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.
• 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.