Patients with BRAF-mutant late-stage melanoma derive a lasting overall survival (OS) benefit from treatment with the combination of dabrafenib and trametinib compared with dabrafenib and placebo, according to the final results from the COMBI-d phase III double-blinded trial.
Georgina V. Long, BSc PhD MBBS FRACP
Patients withBRAF-mutant late-stage melanoma derive a lasting overall survival (OS) benefit from treatment with the combination of dabrafenib and trametinib compared with dabrafenib and placebo, according to the final results from the COMBI-d phase III double-blinded trial, which were presented at the American Society of Clinical Oncology Annual Meeting on May 31, 20151and published simultaneously inThe Lancet.2
Treatment with BRAF-inhibitors such as dabrafenib has been shown to increase progression-free survival (PFS) in patients with advanced melanoma who haveBRAF V600EorV600Kmutations, stated Georgina V. Long, BSc PhD MBBS FRACP, an associate professor of melanoma biology and translational research at the University of Sydney in Australia. However, there is a downside to this genetically targeted therapy. “It causes hyperproliferative skin toxicity, including cutaneous squamous cell carcinoma and hyperkeratotic lesions due to paradoxical activation of the MAP kinase pathway,” Long said.
Long noted that adding an MEK inhibitor counteracted this adverse effect in preclinical studies and helped delay the emergence of drug resistance. These findings led to the launch of 3 phase III clinical trials of a BRAF-inhibitor paired with a MEK inhibitor, including COMBI-d, its sister study COMBI-v, and CoBRIM, a trial comparing MEK-inhibitor cobimetinib and BRAF-inhibitor vemurafenib with cobimetinib alone. All three studies found a decrease in skin toxicity with the combination of a BRAF inhibitor and a MEK inhibitor. The COMBI-d trial is the first of the three studies to report final results.
The COMBI-d study (NCT01584648) enrolled 423 treatment-naïve adults with stage 3C or stage 4 melanoma expressing aBRAF V600EorBRAF V600Kmutation. Only those patients whose tumors could not be surgically removed were included in the study. Half of the enrolled patients (n=211) were randomized to receive dabrafenib and trametinib, while the other half were randomized to receive dabrafenib plus a placebo (n=212).
Preliminary results of the trial published in November 2014 demonstrated that the combination of dabrafenib and trametinib increased PFS.3Patients in the combination group had a median PFS of 9.3 months, compared with 8.8 months in the patients receiving dabrafenib and placebo (HR 0.75; 95% CI, 0.57-0.99,P= .03). Overall, two-thirds of the patients in the combination group responded compared with half of the patients taking dabrafenib and placebo.
Patients in the combination treatment group were also less likely to develop cutaneous squamous cell carcinomas compared with the patients taking dabrafenib and placebo (2% vs 9%); however, more patients in the combination group experienced pyrexia (51% vs 28%), according to the published results.
The final results showed an OS advantage for the combination treatment. The median OS was 25.1 months (95% CI 19.2-not reached) in the combination treatment arm compared with 18.7 months (CI 15.2-23.7) in the dabrafenib plus placebo arm. Three-quarters (74%) of patients in the combination arm were alive at year 1 and 51% were alive at year 2, compared with 68% and 42%, respectively, of patients in the dabrafenib/placebo arm.
In the final analysis, median PFS was 11 months for dabrafenib plus trametinib versus 8.8 months for dabrafenib plus placebo (HR 0.67, 95% CI 0.53-0.84;P= .0004; unadjusted). Toxicities were manageable and no new or unexpected adverse events have been identified during the additional 17 months of follow-up since the primary results, Long said.
“Dabrafenib combined with trametinib represents a new targeted therapy standard of care forBRAF V600mutation-positive primary metastatic melanoma,” Long concluded.
Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, Texas, noted that the COMBI-d study was very well conducted. These new data make it time to take a closer look at whether there is a meaningful difference in the long-term PFS of patients taking dabrafenib with trametinib compared with dabrafenib alone, he said.
Kopetz added that he was impressed by the OS results. He noted that the post-progression therapy received by patients in the trial would have actually favored the dabrafenib plus placebo arm, which suggests that the results are robust despite a potential confounder. Of the 30% of patients in the trial who continued past progression, half of those who were in the dabrafenib plus placebo arm received other therapies, compared with only about one-third of those in the combination arm, Longsaid.
“I’d say it is a very important, meaningful improvement in overall survival,” Kopetz said.
1. Long GV, Stroyakovsky DK, Gogas H, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/Kmutation-positive cutaneous melanoma. Presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 102.
2. Long GV, Stroyakovsky D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial [published online May 31 2015].Lancet. 2015. doi.org/10.1016/S0140-6736(15)60898-4.
3. Long GV, Stroyakovsky D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.N Engl J Med.2014;371(20):1877-1888.