More Positive Data for Dabrafenib/Trametinib in Melanoma

Patrick Vallance, president, Pharmaceuticals R&D at GSK

Patrick Vallance

The risk of death was significantly reduced for patients with BRAFV600E/K mutation-positive metastatic melanoma treated with dabrafenib (Tafinlar) and trametinib (Mekinist) compared with dabrafenib alone, according to GlaxoSmithKline (GSK).

“These final overall survival [OS] results from COMBI-d, the second phase III study to show positive survival results for the combination compared to BRAF inhibitor monotherapy, further reinforce the scientific rationale for combining MEK and BRAF inhibitors and underscore the potential of the combination of dabrafenib and trametinib in the treatment of BRAFV600 mutation-positive metastatic melanoma,” Patrick Vallance, president, Pharmaceuticals R&D at GSK, said in a statement.

Final data will be submitted to the FDA for review in the coming months. The completion of the study is a post-marketing requirement for the FDA’s accelerated approval of the agent, according to GSK.

Risk of death or disease progression was 29% lower among patients receiving the combination compared with those receiving dabrafenib (HR = 0.71; 95% CI, 0.55-0.92;P< .011).

In total, 423 patients in North and South America, Australia, and Europe were randomized 1:1 to receive the combination or dabrafenib alone. The primary endpoint of the trial was progression-free survival (PFS) with secondary endpoints focused on OS, overall response rate (ORR), duration of response, and safety. Crossover was not allowed.

In an analysis presented at the 2014 ASCO Annual Meeting, median PFS was 9.3 and 8.8 months in the combination and dabrafenib monotherapy arms, respectively. Confirmed ORR was 67% (10% complete response) for the combination arm compared with 51% (9% complete response) for the dabrafenib arm.

Adverse events (AEs) associated with the combination were consistent with previous evaluations, according to GSK. The most common AEs observed in the combination arm were arthralgia, chills, diarrhea, fatigue, headache, hypertension, pyrexia, rash, and vomiting. Pyrexia was observed in a higher incidence and greater severity in the group receiving the combination: 51% versus 28% overall and 6% versus 2% grade 3. The incidence of hyperkeratosis was 3% in the combination arm and 32% in the dabrafenib alone arm.

The combination has also shown greater efficacy compared with the BRAF inhibitor vemurafenib (Zelboraf) for the treatment of unresectable (stage IIIC) or metastatic (stage IV) BRAFV600E/K mutation—positive cutaneous melanoma. The combination lowered the risk of death by 31% compared with vemurafenib alone (HR = 0.69; 95% CI, 0.53-0.89;P<.005).

In an interview withTargeted Oncology, Jeffrey S. Weber, MD, PhD, a senior member at Moffitt Cancer Center, said that dabrafenib plus trametinib has proven to be efficacious but that other oncologists doubt the curative potential of a BRAF/MEK combination and treat with immunotherapy first.

&ldquo;Many of my colleagues go with immunotherapy,&rdquo; Weber said. &ldquo;They want to give the patient a curative chance first—if that doesn&rsquo;t work, they can always go to BRAF/MEK.&rdquo;

Weber understands this strategy. He said many patients who fail on a BRAF/MEK combination will progress rapidly and have few subsequent options. Some patients treated with a BRAF/MEK combination, though, remain in remission 4 years out and may actually be cured, Weber hypothesized.

Though the combination has shown efficacy and has been approved by the FDA, research is still ongoing. According to clinicaltrials.gov, 23 trials are recruiting or will begin recruiting for studies evaluating dabrafenib and trametinib in melanoma, including at least one involving the immunotherapies nivolumab and ipilimumab.