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Investigational BRAF inhibitor extended survival in metastatic melanoma patients
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CHICAGO — The investigational BRAF-targeted drug dabrafenib significantly improved PFS and overall response in patients with previously untreated, BRAF-mutant advanced melanoma vs. standard dacarbazine chemotherapy, according to results of the phase 3 BREAK-3 trial.
Treatment with dabrafenib (GlaxoSmithKline) also resulted in fewer skin toxicities, including squamous cell carcinomas, than have been observed in prior trials that evaluated vemurafenib (Zelboraf, Genentech), the current standard targeted drug for these patients, researchers said.
“For 3 decades, we had no new therapies for metastatic melanoma, but we’re quickly gaining momentum,” said Axel Hauschild, MD, professor of dermatology at the University Hospital in Kiel, Germany. “Last year, ipilimumab (Yervoy, Bristol-Myers Squibb) and vemurafenib were approved, and now dabrafenib could be on the horizon.”
Hauschild and colleagues enrolled 250 patients with unresectable stage III/stage IV metastatic melanoma at 93 centers from February to September 2011. All patients had ECOG performance status of zero to 1. Patients were allowed to enter the trial if they had central nervous system metastases, but it had to be stable for at least 3 months.
The patients were stratified by stage. They were randomly assigned to dabrafenib 150 mg orally twice a day (n=187) or dacarbazine chemotherapy 1,000 mg/m2 IV every 3 weeks (n=63).
The primary endpoint was investigator-assessed PFS. Patients assigned to chemotherapy were allowed to crossover to dabrafenib therapy once progression was confirmed by independent review.
Researchers said 141 patients — 127 in the dabrafenib arm and 14 in the chemotherapy arm — remained on study treatment at the data cutoff point. Those patients included 21 of 28 patients who initially were assigned to chemotherapy and later crossed over to dabrafenib therapy.
Median follow-up time was 4.9 months (5.1 months for patients in the dabrafenib arm and 4.8 months for patients in the chemotherapy arm).
Median investigator-assessed PFS was 5.1 months for patients assigned to dabrafenib vs. 2.7 months for patients assigned to chemotherapy, translating to a 70% reduction in risk for disease progression (HR=0.3; 95% CI, 0.18-0.51).
The confirmed investigator-assessed response rate was 53% for patients in the dabrafenib arm vs. 19% for patients in the chemotherapy arm. Response rates as determined by independent review were 50% for patients in the dabrafenib arm and 6% for patients in the chemotherapy arm.
The PFS and response rate benefits associated with dabrafenib were observed in all subgroups, the researchers wrote. OS data are not yet mature.
Both treatments were well tolerated, researchers said.
Dose modifications due to adverse events were similar in both arms. Three percent of patients in each arm discontinued treatment due to adverse events. Eighteen percent of patients in the dabrafenib arm required dose reductions vs. 17% of patients in the chemotherapy arm.
More patients in the dabrafenib group experienced mild to moderate skin reactions, joint pain and fever, whereas more patients randomly assigned to the chemotherapy group experienced drops in blood cell counts, researchers said.
The most common adverse events reported by patients in the dabrafenib arm were hyperkeratosis (37%); headaches (32%); pyrexia (28%); arthralgia (27%); and skin papillomas (24%). Grade-3 or higher adverse events included squamous cell carcinomas (6%); pyrexia (4%) and new primary melanomas (2%).
“These findings represent another advance for melanoma and form the foundation for further studies to evaluate the role of dabrafenib in combination with other drugs,” Hauschild said. “The next step is a combination of dabrafenib and the drug trametinib (GlaxoSmithKline), not only for stage IV disease but also in the adjuvant setting.”
For more information:
Hauschild A. #LBA8500. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.
Disclosure: The researchers report serving in consultant or advisory roles with, receiving research funding or honoraria from, and holding employment or leadership positions with Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Roche and other pharmaceutical companies.
Perspective
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Kari L. Kendra, MD, PhD
The FDA approval of the BRAF inhibitor vemurafenib (Zelboraf, Genentech) has already had a positive impact on the lives of patients with metastatic melanoma. Dabrafenib targets the same V600e-mutated BRAF with similar antitumor responses, but mechanistically it is different. The study presented a lower incidence of reported skin toxicities, such as the development of squamous cell cancers of the skin. This is an exciting promising agent. We have yet to see other potential benefits this drug may hold.
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