Estimate of long-term relapse-free survival (RFS) and analysis of baseline factors associated with RFS in the COMBI-AD trial

Background: 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. Methods: 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. Results: 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: 1250PStratified Cox regression model for RFS (N/naN/n = total population/patients with data available for all covariates. = 870/845)CovariateEffect TestedHR (95% CI)P ValueSexMale/female1.25 (1.02-1.53).030T stage1/4 2/4 3/40.49 (0.34-0.70) 0.76 (0.56-1.02) 0.89 (0.69-1.15)< .001 .071 .377Tumor ulcerationYes/no0.94 (0.74-1.20).630N stage1/3 2/30.67 (0.49-0.93) 0.78 (0.58-1.06).017 .109In-transit metastasesYes/no1.05 (0.76-1.47).753Melanoma subtypeSuperficial spreading/other Nodular/other0.73 (0.57-0.93) 0.88 (0.68-1.13).010 .321a N/n = total population/patients with data available for all covariates. Open table in a new tab Conclusions: 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: NCT01682083. Editorial acknowledgement: Medical writing assistance was provided by Michael Demars, PhD (ArticulateScience LLC), funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study: Novartis Pharmaceuticals Corporation. Funding: Novartis Pharmaceuticals Corporation. Disclosure: 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.