Sara Valpione1, Matteo S Carlino2, Johanna Mangana3, Meghan J Mooradian4, Grant McArthur5, Dirk Schadendorf6, Axel Hauschild7, Alexander M Menzies8, Ana Arance9, Paolo A Ascierto10, AnnaMaria Di Giacomo11, Francesco de Rosa12, James Larkin13, John J Park2, Simone M Goldinger3, Ryan J Sullivan4, Wen Xu5, Elisabeth Livingstone6, Michael Weichenthal7, Rajat Rai14, Lydia Gaba9, Georgina V Long8, Paul Lorigan15. 1. The Christie NHS Foundation Trust, and University of Manchester, Manchester, UK; CRUK Manchester Institute, Manchester, UK. 2. Melanoma Institute Australia and the University of Sydney, Sydney, NSW, Australia; Westmead and Blacktown Hospitals, Westmead, Australia. 3. University Hospital of Zurich, Zurich, Switzerland. 4. Massachusetts General Hospital, Cancer Center, Boston, MA, USA. 5. Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia. 6. University Hospital Essen, Essen and German Cancer Consortium, Germany. 7. Schleswig-Holstein University Hospital, Kiel, Germany. 8. Melanoma Institute Australia and the University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Australia. 9. Hospital Clínic de Barcelona, Barcelona, Spain. 10. Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy. 11. Medical Oncology and Immunotherapy University Hospital of Siena, Siena, Italy. 12. IRCCS - IRST (Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori), Meldola, Italy. 13. The Royal Marsden NHS Foundation Trust, London, UK. 14. Melanoma Institute Australia and the University of Sydney, Sydney, NSW, Australia. 15. The Christie NHS Foundation Trust, and University of Manchester, Manchester, UK. Electronic address: paul.lorigan@christie.nhs.uk.
Abstract
BACKGROUND: Most metastatic melanoma patients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy. PATIENTS AND METHODS: One hundred sixteen metastatic melanoma patients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively. Response rate (RR), overall survival (OS) and progression-free survival (PFS) from the start of retreatment were calculated. RESULTS: The median duration of treatment was 9.4 months for first BRAFi ± MEKi treatment and 7.7 months for the subsequent treatment (immunotherapy 72%, other 17%, drug holiday 11%) after BRAFi discontinuation. Brain metastases were present in 51 (44%) patients at BRAFi retreatment. The RR to rechallenge with BRAFi ± MEKi was 43.3%: complete response (CR) 2.6%, partial response (PR) 40.7%, stable disease (SD) 24.8% and progressive disease 31.9%, 3 missing. Of 83 patients who previously discontinued BRAFi due to disease progression, 31 (37.3%) responded (30 PR and 1 CR) to retreatment. The median OS from retreatment was 9.8 months, and PFS was 5 months. Independent prognostic factors for survival at rechallenge included number of metastatic sites (hazard ratio [HR] = 1.32 for each additional organ with metastases, P < .001), lactic dehydrogenase (HR = 1.37 for each multiple of the upper normal limit, P < .001), while rechallenge with combination BRAFi + MEKi conferred a better OS versus BRAFi alone (HR = 0.5, P = .006). CONCLUSION: Rechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.
BACKGROUND: Most metastatic melanomapatients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy. PATIENTS AND METHODS: One hundred sixteen metastatic melanomapatients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively. Response rate (RR), overall survival (OS) and progression-free survival (PFS) from the start of retreatment were calculated. RESULTS: The median duration of treatment was 9.4 months for first BRAFi ± MEKi treatment and 7.7 months for the subsequent treatment (immunotherapy 72%, other 17%, drug holiday 11%) after BRAFi discontinuation. Brain metastases were present in 51 (44%) patients at BRAFi retreatment. The RR to rechallenge with BRAFi ± MEKi was 43.3%: complete response (CR) 2.6%, partial response (PR) 40.7%, stable disease (SD) 24.8% and progressive disease 31.9%, 3 missing. Of 83 patients who previously discontinued BRAFi due to disease progression, 31 (37.3%) responded (30 PR and 1 CR) to retreatment. The median OS from retreatment was 9.8 months, and PFS was 5 months. Independent prognostic factors for survival at rechallenge included number of metastatic sites (hazard ratio [HR] = 1.32 for each additional organ with metastases, P < .001), lactic dehydrogenase (HR = 1.37 for each multiple of the upper normal limit, P < .001), while rechallenge with combination BRAFi + MEKi conferred a better OS versus BRAFi alone (HR = 0.5, P = .006). CONCLUSION: Rechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.
Authors: Liana Nobre; Michal Zapotocky; Vijay Ramaswamy; Scott Ryall; Julie Bennett; Daniel Alderete; Julia Balaguer Guill; Lorena Baroni; Ute Bartels; Abhishek Bavle; Miriam Bornhorst; Daniel R Boue; Adela Canete; Murali Chintagumpala; Scott L Coven; Ofelia Cruz; Sonika Dahiya; Peter Dirks; Ira J Dunkel; David Eisenstat; Cecile Faure Conter; Elizabeth Finch; Jonathan L Finlay; Didier Frappaz; Maria Luisa Garre; Karen Gauvain; Anne Grete Bechensteen; Jordan R Hansford; Inga Harting; Peter Hauser; Lili-Naz Hazrati; Annie Huang; Sarah G Injac; Valentina Iurilli; Matthias Karajannis; Gurcharanjeet Kaur; Martin Kyncl; Lenka Krskova; Normand Laperriere; Valerie Larouche; Alvaro Lassaletta; Sarah Leary; Frank Lin; Samantha Mascelli; Tara McKeown; Till Milde; Andres Morales La Madrid; Giovanni Morana; Helena Morse; Naureen Mushtaq; Diana S Osorio; Roger Packer; Zdenek Pavelka; Eduardo Quiroga-Cantero; James Rutka; Magnus Sabel; Duarte Salgado; Palma Solano; Jaroslav Sterba; Jack Su; David Sumerauer; Michael D Taylor; Helen Toledano; Derek S Tsang; Mariana Valente Fernandes; Frank van Landeghem; Cornelis M van Tilburg; Bev Wilson; Olaf Witt; Josef Zamecnik; Eric Bouffet; Cynthia Hawkins; Uri Tabori Journal: JCO Precis Oncol Date: 2020-05-20
Authors: Minny Bhatty; Shumei Kato; Sarina A Piha-Paul; Aung Naing; Vivek Subbiah; Helen J Huang; Daniel D Karp; Apostolia M Tsimberidou; Ralph G Zinner; Wen-Jen Hwu; Milind Javle; Sapna P Patel; Mimi I Hu; Gauri R Varadhachary; Anthony P Conley; Nishma M Ramzanali; Veronica R Holley; Razelle Kurzrock; Funda Meric-Bernstam; Young Kwang Chae; Kevin B Kim; Gerald S Falchook; Filip Janku Journal: Cancer Date: 2018-11-01 Impact factor: 6.860