Helen J Gogas1, Keith T Flaherty2, Reinhard Dummer3, Paolo A Ascierto4, Ana Arance5, Mario Mandala6, Gabriella Liszkay7, Claus Garbe8, Dirk Schadendorf9, Ivana Krajsova10, Ralf Gutzmer11, Vanna Chiarion Sileni12, Caroline Dutriaux13, Jan Willem B de Groot14, Naoya Yamazaki15, Carmen Loquai16, Ashwin Gollerkeri17, Michael D Pickard17, Caroline Robert18. 1. Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. Electronic address: helgogas@gmail.com. 2. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. 3. Department of Dermatology, University Hospital Zürich Skin Cancer Center and University Zürich, Zürich, Switzerland. 4. Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. 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, and 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. Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Padua, Italy. 13. Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France. 14. Department of Medical Oncology, Isala, Zwolle, Netherlands. 15. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. 16. Department of Dermatology, University Medical Center Mainz, Mainz, Germany. 17. Array BioPharma Inc., Boulder, CO, USA. 18. Service of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, Villejuif, France.
Abstract
BACKGROUND: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. PATIENTS AND METHODS: Patients with locally advanced, unresectable or metastaticBRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. RESULTS: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. CONCLUSION:Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).
RCT Entities:
BACKGROUND: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. PATIENTS AND METHODS: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. RESULTS: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. CONCLUSION:Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).
Authors: Claire Glen; Yun Yi Tan; Ashita Waterston; Thomas R Jeffry Evans; Robert J Jones; Mark C Petrie; Ninian N Lang Journal: JACC CardioOncol Date: 2022-03-15
Authors: Alexander R Lyon; Susan Dent; Susannah Stanway; Helena Earl; Christine Brezden-Masley; Alain Cohen-Solal; Carlo G Tocchetti; Javid J Moslehi; John D Groarke; Jutta Bergler-Klein; Vincent Khoo; Li Ling Tan; Markus S Anker; Stephan von Haehling; Christoph Maack; Radek Pudil; Ana Barac; Paaladinesh Thavendiranathan; Bonnie Ky; Tomas G Neilan; Yury Belenkov; Stuart D Rosen; Zaza Iakobishvili; Aaron L Sverdlov; Ludhmila A Hajjar; Ariane V S Macedo; Charlotte Manisty; Fortunato Ciardiello; Dimitrios Farmakis; Rudolf A de Boer; Hadi Skouri; Thomas M Suter; Daniela Cardinale; Ronald M Witteles; Michael G Fradley; Joerg Herrmann; Robert F Cornell; Ashutosh Wechelaker; Michael J Mauro; Dragana Milojkovic; Hugues de Lavallade; Frank Ruschitzka; Andrew J S Coats; Petar M Seferovic; Ovidiu Chioncel; Thomas Thum; Johann Bauersachs; M Sol Andres; David J Wright; Teresa López-Fernández; Chris Plummer; Daniel Lenihan Journal: Eur J Heart Fail Date: 2020-08-06 Impact factor: 15.534