Michael A Davies1, Philippe Saiag2, Caroline Robert3, Jean-Jacques Grob4, Keith T Flaherty5, Ana Arance6, Vanna Chiarion-Sileni7, Luc Thomas8, Thierry Lesimple9, Laurent Mortier10, Stergios J Moschos11, David Hogg12, Iván Márquez-Rodas13, Michele Del Vecchio14, Céleste Lebbé15, Nicolas Meyer16, Ying Zhang17, Yingjie Huang17, Bijoyesh Mookerjee17, Georgina V Long18. 1. Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mdavies@mdanderson.org. 2. Service de Dermatologie Générale et Oncologique, Hôpital A Paré, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt, France; EA 4340, Université Versailles Saint-Quentin-en-Yvelines, Boulogne Billancourt, France. 3. Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. 4. Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix Marseille University, Marseille, France. 5. Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA. 6. Department of Medical Oncology, Hospital Clinic of Barcelona, Carrer de Villarroel, Barcelona, Spain. 7. Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. 8. Service de Dermatologie, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. 9. Oncologie Dermatologique, Centre Eugène Marquis, Rennes, France. 10. Clinique de Dermatologie, Unité d'Onco-Dermatologie, Le Centre Hospitalier Régional Universitaire de Lille, University Lille 2, Lille, France. 11. Melanoma Program, Medical Oncology, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. 12. Clinical Cancer Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada. 13. Servicio de Oncología Médica; Hospital General Universitario Gregorio Marañon, Madrid, Spain. 14. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 15. APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Hôpital Saint Louis Paris, Paris, France. 16. Medical Oncology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France. 17. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 18. Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
Abstract
BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAFV600-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases. METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAFV600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAFV600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAFV600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAFV600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947. FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAFV600-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases. FUNDING: Novartis.
BACKGROUND:Dabrafenib plus trametinib improves clinical outcomes in BRAFV600-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases. METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAFV600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAFV600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAFV600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAFV600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947. FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION:Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAFV600-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases. FUNDING: Novartis.
Authors: 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 Krajsova; Axel Hauschild; Paul Lorigan; Pascal Wolter; Georgina V Long; Keith Flaherty; Paul Nathan; Antoni Ribas; Anne-Marie Martin; Peng Sun; Wendy Crist; Jeff Legos; Stephen D Rubin; Shonda M Little; Dirk Schadendorf Journal: N Engl J Med Date: 2014-11-16 Impact factor: 91.245
Authors: Georgina V Long; Daniil Stroyakovskiy; Helen Gogas; Evgeny Levchenko; Filippo de Braud; James Larkin; Claus Garbe; Thomas Jouary; Axel Hauschild; Jean Jacques Grob; Vanna Chiarion Sileni; Celeste Lebbe; Mario Mandalà; Michael Millward; Ana Arance; Igor Bondarenko; John B A G Haanen; Johan Hansson; Jochen Utikal; Virginia Ferraresi; Nadezhda Kovalenko; Peter Mohr; Volodymyr Probachai; Dirk Schadendorf; Paul Nathan; Caroline Robert; Antoni Ribas; Douglas J DeMarini; Jhangir G Irani; Michelle Casey; Daniele Ouellet; Anne-Marie Martin; Ngocdiep Le; Kiran Patel; Keith Flaherty Journal: N Engl J Med Date: 2014-09-29 Impact factor: 91.245
