Dabrafenib-trametinib combination shows durable RFS benefit in BRAF V600-mutant melanoma

Adjuvant treatment with dabrafenib plus trametinib demonstrated a durable RFS benefit compared with placebo for patients with resected stage III BRAF V600-mutant melanoma, according to long-term follow-up from a randomized phase 3 trial.

“Patients with high-risk resectable melanoma represent a broad and diverse group; therefore, there is great clinical interest in understanding outcomes according to baseline characteristics,” Axel Hauschild, MD, PhD, professor and head of Interdisciplinary Skin Cancer Center in the department of dermatology at University Hospital Schleswig-Holstein in Kiel, Germany, and colleagues wrote. “Subgroup analysis of RFS in this study demonstrated that the RFS benefit observed with dabrafenib plus trametinib versus placebo was similar regardless of baseline disease stage, metastatic load or tumor ulceration status.”

The double-blind, placebo-controlled COMBI-AD trial included 870 adults who underwent complete surgical resection of stage IIIA, IIIB or IIIC BRAF V600E or V600K mutant melanoma.

All patients also underwent complete lymphadenectomy and had ECOG performance status of 0 or 1.

Researchers randomly assigned 438 patients to the BRAF inhibitor dabrafenib (Tafinlar, Novartis) dosed at 150 mg twice daily plus the MEK inhibitor trametinib (Mekinist, Novartis) dosed at 2 mg once daily.

The other 432 patients received matching placebos.

Treatment continued for 12 months, development of disease relapse, consent withdrawal, unacceptable toxicity or death.

RFS — dened as the time from random assignment until disease relapse, development of new primary melanoma or death from any cause — served as the primary endpoint. Secondary endpoints included distant metastasis-free survival, OS, freedom from relapse and safety.

Hauschild and colleagues used the Kaplan-Meier method to estimate RFS and distant metastasis-free survival.

Previously released results from the primary analysis — performed after median follow-up of 34 months for the dabrafenib-trametinib group and 33 months for the placebo group — revealed a higher estimated 3-year RFS rate among patients assigned the drug combination (58% vs. 39%; HR = 0.47; P < .001). The regimen also reduced risk for distant metastatic relapse or death (HR = 0.51; P = .001).

On the basis of these results, the FDA approved the combination for adjuvant therapy of resected BRAF V600E- or V600K-mutant stage III melanoma.

At the time of the current analysis — performed after a median 44 months follow-up for the dabrafenib-trametinib group and 42 months for the placebo group — no patients remained on treatment.

Results showed better 3-year RFS (59% vs. 40%) and 4-year RFS (54% vs. 38%) in the treatment group, translating to an HR of 0.49 (95% CI, 0.4-0.59).

Distant metastasis-free survival also favored the treatment group (HR = 0.53; 95% CI, 0.42-0.67).

Hauschild and colleagues calculated estimated cure rates of 54% (95% CI, 49-59) in the dabrafenib-trametinib group and 37% (95% CI, 32-42) in the placebo group.

Researchers did not perform an updated OS analysis because a prespecified number of events had not been reached.

The most common adverse events reported at primary analysis for the dabrafenib-trametinib group were pyrexia (any grade, 63%; grade 3 or grade 4, 5%), fatigue (47%; 4%) and nausea (40%; 1%). Safety results were not updated for the current analysis because no additional drug-related toxicities were anticipated. – by John DeRosier

Disclosures: Hauschild reports honoraria from Amgen, Bristol-Myers Squibb, MedImmune, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, OncoSec, Philogen, Provectus, Regeneron and Roche; consultant or advisory roles with Amgen, Bristol-Myers Squibb, MedImmune, Merck Serono, Merck Sharp & Dohme, Novartis, OncoSec, Roche, Nektar, Philogen, Provectus and Regeneron; and research funding from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis and Roche. Please see the study for all other authors’ relevant financial disclosures.