: Eight patients in the dose-escalation cohort (15%) and 10 patients in the extension cohort (31%) developed cutaneous squamous-cell carcinomas — a total of 35 carcinomas. These were reviewed centrally, and all but one either were keratoacanthomas or had features of a keratoacanthoma. The median time to the appearance of a cutaneous squamous-cell carcinoma was 8 weeks; the majority of the carcinomas were resected, and in no case did any lead to discontinuation of treatment.

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