Authors: Georgina V Long; Uwe Trefzer; Michael A Davies; Richard F Kefford; Paolo A Ascierto; Paul B Chapman; Igor Puzanov; Axel Hauschild; Caroline Robert; Alain Algazi; Laurent Mortier; Hussein Tawbi; Tabea Wilhelm; Lisa Zimmer; Julie Switzky; Suzanne Swann; Anne-Marie Martin; Mary Guckert; Vicki Goodman; Michael Streit; John M Kirkwood; Dirk Schadendorf Journal: Lancet Oncol Date: 2012-10-08 Impact factor: 41.316
Authors: Michael A Davies; Ping Liu; Susan McIntyre; Kevin B Kim; Nicholas Papadopoulos; Wen-Jen Hwu; Patrick Hwu; Agop Bedikian Journal: Cancer Date: 2010-10-19 Impact factor: 6.860
Authors: Reinhard Dummer; Simone M Goldinger; Christian P Turtschi; Nina B Eggmann; Olivier Michielin; Lada Mitchell; Luisa Veronese; Paul René Hilfiker; Lea Felderer; Jeannine D Rinderknecht Journal: Eur J Cancer Date: 2013-11-29 Impact factor: 9.162
Authors: K M Fife; M H Colman; G N Stevens; I C Firth; D Moon; K F Shannon; R Harman; K Petersen-Schaefer; A C Zacest; M Besser; G W Milton; W H McCarthy; J F Thompson Journal: J Clin Oncol Date: 2004-04-01 Impact factor: 44.544
Authors: Sarah B Goldberg; Scott N Gettinger; Amit Mahajan; Anne C Chiang; Roy S Herbst; Mario Sznol; Apostolos John Tsiouris; Justine Cohen; Alexander Vortmeyer; Lucia Jilaveanu; James Yu; Upendra Hegde; Stephanie Speaker; Matthew Madura; Amanda Ralabate; Angel Rivera; Elin Rowen; Heather Gerrish; Xiaopan Yao; Veronica Chiang; Harriet M Kluger Journal: Lancet Oncol Date: 2016-06-03 Impact factor: 41.316
Authors: Heike Niessner; Andrea Forschner; Bernhard Klumpp; Jürgen B Honegger; Maria Witte; Antje Bornemann; Reinhard Dummer; Annemarie Adam; Jürgen Bauer; Ghazaleh Tabatabai; Keith Flaherty; Tobias Sinnberg; Daniela Beck; Ulrike Leiter; Cornelia Mauch; Alexander Roesch; Benjamin Weide; Thomas Eigentler; Dirk Schadendorf; Claus Garbe; Dagmar Kulms; Leticia Quintanilla-Martinez; Friedegund Meier Journal: Cancer Med Date: 2013-02-03 Impact factor: 4.452
Authors: Harriet M Kluger; Veronica Chiang; Amit Mahajan; Christopher R Zito; Mario Sznol; Thuy Tran; Sarah A Weiss; Justine V Cohen; James Yu; Upendra Hegde; Elizabeth Perrotti; Gail Anderson; Amanda Ralabate; Yuval Kluger; Wei Wei; Sarah B Goldberg; Lucia B Jilaveanu Journal: J Clin Oncol Date: 2018-11-08 Impact factor: 44.544
Authors: Christopher R McEvoy; Huiling Xu; Kortnye Smith; Dariush Etemadmoghadam; Huei San Leong; David Y Choong; David J Byrne; Amir Iravani; Sophie Beck; Linda Mileshkin; Richard W Tothill; David D Bowtell; Bindi M Bates; Violeta Nastevski; Judy Browning; Anthony H Bell; Chloe Khoo; Jayesh Desai; Andrew P Fellowes; Stephen B Fox; Owen Wj Prall Journal: J Clin Invest Date: 2019-03-05 Impact factor: 14.808
Authors: Ethan S Srinivasan; Aaron C Tan; Carey K Anders; Ann Marie Pendergast; Dorothy A Sipkins; David M Ashley; Peter E Fecci; Mustafa Khasraw Journal: Mol Cancer Ther Date: 2021-01-05 Impact factor: 6.261
Authors: Ines Pires da Silva; Isabella C Glitza; Lauren E Haydu; Romany Johnpulle; Patricia D Banks; George D Grass; Simone M A Goldinger; Jessica L Smith; Ashlyn S Everett; Peter Koelblinger; Rachel Roberts-Thomson; Michael Millward; Victoria G Atkinson; Alexander Guminski; Rony Kapoor; Robert M Conry; Matteo S Carlino; Wei Wang; Mark J Shackleton; Zeynep Eroglu; Serigne Lo; Angela M Hong; Georgina V Long; Douglas B Johnson; Alexander M Menzies Journal: Pigment Cell Melanoma Res Date: 2019-03-03 Impact factor: 4.693
Authors: Hani M Babiker; Sara A Byron; William P D Hendricks; William F Elmquist; Gautham Gampa; Jessica Vondrak; Jessica Aldrich; Lori Cuyugan; Jonathan Adkins; Valerie De Luca; Raoul Tibes; Mitesh J Borad; Katie Marceau; Thomas J Myers; Linda J Paradiso; Winnie S Liang; Ronald L Korn; Derek Cridebring; Daniel D Von Hoff; John D Carpten; David W Craig; Jeffrey M Trent; Michael S Gordon Journal: Invest New Drugs Date: 2018-09-28 Impact factor: 3.850
Authors: Hussein A Tawbi; Peter A Forsyth; Alain Algazi; Omid Hamid; F Stephen Hodi; Stergios J Moschos; Nikhil I Khushalani; Karl Lewis; Christopher D Lao; Michael A Postow; Michael B Atkins; Marc S Ernstoff; David A Reardon; Igor Puzanov; Ragini R Kudchadkar; Reena P Thomas; Ahmad Tarhini; Anna C Pavlick; Joel Jiang; Alexandre Avila; Sheena Demelo; Kim Margolin Journal: N Engl J Med Date: 2018-08-23 Impact factor: 91.245
Authors: Yang Wang; Bin Lian; Lu Si; ZhiHong Chi; XiNan Sheng; Xuan Wang; LiLi Mao; BiXia Tang; SiMing Li; XieQiao Yan; Xue Bai; Li Zhou; ChuanLiang Cui; Jun Guo Journal: J Cancer Res Clin Oncol Date: 2021-02-21 Impact factor: 4.553