Improved survival with MEK inhibition in BRAF-mutated melanoma
Keith T Flaherty, Caroline Robert, Peter Hersey, Paul Nathan, Claus Garbe, Mohammed Milhem, Lev V Demidov, Jessica C Hassel, Piotr Rutkowski, Peter Mohr, Reinhard Dummer, Uwe Trefzer, James M G Larkin, Jochen Utikal, Brigitte Dreno, Marta Nyakas, Mark R Middleton, Jürgen C Becker, Michelle Casey, Laurie J Sherman, Frank S Wu, Daniele Ouellet, Anne-Marie Martin, Kiran Patel, Dirk Schadendorf, METRIC Study Group, G Cinat, S Begbie, J Cebon, K Cheong, A M Haydon, D Leong, P Mainwaring, T Price, D Thomson, S Varma, C Hoeller, J-F Baurain, V Buyse, J Kerger, B Neyns, V Renard, A Rutten, P Schöffski, V Verschaeve, K Belanger, J Chang, T Cheng, M Davis, D Hogg, R Klasa, C Mihalcioiu, X Song, R Tozer, M Kohoutek, I Krajsova, E Kubala, Y Vantuchova, B Guillot, C Lebbe, M-T Leccia, C Lefeuvre-Plesse, P Saiag, A Gesierich, A Stein, W Stolz, P Terheyden, D Bafaloukos, H Gogas, G Fountzilas, M Del Vecchio, A Falcone, L Pilla, A Testori, C Barrow, B M Fitzharris, C Jackson, P Murawa, T Sarosiek, N A Chekha, O A Gladkov, E V Levchenko, J Hansson, L Lundgren, U Stierner, G Ullenhag, T Walz, N V Banakhevych, I N Bondarenko, I Y Galaychuk, Y S Hotko, A V Kurochkin, T M Popovska, I B Shchepotin, Y Shparyk, V M Sorkin, T Arkenau, P Corrie, N G Davidson, P Lorigan, M Marples, M Nicolson, C Ottensmeier, N Steven, J Blakely, L Cranmer, R C Hermann, J R Infante, T Olencki, Keith Flaherty, Paul Nathan, Dirk Schadendorf, Caroline Robert, Peter Hersey, Kiran Patel, Laurie Sherman, Rene Gonzalez, Teresa Petrella, Yu Shyr, Wendy Crist, Julia Williams, Mike Gunshenan, Mary Richardson, Keith T Flaherty, Caroline Robert, Peter Hersey, Paul Nathan, Claus Garbe, Mohammed Milhem, Lev V Demidov, Jessica C Hassel, Piotr Rutkowski, Peter Mohr, Reinhard Dummer, Uwe Trefzer, James M G Larkin, Jochen Utikal, Brigitte Dreno, Marta Nyakas, Mark R Middleton, Jürgen C Becker, Michelle Casey, Laurie J Sherman, Frank S Wu, Daniele Ouellet, Anne-Marie Martin, Kiran Patel, Dirk Schadendorf, METRIC Study Group, G Cinat, S Begbie, J Cebon, K Cheong, A M Haydon, D Leong, P Mainwaring, T Price, D Thomson, S Varma, C Hoeller, J-F Baurain, V Buyse, J Kerger, B Neyns, V Renard, A Rutten, P Schöffski, V Verschaeve, K Belanger, J Chang, T Cheng, M Davis, D Hogg, R Klasa, C Mihalcioiu, X Song, R Tozer, M Kohoutek, I Krajsova, E Kubala, Y Vantuchova, B Guillot, C Lebbe, M-T Leccia, C Lefeuvre-Plesse, P Saiag, A Gesierich, A Stein, W Stolz, P Terheyden, D Bafaloukos, H Gogas, G Fountzilas, M Del Vecchio, A Falcone, L Pilla, A Testori, C Barrow, B M Fitzharris, C Jackson, P Murawa, T Sarosiek, N A Chekha, O A Gladkov, E V Levchenko, J Hansson, L Lundgren, U Stierner, G Ullenhag, T Walz, N V Banakhevych, I N Bondarenko, I Y Galaychuk, Y S Hotko, A V Kurochkin, T M Popovska, I B Shchepotin, Y Shparyk, V M Sorkin, T Arkenau, P Corrie, N G Davidson, P Lorigan, M Marples, M Nicolson, C Ottensmeier, N Steven, J Blakely, L Cranmer, R C Hermann, J R Infante, T Olencki, Keith Flaherty, Paul Nathan, Dirk Schadendorf, Caroline Robert, Peter Hersey, Kiran Patel, Laurie Sherman, Rene Gonzalez, Teresa Petrella, Yu Shyr, Wendy Crist, Julia Williams, Mike Gunshenan, Mary Richardson
Abstract
Background: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.
Methods: In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.
Results: Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.
Conclusions: Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).
Source: PubMed