Two phase III trials have shown that the strategy of adding MEK inhibitor therapy to BRAF inhibitor therapy significantly improves progression-free survival in previously untreated patients with advanced BRAF-mutant melanoma.^1,2 Overall survival benefit is also suggested by interim analysis in both trials. In both trials, combination therapy reduced the incidence of hyperproliferative cutaneous adverse events.

Dabrafenib Plus Trametinib

In a double-blind trial performed in 113 centers worldwide, reported by Georgina V. Long, MD, PhD, of Melanoma Institute Australia, University of Sydney, and Mater Hospital, Sydney, and colleagues in The New England Journal of Medicine,¹ 423 patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E or V600K mutation were randomly assigned between May 2012 and January 2013 to receive dabrafenib (Tafinlar), 150 mg twice daily, and trametinib (Mekinist), 2 mg once daily (n = 211) or dabrafenib and placebo (n = 212). The primary endpoint was progression-free survival in the intent-to-treat population.

Patients in the combination and placebo groups were generally balanced for age (median, 55 and 56.5 years), sex (53% and 54% male), previous immunotherapy (27% and 29%), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 74% and 71%), BRAF mutation status (V600E mutation in 85% in both), tumor stage (stage IV M1c in 67% and 65%), elevated lactate dehydrogenase (37% and 34% above the upper limit of normal), visceral disease (78% vs 68%), and number of disease sites (≥ 3 in 48% and 44%).

Key Findings

Median follow-up was 9 months. Median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib group (hazard ratio [HR] = 0.75, P = .03). Subgroup analysis showed that hazard ratios favored combination treatment in nearly all subgroups. In patients with elevated lactate dehydrogenase, median progression-free survival was 7.1 vs 3.8 months (HR = 0.64, 95% confidence interval [CI] = 0.42–0.95).

The overall response rate was 67% in the dabrafenib-trametinib group vs 51% in the dabrafenib group (P = .002). A preplanned interim analysis showed 6-month overall survival of 93% vs 85% (HR = 0.63, P = 0.02), with median overall survival not reached in either group. However, the specified efficacy stopping boundary (P = .00028) was not crossed. In patients with elevated lactate dehydrogenase, median overall survival was 13.7 vs 8.9 months (HR = 0.48, 95% CI = 0.29–0.80). Subsequent anticancer therapy was received by 20% vs 31% of patients and study treatment was continued beyond progression in 19% vs 16% of patients.

Toxicity

The most common adverse events of any grade in the combination and dabrafenib groups were pyrexia (51% vs 28%), fatigue (35% vs 35%), nausea (30% vs 26%), headache (30% vs 29%), chills (30% vs 16%), diarrhea (24% vs 14%), arthralgia (24% vs 27%), rash (23% vs 22%), and hypertension (22% vs 14%). Grade 3 adverse events occurred in 32% vs 34% of patients, with the most common being pyrexia (6% vs 2%) and hypertension (4% vs 5%). Incident cutaneous squamous cell carcinoma occurred in 2% vs 9% and cutaneous hyperkeratoses occurred in 3% vs 32%.

Adverse events led to dose reduction in 25% vs 13%, interruption in 49% vs 33%, and discontinuation in 9% vs 5% of patients. Pyrexia was the most common reason for dose reduction (13% vs 3%) and interruption (32% vs 13%). The most common reason for discontinuation was pyrexia in the combination group (2%) and decreased ejection fraction in the dabrafenib group (1%).

Dr. Long and colleagues concluded: “A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.”

Vemurafenib Plus Cobimetinib

In a double-blind trial performed in 135 centers worldwide, reported by James Larkin, MD, PhD, of Royal Marsden Hospital, London, and colleagues in The New England Journal of Medicne,² 495 patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E or V600K mutation were randomly assigned between January 2013 and January 2014 to receive vemurafenib (Zelboraf) at 960 mg twice daily plus cobimetinib at 60 mg once daily for 21 of 28 days (n = 247) or vemurafenib plus placebo (n = 248). The primary endpoint was progression-free survival in the intent-to-treat population.

The combination and placebo groups were generally balanced for age (median, 56 and 55 years), sex (59% and 56% male), ethnicity (92% and 95% white), ECOG performance status (0 in 76% and 67%), BRAF mutation status (V600E in 69% and 70%, V600K in 10% and 13%, could not be evaluated in 21% and 17%), metastatic status (M1c in 59% and 62%), and elevated lactate dehydrogenase (46% and 43%).

Key Findings

Median follow-up was 7.3 months. Median progression-free survival was 9.9 months in the combination group vs 6.2 months in the placebo group (HR = 0.51, P < .001). Subgroup analysis showed that hazard ratios favored combination treatment in all subgroups.

The overall response rate was 68% in the combination group vs 45% in the vemurafenib group (P < .001). A preplanned interim analysis showed 9-month overall survival of 81% vs 73% (HR = 0.65, P = .046), with median overall survival not being reached in either group. However, the specified efficacy stopping boundary (HR = 0.65, boundary P < .0000037) was not crossed.

Toxicity

The most common adverse events of any grade in the combination group were diarrhea (46% vs 28%), nausea (40% vs 24%), rash (39% vs 35%), fatigue (32% vs 31%), and arthralgia (32% vs 40%). Grade 3 or 4 adverse events occurred in 65% vs 59%; the most common were increased creatine kinase (11%, including grade 4 in 4%, vs 0%), increased alanine transaminase (11% vs 6%), increased aspartate transaminase (8% vs 2%), diarrhea (6% vs 0%), and rash (6% vs 5%). Grade 3 incident cutaneous squamous cell carcinoma occurred in 2% vs 11% and grade 3 keratoacanthoma occurred in 1% vs 8%. Adverse events led to treatment discontinuation in 13% vs 12% of patients.

Dr. Larkin and colleagues concluded: “The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity.” ■

Disclosure: The Long et al study of dabrafenib plus trametinib was funded by GlaxoSmithKline. The Larkin et al study of vemurafenib plus cobimetinib was funded by F. Hoffmann-La Roche/Genentech. For full disclosures of the study authors, visit www.nejm.org.

References

1. Long GV, Stroyakovskiy D, Gogas H, et al: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. September 29, 2014 (early release online).

2. Larkin J, Ascierto PA, Dréno B, et al: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. September 29, 2014 (early release online).