Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial - 01/09/16
, Brigitte Dréno, ProfMD d, Victoria Atkinson, MD e, Gabrielle Liszkay, MD f, Anna Maria Di Giacomo, MD g, Mario Mandalà, MD h, Lev Demidov, MD i, Daniil Stroyakovskiy, MD j, Luc Thomas, ProfMD k, l, Luis de la Cruz-Merino, MD m, Caroline Dutriaux, MD n, Claus Garbe, ProfMD o, Yibing Yan, PhD p, Matthew Wongchenko, BS p, Ilsung Chang, PhD p, Jessie J Hsu, PhD p, Daniel O Koralek, PhD p, Isabelle Rooney, MBChB p, Antoni Ribas, ProfMD q, James Larkin, FRCP rSummary |
Background |
The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAFV600-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.
Methods |
In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAFV600 mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.
Findings |
Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5–17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5–13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6–7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46–0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3–not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0–19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55–0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3–4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.
Interpretation |
These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAFV600-mutant melanoma.
Funding |
F Hoffmann-La Roche–Genentech.
Le texte complet de cet article est disponible en PDF.Plan
Vol 17 - N° 9
P. 1248-1260 - septembre 2016 Retour au numéro
Article précédent
- Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study
- Zheng Li, Yi Xia, Li-Na Feng, Jie-Rong Chen, Hong-Min Li, Jing Cui, Qing-Qing Cai, Kar Seng Sim, Maarja-Liisa Nairismägi, Yurike Laurensia, Wee Yang Meah, Wen-Sheng Liu, Yun-Miao Guo, Li-Zhen Chen, Qi-Sheng Feng, Chi Pui Pang, Li Jia Chen, Soo Hong Chew, Richard P Ebstein, Jia Nee Foo, Jianjun Liu, Jeslin Ha, Lay Poh Khoo, Suk Teng Chin, Yi-Xin Zeng, Tin Aung, Balram Chowbay, Colin Phipps Diong, Fen Zhang, Yan-Hui Liu, Tiffany Tang, Miriam Tao, Richard Quek, Farid Mohamad, Soo Yong Tan, Bin Tean Teh, Siok Bian Ng, Wee Joo Chng, Choon Kiat Ong, Yukinori Okada, Soumya Raychaudhuri, Soon Thye Lim, Wen Tan, Rou-Jun Peng, Chiea Chuen Khor, Jin-Xin Bei
- Monogenic and polygenic determinants of sarcoma risk: an international genetic study
- Mandy L Ballinger, David L Goode, Isabelle Ray-Coquard, Paul A James, Gillian Mitchell, Eveline Niedermayr, Ajay Puri, Joshua D Schiffman, Gillian S Dite, Arcadi Cipponi, Robert G Maki, Andrew S Brohl, Ola Myklebost, Eva W Stratford, Susanne Lorenz, Sung-Min Ahn, Jin-Hee Ahn, Jeong Eun Kim, Sue Shanley, Victoria Beshay, Robert Lor Randall, Ian Judson, Beatrice Seddon, Ian G Campbell, Mary-Anne Young, Rajiv Sarin, Jean-Yves Blay, Seán I O’Donoghue, David M Thomas, International Sarcoma Kindred Study †
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?