Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma.

Melanoma/Skin Cancers
Session Type and Session Title: 
Clinical Science Symposium, Targeted Therapies: Does the Disease Still Matter?
Abstract Number: 


J Clin Oncol 33, 2015 (suppl; abstr 102)
Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, Evgeny Levchenko, Filippo G. De Braud, James M. G. Larkin, Claus Garbe, Thomas Jouary, Axel Hauschild, Jean Jacques Grob, Vanna Chiarion-Sileni, Celeste Lebbe, Mario Mandalà, Michael Millward, Douglas James DeMarini, Jhangir G Irani, Fan Jin, R. Suzanne Swann, Bijoyesh Mookerjee, Keith Flaherty; Melanoma Institute Australia and The University of Sydney, North Sydney, Australia; Moscow City Oncology Hospital #62, Chemotherapy Department, Moscow, Russia; 1st Department of Medicine, Medical School, University of Athens, Athens, Greece; Petrov Research Institute of Oncology, Saint Petersburg, Russia; Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; The Royal Marsden NHS Foundation Trust, London, United Kingdom; University of Tübingen, Tübingen, Germany; Hôpital François Mitterrand, Pau, France; University of Kiel, Kiel, Germany; Aix-Marseille University, Hopital de la Timone, Marseille, France; Veneto Oncology Institute, Padova, Italy; Dermatology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France; Papa Giovanni XXIII Hospital, Bergamo, Italy; Sir Charles Gairdner Hospital, Perth, Australia; GlaxoSmithKline, Collegeville, PA; Massachusetts General Hospital and Dana-Farber Cancer Institute, Boston, MA

Abstract Disclosures


Background: This phase III study (NCT01584648) of dabrafenib (D) + trametinib (T) compared with D + placebo (P) demonstrated superior progression-free survival (PFS) for D+T compared with D+P (HR = 0.75 ; 95% CI: 0.57–0.99; p = 0.035) in pts with BRAF V600E/K mutant, metastatic melanoma at the primary analysis (N Engl J Med 2014;371:1877). The interim overall survival (OS) favored D+T (40 deaths on D+T vs 55 on D+P), but did not cross the pre-planned stopping boundary for efficacy. Median time on study at the primary analysis was 9 months (0–16 months). Rates of adverse events (AEs) were similar for both arms. More pts had AEs leading to dose modifications with D+T vs D+P, and fewer hyperproliferative skin AEs were reported with D+T. The study was continued after the primary analysis to evaluate OS without crossover from D+P to D+T. Methods: Pts were randomized 1:1 to receive D (150mg twice daily) + T (2mg once daily) or D+P as first-line therapy. Eligible pts were age 18 or older, ECOG performance status ≤ 1, and had histologically confirmed unresectable stage IIIC or IV, BRAF V600E/K mutant cutaneous melanoma. The primary endpoint was investigator-assessed PFS; secondary endpoints were OS, overall response rate (ORR), duration of response (DoR), and safety. The final statistical OS comparison was to be initiated when 220 events were reported. Results: From May 2012 to January 2013, 423 pts were randomized (211 to D+T, 212 to D+P). The 220th death was reported on Jan 12, 2015; analysis is expected to be completed in Mar 2015. Estimated median time on study at data cut off is 20 months (0-31 months). Conclusions: The statistical analysis will evaluate the superiority of D+T vs D+P for OS. A 2-year OS landmark analysis, updated PFS, ORR, DoR, and safety will be presented. Clinical trial information: NCT01584648