• Caroline Robert, Jean J Grob, Daniil Stroyakovskiy, Boguslawa Karaszewska, Axel Hauschild, Evgeny Levchenko, Chiarion Sileni Vanna V From Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Aix-Marseille University, Marseille (J.J.G.), and Assistance, Jacob Schachter, Claus Garbe, Igor Bondarenko, Helen Gogas, Mario Mandalá, Haanen John B A G JBAG From Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Aix-Marseille University, Marseille (J.J.G.), and Assistance , Celeste Lebbé, Andrzej Mackiewicz, Piotr Rutkowski, Paul D Nathan, Antoni Ribas, Michael A Davies, Keith T Flaherty, Paul Burgess, Monique Tan, Eduard Gasal, Maurizio Voi, Dirk Schadendorf, and Georgina V Long.
• From Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Aix-Marseille University, Marseille (J.J.G.), and Assistance Publique-Hôpitaux de Paris Dermatology and Clinical Investigation Center, Unité 976, Université de Paris, Hôpital Saint-Louis, Paris (C.L.) - all in France; Moscow City Oncology Hospital, Moscow (D. Stroyakovskiy), and the Petrov Research Institute of Oncology, St. Petersburg (E.L.) - both in Russia; Przychodnia Lekarska Komed, Konin (B.K.), the University of Medical Sciences, Poznań (A.M.), and the Maria Skłodowska-Curie Institute-Oncology Center, Warsaw (P.R.) - all in Poland; the University Hospital Schleswig-Holstein, Kiel (A.H.), the Department of Dermatology, University of Tübingen, Tübingen (C.G.), University Hospital Essen, Essen (D. Schadendorf), and the German Cancer Consortium, Heidelberg (D. Schadendorf) - all in Germany; the Veneto Institute of Oncology, Padua (V.C.S.), and Papa Giovanni XXIII Hospital, Bergamo (M.M.) - both in Italy; the Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer (J.S.), and Sackler Medical School, Tel Aviv University, Tel Aviv (J.S.) - both in Israel; Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine (I.B.); Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens (H.G.); the Netherlands Cancer Institute, Amsterdam (J.B.A.G.H.); Mount Vernon Cancer Centre, Northwood, United Kingdom (P.D.N.); the University of California, Los Angeles, Los Angeles (A.R.); the University of Texas M.D. Anderson Cancer Center, Houston (M.A.D.); Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (K.T.F.); Novartis Pharma, Basel, Switzerland (P.B.); Novartis Pharmaceuticals, East Hanover, NJ (M.T., E.G., M.V.); and the Melanoma Institute Australia, the University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.).
• N. Engl. J. Med. 2019 Aug 15; 381 (7): 626-636.

BackgroundPatients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.MethodsWe analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.ResultsA total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years.ConclusionsFirst-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).Copyright © 2019 Massachusetts Medical Society.

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