Dual pathway inhibition prolongs advanced melanoma survival beyond 2 years

Issue: November 10, 2015

A combination of targeted agents dabrafenib and trametinib significantly improved survival in patients with BRAF V600-mutated advanced melanoma compared with vemurafenib monotherapy, according to study findings presented at the European Society of Medical Oncology’s European Cancer Congress.

Caroline Robert, MD, a medical oncologist at Gustave Roussy Institute in Villejuif, France, and colleagues analyzed data from the phase 3 COMBI-v trial and determined that median OS for the combination of BRAF inhibitor dabrafenib (Tafinlar, Novartis) with MEK inhibitor trametinib (Mekinist, Novartis) extended beyond 2 years, and more patients assigned this combination vs. the BRAF inhibitor vemurafenib (Zelboraf, Hoffmann-LaRoche) alone achieved 2-year OS.

Caroline Robert

“We observed a statistically significant reduction of 34% in the risk of death among patients receiving the combination therapy,” Robert said in a press release. “The increased survival among these patients is remarkable, and this median overall survival of more than 2 years is the longest in this category of patients in a phase 3 randomized trial.”

Researchers randomly assigned 704 patients who harbored BRAF V600E or V600K mutations to receive the combination (n = 352; 150 mg dabrafenib twice daily, 2 mg trametinib daily) or vemurafenib monotherapy (n = 352; 960 mg twice daily) between June 2012 and Oct. 2013. All patients had unresectable or metastatic disease.

OS served as the primary endpoint. Secondary endpoints included PFS, response and safety.

At a pervious interim analysis, researchers found the combination conferred a 31% reduction in the risk for death (HR = 0.69; 95% CI, 0.53-0.89). The study was stopped in July 2014 when it was evident that the combination therapy was superior to vemurafenib alone.

Researchers conducted the updated analysis in March 2015. By this time, researchers had followed patients for approximately 18 months, and around 50% (349 of 704) of the patients had died.

Results showed the median OS for the combination therapy was 25.6 months compared with 18 months for the vemurafenib arm (HR = 0.66; 95% CI, 0.53-0.81). Fifty-one percent of patients who received the combination achieved 2-year OS compared with 38% of patients who received vemurafenib monotherapy.

Patients who received the combination achieved a median PFS of 12.6 months, whereas median PFS in the vemurafenib arm was 7.3 months (HR = 0.61; 95% CI, 0.51-0.73). The 12.6-month median PFS is the longest PFS achieved to date in a randomized trial for patients with a BRAF V600 mutation, Robert said.

Adverse events appeared comparable between the study arms, and no new safety signals occurred during the extended follow-up. Further, researchers also found the combination appeared associated with improve quality of life, particularly for overall health, physical and social functioning and symptom improvements for pain, insomnia, loss of appetite, diarrhea and fatigue.

“This combination therapy is already available in the U.S.,” Robert said in the release. “This long-term benefit in terms of OS confirms the major potential of this combination in patients with metastatic melanoma. A further question to investigate is the combination treatment versus new immunotherapies or combined with them.”

The study was based on preclinical researcher that suggested an improvement in outcomes with dual pathway inhibition for BRAF-mutated advanced melanoma, according to Reinhard Dummer, MD, study researcher and head of the skin cancer center at the UniversitätsSpital Zürich in Switzerland.

“This trial now impressively shows the improved response rate, PFS and OS with excellent tolerability,” Dummer said in the press release. “Based on this study, dual pathway inhibition must be integrated into the management algorithms for this patient population.” – by Anthony SanFilippo

Reference: Robert C, et al. Abstract #3301. Presented at: European Cancer Congress; Sept. 25-29, 2015; Vienna.

Disclosure: This study was funded by GlaxoSmithKline. Robert reports consultant/advisory roles with Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis and Roche. Dummer reports consultant/advisory roles for Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.