New Melanoma Agent Data Published, Questions Now Arise

Nick Mulcahy

June 25, 2012

June 25, 2012 — The investigational BRAF-inhibitor dabrafenib (GlaxoSmithKline) significantly improved progression-free survival in patients with metastatic melanoma compared with chemotherapy, according to results recently reported by Medscape Medical News at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) and published online June 25 in the Lancet.

In the new 250-patient trial, known as BREAK-3, median progression-free survival was 5.1 months with dabrafenib and 2.7 months with dacarbazine.

Dabrafenib (150 mg twice daily) reduced the risk for disease progression by 70% compared with dacarbazine (1000 mg/m² intravenously every 3 weeks). The difference in the risk of disease progression was statistically significant (hazard ratio [HR], 0.30; P < .0001), report the authors, led by Axel Hauschild, MD, from the Schleswig-Holstein University Hospital in Kiel, Germany.

The trial immediately raises the question: Is dabrafenib more effective than BRAF-targeted drug vemurafenib (Zelboraf, Roche)? Vemurafenib is approved by the US Food and Drug Administration and the European Medicines Agency and is the current standard of care for patients with metastatic melanoma and BRAF mutations.

A melanoma expert not involved with the study answered this question broadly: "Follow-up for overall survival [with dabrafenib] is continuing, but is expected to show much the same benefit as the licensed BRAF inhibitor vemurafenib," writes Kim Margolin, MD, in an accompanying editorial.

However, Dr. Margolin, who is from the Seattle Cancer Care Alliance in Washington, also points out that there is another player in this setting now.

The investigational oral MEK inhibitor trametinib (GlaxoSmithKline) has also shown improved median progression-free survival compared with chemotherapy (4.8 months vs 1.5 months; HR, 0.45; 95% confidence interval, 0.33 - 0.63).

So which one will clinicians ultimately prefer?

That depends on a variety of considerations, suggests Dr. Margolin, and the choice ultimately may not be so dramatic, as combination therapy with BRAF plus MEK inhibition is "likely to be most valuable for improved and lasting results," she writes.

This comment is an indirect reference to the problem of resistance with single targeted therapy for melanoma.

Melanoma cells become resistant quite quickly

The problem is in evidence in the current trial, say the study authors. Despite the "encouraging" response rate and "improvement" in progression-free survival, the trial results "show that melanoma cells become resistant quite quickly," write Dr. Hauschild and colleagues.

Other Questions at Hand

In surveying the emerging metastatic melanoma treatments, Dr. Margolin explores a number of questions that, when answered, will likely help oncologists determine treatment approach.

First, are there important differences in antitumor activity between dabrafenib, vemurafenib, and trametinib, all of which have "related mechanisms of action?" asks Dr. Margolin.

The objective response rates in clinical trials favor dabrafenib (50%) and vemurafenib (57%) over trametinib (22%), she points out.

However, efficacy may depend on study demographics because "cells with BRAFV600K might be less responsive than cells with BRAFV600E, and BRAFV600K melanomas are more common in Australia than in the USA and in older versus younger patients."

To date, similar overall survival curves suggest that "all 3 agents have much the same benefit in BRAFV600E melanoma," she says.

However, the MEK inhibitor trametinib might provide an option for BRAF wild-type tumors "driven by other upstream mutations that signal through MEK," she adds.

Second, does dabrafenib provide broader molecular coverage than vemurafenib? That is not knowable right now for a variety of reasons, she says. More study will be necessary "to understand the importance of variant BRAF mutations." However, Dr. Margolin points out that "the MEK inhibitor trametinib appeared less active in patients whose tumours had MAP kinase activation by BRAFV600K, suggesting that this difference could be therapeutically important."

Adverse Effect Profiles

Between the 2 BRAF inhibitors, "differences in side effects might emerge as the most important factor if treatments have much the same activities," observes Dr. Margolin, referring especially to skin toxicities.

Indeed, at ASCO, Dr. Hauschild emphasized the findings about the secondary skin cancers, squamous cell carcinomas, and keratoacanthomas were seen in only 7% of the patients. In contrast, the recent phase 3 trial of vemurafenib (the Study of Vemurafenib [RO5185426] in Comparison With Dacarbazine in Previously Untreated Patients With Metastatic Melanoma [BRIM 3]) showed that cutaneous squamous cell carcinoma, keratoacanthoma, or both developed in 18% of patients.

However, this may be made less of an issue by the fact that "combining BRAF and MEK inhibition abrogates the risk of low-grade squamous cancers and keratoacanthomas." observes Dr. Margolin.

However, inflammatory syndromes with such pyrexia syndrome are more common with dabrafenib, occurring in about 11% of patients, but are rare with vemurafenib, she says.

In the current study, treatment-related adverse events (grade 2 or higher) occurred in 53% of the patients who received dabrafenib and in 44% of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. Grade 3 to 4 adverse events were uncommon in both the dabrafenib and chemotherapy groups, report the authors.

Median time on study was 4.9 months for the participants. At the data cutoff point, 57% of the patients in the dabrafenib group and 22% in the dacarbazine group remained on randomized treatment.

The trial was funded by GlaxoSmithKline. Dr. Hauschild reports financial ties to GlaxoSmithKline. Some coauthors also report financial ties to GlaxoSmithKline, and some are employees of the company. Dr. Margolin was an investigator in the dabrafenib and vemurafenib trials.

Lancet. Published online June 25, 2012. Article abstract, Editorial extract

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