Paolo A Ascierto1, Reinhard Dummer2, Helen J Gogas3, Keith T Flaherty4, Ana Arance5, Mario Mandala6, Gabriella Liszkay7, Claus Garbe8, Dirk Schadendorf9, Ivana Krajsova10, Ralf Gutzmer11, Jan Willem B de Groot12, Carmen Loquai13, Ashwin Gollerkeri14, Michael D Pickard14, Caroline Robert15. 1. Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. 2. Department of Dermatology, University Hospital Zürich Skin Cancer Center and University Zürich, Zürich, Switzerland. 3. Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. 4. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. 5. Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. 6. Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. 7. Department of Dermatology, National Institute of Oncology, Budapest, Hungary. 8. Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. 9. Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. 10. Department of Dermato-oncology, University Hospital Prague and Charles University First Medical Faculty, Prague, Czech Republic. 11. Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. 12. Department of Medical Oncology, Isala, Zwolle, Netherlands. 13. Department of Dermatology, University Medical Center Mainz, Mainz, Germany. 14. Pfizer Inc., Boulder, CO, USA. 15. Service of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, Villejuif, France.
Abstract
BACKGROUND: BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up. METHODS: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups. RESULTS: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM. CONCLUSIONS: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma.
RCT Entities:
BACKGROUND:BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up. METHODS: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinibBID (COMBO450) vs 960 mg of vemurafenibBID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups. RESULTS: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM. CONCLUSIONS: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma.
Authors: Reinhard Dummer; Celeste Lebbé; Victoria Atkinson; Mario Mandalà; Paul D Nathan; Ana Arance; Erika Richtig; Naoya Yamazaki; Caroline Robert; Dirk Schadendorf; Hussein A Tawbi; Paolo A Ascierto; Antoni Ribas; Keith T Flaherty; Neha Pakhle; Catarina D Campbell; Daniel Gusenleitner; Aisha Masood; Jan C Brase; Eduard Gasal; Georgina V Long Journal: Nat Med Date: 2020-10-05 Impact factor: 53.440
Authors: Sarah Zhou; Daniel Sikorski; Honghao Xu; Andrei Zubarev; May Chergui; François Lagacé; Wilson H Miller; Margaret Redpath; Stephanie Ghazal; Marcus O Butler; Teresa M Petrella; Joël Claveau; Carolyn Nessim; Thomas G Salopek; Robert Gniadecki; Ivan V Litvinov Journal: Cancers (Basel) Date: 2021-05-10 Impact factor: 6.639