An open label, non-randomised, phase IIIb study of trametinib in combination with dabrafenib in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: A subgroup analysis of patients with brain metastases.

Background: Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T).
Patients and Methods: This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05.
Results: Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors.
Conclusion: This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.
Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Caroline Dutriaux has served as a member of an advisory board or as an investigator for Novartis. Caroline Robert has acted as a consultant for BMS, MSD, Sanofi, Novartis, Roche and Amgen, and has served as a member of an advisory board and steering committee for Pierre Fabre. Jean-Jacques Grob has received honoraria from BMS, MSD, Merck, Pfizer, Incyte, Novartis, Roche, Amgen and Pierre Fabre, has received travel grant support from BMS, MSD and Roche, has acted as a consultant and advisor for BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer and Incyte. Laurent Mortier has acted as a consultant and advisor for BMS, MSD, Roche, Novartis, Amgen, and Leo and has participated to clinical studies sponsored by Amgen, BMS, Roche, GSK/Novartis, Merck Serono, Leo, and MSD. He has received honoraria from Roche, BMS, MSD, Sanofi, Novartis, Amgen and Pierre Fabre. Céléste Lebbe has received honoraria from BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer and Incyte, has acted as a consultant or has served as a member of an advisory board for BMS, and has received travel grant support from BMS and MSD. Sandrine Mansard has served as a member of an advisory board for Novartis. Eve-Marie Neidhart has received honoraria from BMS. Florent Grange has served as a member of an advisory board for Novartis. Thierry Lesimple has served as a member of an advisory board for MSD, Incyte and Pierre Fabre; He has participated to research sponsored by Roche. Christophe Bedane has served as a member of an advisory board for Novartis. Sophie Dalac-Rat has served as a member of an advisory board for Novartis, Roche, BMS and Pierre Fabre. Charlée Nardin has acted as a consultant for Novartis, BMS and MSD. Alexandra Szenik and Amine Denden are employees of Novartis. Olivier Dereure, Laurent Machet and Hervé Maillard have nothing to disclose related to this research. Philippe Saiag has received personal fees from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, Sanofi and Novartis; he has received nonfinancial support from Bristol-Myers Squibb, MSD, Roche-Genentech, and Novartis; and has received a funding grant from Roche-Genentech.
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