Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma

Author(s): Georgina V. Long, M.D., Ph.D. https://orcid.org/0000-0001-8894-3545, Axel Hauschild, M.D., Mario Santinami, M.D., John M. Kirkwood, M.D., Victoria Atkinson, M.B., B.S., Mario Mandala, M.D., Barbara Merelli, M.D., Vanna Chiarion Sileni, M.D., Marta Nyakas, M.D., Andrew Haydon, Ph.D., Caroline Dutriaux, M.D., Caroline Robert, M.D., Ph.D., Laurent Mortier, M.D., Ph.D., Jacob Schachter, M.D., Dirk Schadendorf, M.D. https://orcid.org/0000-0003-3524-7858, Thierry Lesimple, M.D., Ph.D., Ruth Plummer, M.D., James Larkin, M.D., Ph.D., Monique Tan, M.D., M.P.H., Sachin Bajirao Adnaik, Ph.D., Paul Burgess, M.Sci., Tarveen Jandoo, M.D., and Reinhard Dummer, M.D.

Source: DOI: 10.1056/NEJMoa2404139

Dr. Maen Hussein's Thoughts

Combination vs. placebo improved PFS, where there was improvement in OS as the risk of death was 20% lower but was not significant, in BRAF V600E, the risk of death was reduced by 25%. For BRAF V600E, NCCN recommends using this regimen in the adjuvant setting.

Background

The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis–free survival than placebo among patients with BRAF V600–mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival.

Methods

We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis–free survival.

Results

The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan–Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P=0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis–free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports.

Conclusions

After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis–free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)

Author Affiliations

From the Melanoma Institute Australia, the University of Sydney, Royal North Shore Hospital, and Mater Hospital, Sydney (G.V.L.), Princess Alexandra Hospital, the Gallipoli Medical Research Foundation, and the University of Queensland, Woolloongabba (V.A.), and Alfred Hospital, Melbourne, VIC (A.H.) — all in Australia; the Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel (A.H.), and the German Cancer Consortium, National Center for Tumor Diseases, University Hospital Essen, Campus Essen, and the University Alliance Ruhr, Research Center One Health, University of Duisburg-Essen, Essen (D.S.) — all in Germany; Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan (M.S.), the Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo (B.M., M.M.), and Oncology 2, Veneto Institute of Oncology IOV–IRCCS, Padua (V.C.S.) — all in Italy; the Melanoma Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.); Oslo University Hospital and the Norwegian Radium Hospital, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux and Hôpital Saint-André, Bordeaux (C.D.), Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Université de Lille, INSERM Unité 1189, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) — all in France; the Ella Lemelbaum Institute for Immuno Oncology and Melanoma, Sheba Medical Center, and the Sackler School of Medicine, Tel-Aviv University, Ramat Gan, Israel (J.S.); Northern Centre for Cancer Care, Freeman Hospital, and Newcastle University, Newcastle (R.P.), and the Royal Marsden National Health Services Foundation Trust, London (J.L.) — all in the United Kingdom; Novartis Pharmaceuticals, East Hanover, NJ (M.T.); Novartis Healthcare, Hyderabad, India (S.B.A., T.J.); and Novartis Pharma, Basel (P.B.), and the University Hospital Zürich Skin Cancer Center, Zurich (R.D.) — both in Switzerland.

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