As reported in The New England Journal of Medicine by Caroline Robert, MD, PhD, of the Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif, and colleagues, the long-term follow-up of the phase III COMBI-d and COMBI-v trials has shown a pooled 5-year overall survival rate of 34% with combined dabrafenib and trametinib treatment in patients with previously untreated metastatic melanoma with a BRAF V600E or V600K mutation.¹ The analysis identified factors associated with prolonged progression-free survival and higher rates of overall survival.

Caroline Robert, MD, PhD

Study Details

The analysis included 563 patients (211 in COMBI-d; 352 in COMBI-v) with previously untreated unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. The COMBI-d trial was a double-blind trial comparing dabrafenib plus trametinib vs dabrafenib plus placebo; the COMBI-v trial was an open-label trial comparing dabrafenib plus trametinib vs vemurafenib. In both trials, patients were stratified according to BRAF genotype and baseline lactate dehydrogenase (LDH) level and were treated until disease progression or unacceptable toxicity. Of the 563 patients, 363 (64%) had stage IV M1c disease, and 194 (34%) had an elevated LDH level (above the upper limit of normal [ULN]). The median duration of follow-up was 22 months (range = 0–76 months).

Progression-Free Survival

The median progression-free survival was 11.1 months. Progression-free survival was 21% at 4 years and 19% at 5 years. Progression-free survival at 5 years was 25% among patients with a baseline LDH level at or below ULN vs 8% in those with a higher LDH level. A subgroup of 216 patients (38%) with a normal LDH level and less than three disease sites at baseline exhibited prolonged progression-free survival, with a 5-year rate of 31%. Progression-free survival at 5 years was 49% among 109 patients with a complete response to treatment as best response, 16% among 274 patients with a partial response, and 1% among 130 patients with stable disease.

First-line treatment with dabrafenib plus trametinib led to 5-year survival in approximately one-third of patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

— Caroline Robert, MD, PhD, and colleagues

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On multivariate analysis, the researchers found factors that were significantly associated with improved progression-free survival. They were age (hazard ratio [HR] = 0.92/10-year increment, P = .02), female vs male sex (HR = 0.74, P = .003), BRAF genotype (HR = 0.65 for V600E vs V600K or V600E plus V600K, P = .004), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 vs 1 (HR = 0.68, P < .001), normal vs elevated LDH level (HR = 0.50, P < .001), and up to three vs three or more organ sites with metastases (HR = 0.72, P = .005).

After discontinuation of study treatment, 299 patients (53%) received subsequent anticancer treatment, including immunotherapy in 196 (66%); immunotherapy included anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) therapy in 151 (51%) and anti–programmed cell death protein 1 (PD-1) therapy in 102 (34%).

Overall Survival

The median overall survival was 25.9 months. The overall survival rates were 37% at 4 years and 34% at 5 years. Overall survival at 5 years was 43% among patients with normal LDH levels at baseline, 16% among those with an elevated LDH level, and 55% among those with a normal LDH level and fewer than three organ sites with metastasis.

In multivariate analyses, the investigators identified baseline factors associated with improved overall survival. They included age (HR = 0.92/10-year increment, P = .04), female vs male sex (HR = 0.68, P < .001), disease stage (HR = 0.76, P = .05, for III, IVM1a, or IVM1b vs IVM1c), an ECOG performance status of 0 vs 1 (HR = 0.49, P < .001), LDH level of normal vs elevated (HR = 0.47, P < .001), and number of organ sites with metastasis (HR = 0.58 for < 3 vs ≥ 3, P < .001).

The 5-year overall survival rates were 71% among 109 patients with a complete response as best response, 32% among 274 with a partial response, and 16% among 130 with stable disease.

Among 161 surviving patients continuing in the trials at the time of analysis, 69 (43%) were receiving dabrafenib, trametinib, or both. A total of 72 patients received additional therapy, with the most common being immunotherapy in 56 patients, including anti–PD-1 therapy in 48 and anti–CTLA-4 therapy in 30. A total of 89 patients did not report receiving any subsequent anticancer therapy at any time during the trials.

Adverse Events

No unexpected adverse events were reported during the extended follow-up. Overall, adverse events of any grade occurred in 98% of patients and led to discontinuation of a trial agent in 18%; the most common reasons for treatment discontinuation were pyrexia (4%), decreased ejection fraction (4%), and increased alanine aminotransferase level (1%). No deaths considered related to dabrafenib plus trametinib were reported.

The investigators concluded: “[W]e found that first-line treatment with dabrafenib plus trametinib led to 5-year survival in approximately one-third of patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Having a complete response to the combined treatment appears to be a strong and early predictor of prolonged benefit. However, no biomarkers are currently available to determine which patients who discontinue therapy are likely to have disease progression.” ■

DISCLOSURE: Dr. Robert has served as an occasional paid consultant for BMS, MSD, Roche, Novartis, Amgen, Pierre Fabre, and Sanofi. The study was funded by GlaxoSmithKline and Novartis. For full disclosures of the study authors, visit nejm.org.

REFERENCE

1. Robert C, Grob JJ, Stroyakovskiy D, et al: Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med 381:626-636, 2019.