Adjuvant therapy with dabrafenib plus trametinib (D + T) for 12 months significantly reduced the risk of relapse or death vs placebo (Pbo; HR, 0.47; P < .001) in patients (pts) in the COMBI-AD trial with resected BRAF V600–mutant stage III melanoma (NCT01682083), leading to the recent US FDA approval in this indication. We used a cure-rate model to estimate long-term RFS benefit and explore the association of baseline factors with RFS to better characterize pts likely to benefit from adjuvant treatment.
COMBI-AD randomized pts with completely resected BRAF V600E/K–mutant stage III melanoma to receive adjuvant D (150 mg twice daily) + T (2 mg once daily) or Pbo for 12 months. Long-term RFS (proportion of pts who did not experience an event) was estimated using a Weibull cure-rate model. Baseline covariates were analyzed using a stratified Cox regression model for RFS, with P values calculated using a Wald χ2 test. AJCC 7th edition criteria were used for pt staging at baseline.
Eight hundred seventy pts were enrolled (D + T, n = 438; Pbo, n = 432). The median follow-up was 2.8 years. Estimation of long-term RFS using a cure-rate model showed a 55% (95% CI, 49%-61%) long-term RFS rate in the D + T arm vs 38% (95% CI, 33%-43%) in the Pbo arm. Evaluation of the association between baseline disease characteristics and RFS demonstrated that lower T stage, lesser nodal involvement, and a superficial spreading melanoma subtype were independently associated with better RFS (Table). Conversely, tumor ulceration and the presence of in-transit metastases were not associated with RFS. With respect to baseline patient demographics, an association was observed between female sex and RFS benefit (P = .030). Table: 1250P
Stratified Cox regression model for RFS (N/na = 870/845)
|Covariate||Effect Tested||HR (95% CI)||P Value|
|T stage||1/4 2/4 3/4||0.49 (0.34-0.70) 0.76 (0.56-1.02) 0.89 (0.69-1.15)||< .001 .071 .377|
|Tumor ulceration||Yes/no||0.94 (0.74-1.20)||.630|
|N stage||1/3 2/3||0.67 (0.49-0.93) 0.78 (0.58-1.06)||.017 .109|
|In-transit metastases||Yes/no||1.05 (0.76-1.47)||.753|
|Melanoma subtype||Superficial spreading/other Nodular/other||0.73 (0.57-0.93) 0.88 (0.68-1.13)||.010 .321|
N/n = total population/patients with data available for all covariates.
The results of the long-term RFS analysis suggest potential long-term RFS in > 50% of pts treated with D + T. Lower T stage and less nodal involvement at baseline were associated with better RFS.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
Medical writing assistance was provided by Michael Demars, PhD (ArticulateScience LLC), funded by Novartis Pharmaceuticals Corporation.
R. Dummer: Intermittent, consulting, advisor: Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma outside the submitted work. D. Schadendorf: Personal fees: Amgen, Boehringer Ingelheim, Leo Pharma, Roche, Novartis, Incyte, Regeneron, 4SC, AstraZeneca, Bristol-Myers Squibb, MS, Pierre Fabre, Merck-EMD, Pfizer, Philiogen, Array; Patients' fees to institution: MSD, Roche, Novartis, Regeneron, Brisol-Myers Squibb, Merck-EMD, Philiogen. A. Hauschild: Consultancy: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec; Research funding: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche; Honoraria: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Roche. V.G. Atkinson: Consulting or advisory role: Bristol-Myers Squibb, MSD, Novartis, Merck Serono, Pierre Fabre; Honoraria: Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Merck Serono; Speakers’ bureau: Bristol-Myers Squibb, MSD, Novartis, Roche; Travel, accommodations, expenses: Bristol-Myers Squibb; . M. Mandala: Research funding, Honoraria, Speakers bureau: Novartis, Roche. V. Chiarion Sileni: Consultancy: Bristol-Myers Squibb, MSD, Novartis, Pierre-Fabre, Merck Serono. J. Larkin: Consultancy, Honoraria: Eisai, Bristol-Myers Squibb, MSD, GlaxoSmithKline, Kymab, Pfizer, Novartis, Roche, Genentech, Secarna, Pierre-Fabre, EUSA Pharma; Research funding: Bristol-Myers Squibb, MSD, Novartis, Pfizer. M.S. Nyakas: Honoraria (institution) for advisory board: Novartis, Incyte. C. Dutriaux: Consultancy: Bristol-Myers Squibb, MSD; Membership on board of directors or advisory committee: Bristol-Myers Squibb, Roche, Novartis, Merck Serono, MSD; Clinical trials investigator: Bristol-Myers Squibb, Roche, Novartis, Merck Serono, MSD, Amgen. A. Haydon: Honoraria: Novartis. L. Mortier: Research funding: Novartis. C. Robert: Advisory board participation: Merck, MSD, Novartis, Roche. J. Schachter: Honoraria: Bristol-Myers Squibb, MSD; Travel, accommodations, expenses: Bristol-Myers Squibb. X. Feng, E. de Jong: Employee: Novartis. B. Mookerjee: Employee: Novartis; Stock ownership: Novartis, GlaxoSmithKline, AstraZeneca. R. Kefford: Membership on board of directors or advisory committees: Bristol-Myers Squibb, Amgen, Merck, Novartis, Teva; Conference travel: Bristol-Myers Squibb, Amgen. J.M. Kirkwood: Consultancy: Bristol-Myers Squibb, Novartis, Array Biopharma, Merck, Roche, Amgen, Immunocore, Prometheus; Research funding: Merck. G.V. Long: Consultancy: Amgen, Bristol-Myers Squibb, Merck MSD, Novartis, Roche, Pierre-Fabre, Array; Honoraria: Bristol-Myers Squibb, MSD, Roche, Novartis, Incyte. All other authors have declared no conflicts of interest.