BRAF and Melanoma: Taking It Personally
More than 80% of melanoma patients with an activating mutation in BRAF responded to treatment with PLX4032.
Ever since researchers first described the role of BRAF mutations in melanoma, we have eagerly awaited a clinically effective anti-BRAF drug. A recent multicenter trial of a new agent seems to be the first step toward personalized medicine for melanoma. Investigators conducted a dose-escalation trial, with an extension phase, of PLX4032, an orally available kinase inhibitor of mutated BRAF; the co-developers of this agent supported the research. Fifty-five patients (49 with melanoma) were enrolled in an initial dose-escalation phase; another 32 patients with metastatic melanoma and tumors harboring the BRAFV600E mutation were enrolled in an extension phase.
In the first phase, the investigators analyzed antitumor activity and dose-limiting toxicity to arrive at a dose of 960 mg twice daily for the extension phase. Cutaneous squamous cell carcinomas (SCCs) occurred in 8 (15%) and 10 (31%) of the patients in the dose-escalation and extension cohorts, respectively, (median onset, 8 weeks). All but one of the SCCs were or had features of keratoacanthoma, and none required therapy discontinuation. Sixteen patients in the first phase harbored the BRAFV600E mutation; 11 (69%) had a response, 10 partial and 1 complete. Patients without BRAF mutations showed no evidence of tumor regression; four had progressive disease within the first 2 months of treatment. The extension phase included only patients with the BRAFV600E mutation. Of these 32 patients, 26 (81%) had a response, 2 complete and 24 partial. The estimated median progression-free survival among these patients at the time of analysis was more than 7 months.
Comment: This trial has been widely publicized, and the general enthusiasm seems warranted. PLX4032 is the most selective and effective targeted agent against melanoma to date, although it is not the first anti-BRAF compound to undergo clinical trials. The results have to be interpreted in context. For instance, most acral lentiginous and mucosal melanomas have KIT rather than BRAF mutations and would not respond to PLX4032. Some in vitro evidence suggests that BRAF-normal melanoma cells may actually be stimulated by PLX4032.
In an era of personalized therapy, the genetics of a patient's melanoma will dictate treatment. Careful tumor genotyping will become commonplace. KIT-mutated, BRAF-mutated and NRAS-mutated melanomas will require completely different regimens, so histological and molecular diagnostics will be important. Even with profound responses such as those observed here, many melanomas relapse; therefore, resistance mechanisms have become the focus of intense research, and additional drugs may be needed to fully tame metastatic melanoma.
Published in Journal Watch Dermatology August 25, 2010
Flaherty KT et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010 Aug 26; 363:809.
- Medline abstract (Free)
Smalley KSM and Sondak VK. Melanoma — An unlikely poster child for personalized cancer therapy. N Engl J Med 2010 Aug 26; 363:876.
- Medline abstract (Free)
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