Journal ArticleDOI
Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial
Reinhard Dummer,Paolo A. Ascierto,Helen Gogas,Ana Arance,Mario Mandalà,Gabriella Liszkay,Claus Garbe,Dirk Schadendorf,Ivana Krajsová,Ralf Gutzmer,Vanna Chiarion Sileni,Caroline Dutriaux,Jan Willem de Groot,Naoya Yamazaki,Carmen Loquai,Laure Moutouh-de Parseval,Michael D Pickard,Victor Sandor,Caroline Robert,Keith T. Flaherty +19 more
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TLDR
The prespecified interim overall survival analysis of the COLUMBUS trial improved progression-free survival compared with vemurafenib in patients with BRAFV600-mutant melanoma and provided clinically meaningful efficacy as shown by overall survival.Abstract:
Summary Background Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF V600 -mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival. Methods COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF V600E or BRAF V600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. Findings Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9–37·5). Median overall survival was 33·6 months (95% CI 24·4–39·2) with encorafenib plus binimetinib and 16·9 months (14·0–24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47–0·79]; two-sided p Interpretation The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF V600 -mutant melanoma. Funding Array BioPharma, Novartis.read more
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Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer
Scott Kopetz,Axel Grothey,Rona Yaeger,Eric Van Cutsem,Jayesh Desai,Takayuki Yoshino,Harpreet Wasan,Fortunato Ciardiello,Fotios Loupakis,Yong Sang Hong,Neeltje Steeghs,Tormod Kyrre Guren,Hendrik Tobias Arkenau,Pilar García-Alfonso,Per Pfeiffer,Sergey Orlov,Sara Lonardi,Elena Elez,Tae Won Kim,Jan H.M. Schellens,Christina Guo,Asha Krishnan,Jeroen Dekervel,Van Morris,Aitana Calvo Ferrándiz,Line Schmidt Tarpgaard,Michael Braun,Ashwin Gollerkeri,Christopher Hunt Keir,Kati Maharry,Michael D Pickard,Janna Christy-Bittel,Lisa Anderson,Victor Sandor,Josep Tabernero +34 more
TL;DR: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation.
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Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.
Caroline Robert,Jean J. Grob,Daniil Stroyakovskiy,Boguslawa Karaszewska,Axel Hauschild,Evgeny Levchenko,Vanna Chiarion Sileni,Jacob Schachter,Claus Garbe,Igor Bondarenko,Helen Gogas,Mario Mandalà,John B A G Haanen,C. Lebbé,Andrzej Mackiewicz,Piotr Rutkowski,Paul Nathan,Antoni Ribas,Michael A. Davies,Keith T. Flaherty,Paul Burgess,Monique Tan,Eduard Gasal,Maurizio Voi,Dirk Schadendorf,Georgina V. Long +25 more
TL;DR: First-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.
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Cutaneous melanoma, version 2.2019
Daniel G. Coit,John A. Thompson,Mark R. Albertini,Christopher A. Barker,William E. Carson,Carlo M. Contreras,Gregory A. Daniels,Dominick J. DiMaio,Ryan C. Fields,Martin D. Fleming,Morganna Freeman,Anjela Galan,Brian R. Gastman,Valerie Guild,Douglas B. Johnson,Richard W. Joseph,Julie R. Lange,Sameer K. Nath,Anthony J. Olszanski,Patrick A. Ott,Aparna Priyanath Gupta,Merrick I. Ross,April K.S. Salama,Joseph J. Skitzki,Jeffrey A. Sosman,Susan M. Swetter,Kenneth K. Tanabe,Evan Wuthrick,Nicole R. McMillian,Anita M. Engh +29 more
TL;DR: The data and rationale supporting extensive changes to the recommendations for systemic therapy as adjuvant treatment of resected disease and as treatment of unresectable or distant metastatic disease are summarized.
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Immune checkpoint inhibitors in melanoma
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Synthetic lethality as an engine for cancer drug target discovery.
TL;DR: This Review discusses how the genetic concept of synthetic lethality paired with CRISPR-based functional genomic screening can be applied to identify additional synthetic lethal pairs as new and druggable cancer targets.
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Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations
Keith T. Flaherty,J. R. Infante,Adil Daud,Rene Gonzalez,Richard F. Kefford,Jeffrey A. Sosman,Omid Hamid,Lynn M. Schuchter,Jonathan Cebon,Nageatte Ibrahim,Ragini Kudchadkar,Howard A. Burris,Gerald S. Falchook,Alain Algazi,Karl D. Lewis,Georgina V. Long,Igor Puzanov,Peter F. Lebowitz,Ajay Singh,Shonda M Little,Peng Sun,Alicia Allred,Daniele Ouellet,Kevin B. Kim,Kiran Patel,Jeffrey S. Weber +25 more
TL;DR: Dabrafenib and trametinib were safely combined at full monotherapy doses, and the rate of pyrexia was increased with combination therapy, whereas the rates of proliferative skin lesions was nonsignificantly reduced.
Journal ArticleDOI
Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib
Caroline Robert,Boguslawa Karaszewska,Jacob Schachter,Piotr Rutkowski,Andrzej Mackiewicz,Daniil Stroiakovski,Michael Lichinitser,Reinhard Dummer,Florent Grange,Laurent Mortier,Vanna Chiarion-Sileni,Kamil Drucis,Ivana Krajsová,Axel Hauschild,Paul Lorigan,Pascal Wolter,Georgina V. Long,Keith T. Flaherty,Paul Nathan,Antoni Ribas,Antoni Ribas,Anne-Marie Martin,Peng Sun,Wendy A. Crist,Jeff Legos,Stephen D. Rubin,Shonda M Little,Dirk Schadendorf +27 more
TL;DR: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.
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