Christian Menzer1,2, Alexander M Menzies3,4, Matteo S Carlino3,5, Irene Reijers6, Emma J Groen6, Thomas Eigentler7, Jan Willem B de Groot8, Astrid A M van der Veldt9, Douglas B Johnson10, Frank Meiss11, Max Schlaak12,13, Bastian Schilling14, Hans M Westgeest15, Ralf Gutzmer16, Claudia Pföhler17, Friedegund Meier18, Lisa Zimmer19, Karijn P M Suijkerbuijk20, Thomas Haalck21, Kai-Martin Thoms22, Karin Herbschleb23, Jonas Leichsenring1, Alexander Menzer24, Annette Kopp-Schneider25, Georgina V Long3,4, Richard Kefford3,26, Alexander Enk1, Christian U Blank6, Jessica C Hassel1. 1. Heidelberg University Hospital, Heidelberg, Germany. 2. Memorial Sloan Kettering Cancer Center, New York, NY. 3. The University of Sydney, Sydney, NSW, Australia. 4. Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. 5. Crown Princess Mary Cancer Centre Westmead, Sydney, NSW, Australia. 6. Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands. 7. University Medical Center Tübingen, Tübingen, Germany. 8. Isala Zwolle, Zwolle, the Netherlands. 9. Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 10. Vanderbilt University Medical Center, Nashville, TN. 11. Medical Center-University of Freiburg and University of Freiburg, Freiburg, Germany. 12. University Hospital Cologne, Cologne, Germany. 13. University Hospital, LMU Munich, Munich, Germany. 14. University Hospital Würzburg, Würzburg, Germany. 15. Amphia Hospital, Breda, the Netherlands. 16. Hannover Medical School, Hannover, Germany. 17. Saarland University Medical Center, Homburg/Saar, Germany. 18. Dresden University Hospital, Dresden, Germany. 19. University Hospital Essen, University Duisburg-Essen, Essen, Germany. 20. University Medical Center Utrecht Cancer Center, Utrecht, the Netherlands. 21. University Hospital Hamburg-Eppendorf, Hamburg, Germany. 22. University Medical Center Göttingen, Göttingen, Germany. 23. Radboudumc, Nijmegen, the Netherlands. 24. University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 25. German Cancer Research Center, Heidelberg, Germany. 26. Macquarie University, Sydney, NSW, Australia.
Abstract
PURPOSE: BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS: In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS: Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively (P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION: Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.
PURPOSE:BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS: In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS: Fifty-eight patienttumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively (P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION:Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.
Authors: Brian A Keller; Brian J Laight; Oliver Varette; Aron Broom; Marie-Ève Wedge; Benjamin McSweeney; Catia Cemeus; Julia Petryk; Bryan Lo; Bruce Burns; Carolyn Nessim; Michael Ong; Roberto A Chica; Harold L Atkins; Jean-Simon Diallo; Carolina S Ilkow; John C Bell Journal: J Cancer Res Clin Oncol Date: 2021-02-08 Impact factor: 4.553
Authors: Caroline A Nebhan; Douglas B Johnson; Ryan J Sullivan; Roda N Amaria; Keith T Flaherty; Jeffrey A Sosman; Michael A Davies Journal: Oncologist Date: 2021-05-04 Impact factor: 5.837
Authors: Margaret Ottaviano; Emilio Francesco Giunta; Marianna Tortora; Marcello Curvietto; Laura Attademo; Davide Bosso; Cinzia Cardalesi; Mario Rosanova; Pietro De Placido; Erica Pietroluongo; Vittorio Riccio; Brigitta Mucci; Sara Parola; Maria Grazia Vitale; Giovannella Palmieri; Bruno Daniele; Ester Simeone Journal: Int J Mol Sci Date: 2021-03-27 Impact factor: 5.923
Authors: Jeff Owsley; Matthew K Stein; Jason Porter; Gino K In; Mohamed Salem; Steven O'Day; Andrew Elliott; Kelsey Poorman; Geoffrey Gibney; Ari VanderWalde Journal: Exp Biol Med (Maywood) Date: 2020-10-05