In a phase I trial, 10 of the 16 patients with melanoma tumors carrying the V600E mutation in the serine–threonine protein kinase B-RAF (BRAF) gene had a partial response when treated with at least 240 mg of the agent known as PLX4032, or RG7204.

One of these patients had a complete response to the oral inhibitor of mutated BRAF, Keith T. Flaherty, MD, of the Massachusetts General Hospital Cancer Center in Boston, and colleagues found.

The results looked even better in an extension phase of trial in BRAF-mutation metastatic melanoma, the researchers reported in the Aug. 26 issue of the New England Journal of Medicine.

Altogether, 81% of melanoma patients with the mutation responded, noted co-author Jeffrey A. Sosman, MD, of Vanderbilt University in Nashville, Tenn.

"These responses occur rapidly, in organs where we infrequently see tumor regression, and patients can actually feel better overnight with this therapy," he said in an interview.

The dramatic results were "much beyond" that expected from such an early phase study, Vernon K. Sondak, MD, of the Moffitt Cancer Center and Research Institute in Tampa, Fla., said in an interview.

Even in phase III melanoma trials with standard drugs the typical response rate might be only 6% to 12%, he explained.

"Overall, I think this is quite significant," he said in the interview, particularly since about half of melanoma cases are associated with the mutation targeted by the drug in the study.

In an accompanying editorial with Keiran S.M. Smalley, PhD, also of the Moffitt Cancer Center and Research Institute, he called the results a major breakthrough that provides proof of principle for individualized treatment of a substantial proportion of metastatic melanoma.

A similar strategy of imatinib (Gleevec) has some evidence of efficacy against melanoma in which mutations in the KIT gene are culprit, but these are found in only a small minority of melanomas, the editorialists pointed out.

Pretreatment screening for mutations in BRAF, KIT, and probably other key genes is likely on the horizon, they suggested.

In the case of BRAF, they recommended confirmation of mutation before giving an inhibitor of this pathway since these drugs paradoxically stimulate cell proliferation via another route in cell lines without the mutations.

Indeed, the study showed an unexpectedly high rate of cutaneous squamous cell carcinomas, nearly all of the keratoacanthoma type, in patients treated with PLX4032 -- eight (15%) in the dose-escalation cohort and 10 (31%) in the extension cohort.

All of these cancers were resected with none leading to treatment discontinuation.

The multicenter study included 55 patients in the dose-escalation phase who had a variety of solid-tumor types refractory to therapy or for which standard or curative therapy was not available. Among them, 49 had melanoma.

Patients received PLX4032 twice daily until disease progression. Doses started at 160 mg twice daily and escalated to 1,120 mg twice daily with progressive enrollment.

The recommended dose going forward was 960 mg twice daily. Beyond that dose, grade 2 or 3 rash, fatigue, and arthralgia limited escalation.

In the extension phase, 32 additional patients with metastatic melanoma with confirmed V600E BRAF mutation got this recommended dose.

Among them, 24 had a partial response and two had a complete response. These responses occurred in visceral organs and bone metastases as well as sites where responses are common with other drugs, such as the lungs and lymph nodes.

Symptom improvement occurred within one to two weeks, including reduced need for narcotics in three patients.

In the entire treated cohort, the estimated median progression-free survival extended more than seven months with a substantial proportion still on study.

So the novel agent isn't a cure for melanoma, Sosman noted.

But there are good prospects for combining this targeted therapy with others, such as the novel immune-stimulating drug ipilimumab which recently showed the first ever overall survival impact in metastatic melanoma, Sosman and the editorialists agreed.

The mechanisms for the primary and secondary resistance seen to PLX4032 aren't known but warrant study, the researchers concluded.

A phase III trial with the BRAF inhibitor is underway to determine whether it can improve overall survival similar to ipilimumab.

This article was developed in collaboration with ABC News.

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