Overall survival results of the phase III COMBI-d trial reported in The Lancet by Georgina V. Long, MD, and colleagues showed that the combination of the BRAF inhibitor ­dabrafenib (Tafinlar) with the MEK inhibitor trametinib (Mekinist) resulted in significantly prolonged overall survival vs dabrafenib alone in BRAF V600–mutant melanoma.¹ The primary analysis of the trial had shown that the combination significantly prolonged progression-free survival.²

Study Details

In this double-blind trial, 423 previously untreated patients from 14 countries with BRAF V600E/K mutation–positive unresectable stage IIIC or IV melanoma were randomly assigned between May 2012 and November 2012 to receive oral dabrafenib at 150 mg twice daily and oral trametinib at 2 mg once daily (n = 211) or dabrafenib and placebo (n = 212). The primary endpoint was progression-free survival; overall survival was a secondary endpoint.

The combination and dabrafenib groups were generally balanced for age (median, 55 and 56.5 years), sex (53% and 54% male), Eastern Cooperative Oncology Group performance status (0 for 73% and 71%, 1 for 26% and 29%), BRAF mutation (V600E in 85% in both, V600K in 15% and 14%), stage (IVM1c in 67% and 65%; IIIc, IVM1a-b in 33% and 34%), lactate dehydrogenase level (greater than the upper limit of normal in 36% and 33%), visceral disease (78% and 68%), and number of disease sites (at least three in 48% and 43%).

Improved Overall Survival

At the final data cutoff (January 2015), after 222 patients had died, median overall survival was 25.1 months (95% confidence interval [CI] = 19.2 months to not reached) in the combination group vs 18.7 months (95% CI = 15.2–23.7 months) in the dabrafenib group (hazard ratio [HR] = 0.71, P = .0107). Overall survival was 74% vs 68% at 1 year and 51% vs 42% at 2 years.

Consistent benefit of the combination was observed across all subgroups, with hazard ratios significantly favoring the combination among patients with Val600Glu mutation, stage IVM1c disease, baseline lactate dehydrogenase above the upper limit of normal, visceral disease, and at least three disease sites.

At the current analysis, after an additional 17 months of follow-up since the primary analysis, median progression-free survival was 11.0 months (95% CI = 8.0–13.9 months) in the combination group vs 8.8 months (95% CI = 5.9–9.3 months) in the dabrafenib group (HR = 0.67, P = .0004, unadjusted for multiple testing). Consistent benefit of the combination was observed across all subgroups.

In the primary analysis, at a median follow-up of 9 months, median progression-free survival had been 9.3 vs 8.8 months (HR = 0.75, P = .0348). Overall response rates were 69% (complete response in 16%) vs 53% (complete response in 13%, P = .0014).

Subsequent Therapy

A total of 29% of the combination group and 31% of the dabrafenib group continued study treatment for at least 15 days after progression. Subsequent therapy, excluding study therapy, was used in 33% and 51% of patients, in the combination and dabrafenib groups, respectively, with the most common treatments being ipilimumab (Yervoy, 18% and 28%), dacarbazine (8% and 11%), and vemurafenib (Zelboraf, 8% and 11%); anti–programmed cell death protein 1 (PD-1) treatment was received by 3% and 7%.

Adverse Events

The most common treatment-related adverse events of any grade in the combination group were pyrexia (52% vs 25%), chills (28% vs 14%), fatigue (27% vs 28%), and rash (24% vs 20%), whereas those in the dabrafenib group were hyperkeratosis (33% vs 6%), fatigue (28% vs 27%), hand-foot syndrome (27% vs 6%), and alopecia (26% vs 5%). The combination group also had lower rates of cutaneous squamous cell carcinoma (3% vs 9%), and skin papilloma (1% vs 18%).

Treatment-related grade 3 adverse events occurred in 32% vs 30% of patients (grade 4 events in one combination recipient and three dabrafenib recipients), with the most common being pyrexia (7% vs 2%) in the combination group and cutaneous squamous cell carcinoma (9% vs 3%) in the dabrafenib group. New primary malignant melanomas occurred in < 1% and 2% of patients and noncutaneous treatment-emergent cancers were reported in 1% and 2%.

Treatment was discontinued due to adverse events in 11% of the combination group vs 7% of the dabrafenib group, with the most common reasons being pyrexia (2% vs 1%) and decreased ejection fraction (1% vs 1%).

The investigators concluded: “The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation–positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.” ■

Disclosure: The study was funded by GlaxoSmithKline. For full disclosures of the study authors, visit www.thelancet.com.

References

1. Long GV, Stroyakovskiy 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. Lancet 386:444-451, 2015.

2. Long GV, Stroyakovskiy D, Gogas H, et al: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877-1888, 2014.