Selma Ugurel1, Joachim Röhmel2, Paolo A Ascierto3, Jürgen C Becker4, Keith T Flaherty5, Jean J Grob6, Axel Hauschild7, James Larkin8, Elisabeth Livingstone9, Georgina V Long10, Paul Lorigan11, Grant A McArthur12, Antoni Ribas13, Caroline Robert14, Lisa Zimmer9, Dirk Schadendorf9, Claus Garbe15. 1. Department of Dermatology, University Hospital Essen, University of Duisburg-Essen & German Cancer Consortium Heidelberg, Germany. Electronic address: selma.ugurel@uk-essen.de. 2. Bremen, Germany. 3. Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy. 4. Translational Skin Cancer Research, German Consortium of Translational Cancer Research (DKTK), Essen, & German Cancer Research Center (DKFZ), Heidelberg, Germany. 5. Massachusetts General Hospital Cancer Center, Boston, MA, USA. 6. Department of Dermatology, Timone Hospital and Aix-Marseille University, Marseille, France. 7. Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany. 8. Royal Marsden Hospital NHS Foundation Trust, London, UK. 9. Department of Dermatology, University Hospital Essen, University of Duisburg-Essen & German Cancer Consortium Heidelberg, Germany. 10. Melanoma Institute Australia, The University of Sydney, And Royal North Shore Hospital, Sydney, NSW, Australia. 11. University of Manchester / the Christie NHS Foundation Trust, Manchester, UK. 12. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia and University of Melbourne, Parkville, VIC, Australia. 13. University of California, Los Angeles, CA, USA. 14. Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. 15. Center for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany.
Abstract
BACKGROUND: Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanoma patients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking. METHODS: We performed an exploratory analysis of survival data from selected clinical trials representative for these two treatment strategies in advanced metastatic melanoma. 84 Kaplan-Meier survival curves from 26 trials were digitised and grouped by therapy strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. RESULTS: Survival curves grouped together by therapy strategy revealed a high concordance, with a larger extent in the first-line setting compared to higher treatment lines. In first-line therapy, the averaged 3-year OS proportions were 41.3% for BRAF plus MEK inhibition, 49.9% for PD-1 inhibition, and 58.4% for CTLA-4 plus PD-1 inhibition. Comparison of the mean PFS and OS curves of kinase inhibition and checkpoint blockade revealed a superiority of combined BRAF plus MEK inhibition within the first 12 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockade. In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years; averaged 3-year OS proportions were 42.4% for BRAF plus MEK inhibition, and 40.1% for PD-1 inhibition. CONCLUSIONS: and relevance: These results need confirmation by head-to-head comparative randomised clinical trials.
BACKGROUND: Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanomapatients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking. METHODS: We performed an exploratory analysis of survival data from selected clinical trials representative for these two treatment strategies in advanced metastatic melanoma. 84 Kaplan-Meier survival curves from 26 trials were digitised and grouped by therapy strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. RESULTS: Survival curves grouped together by therapy strategy revealed a high concordance, with a larger extent in the first-line setting compared to higher treatment lines. In first-line therapy, the averaged 3-year OS proportions were 41.3% for BRAF plus MEK inhibition, 49.9% for PD-1 inhibition, and 58.4% for CTLA-4 plus PD-1 inhibition. Comparison of the mean PFS and OS curves of kinase inhibition and checkpoint blockade revealed a superiority of combined BRAF plus MEK inhibition within the first 12 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockade. In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years; averaged 3-year OS proportions were 42.4% for BRAF plus MEK inhibition, and 40.1% for PD-1 inhibition. CONCLUSIONS: and relevance: These results need confirmation by head-to-head comparative randomised clinical trials.
Authors: Eva Mendes Serrao; Ana Maria Costa; Sergio Ferreira; Victoria McMorran; Emma Cargill; Caroline Hough; Ashley S Shaw; Brent O'Carrigan; Christine A Parkinson; Pippa G Corrie; Timothy J Sadler Journal: Insights Imaging Date: 2022-10-04
Authors: Eva Mendes Serrao; Emily Joslin; Victoria McMorran; Caroline Hough; Cheryl Palmer; Sarah McDonald; Emma Cargill; Ashley S Shaw; Brent O'Carrigan; Christine A Parkinson; Pippa G Corrie; Timothy J Sadler Journal: Cancer Imaging Date: 2022-06-14 Impact factor: 5.605
Authors: Carl M Thielmann; Johanna Matull; Anne Zaremba; Rajmohan Murali; Eleftheria Chorti; Georg Lodde; Philipp Jansen; Rudolf Herbst; Patrick Terheyden; Jochen Utikal; Claudia Pföhler; Jens Ulrich; Alexander Kreuter; Peter Mohr; Ralf Gutzmer; Friedegund Meier; Edgar Dippel; Michael Weichenthal; Julia Kretz; Inga Möller; Antje Sucker; Annette Paschen; Elisabeth Livingstone; Lisa Zimmer; Eva Hadaschik; Selma Ugurel; Dirk Schadendorf; Klaus G Griewank Journal: Eur J Cancer Date: 2021-12-20 Impact factor: 10.002
Authors: Carl M Thielmann; Eleftheria Chorti; Johanna Matull; Rajmohan Murali; Anne Zaremba; Georg Lodde; Philipp Jansen; Luisa Richter; Julia Kretz; Inga Möller; Antje Sucker; Rudolf Herbst; Patrick Terheyden; Jochen Utikal; Claudia Pföhler; Jens Ulrich; Alexander Kreuter; Peter Mohr; Ralf Gutzmer; Friedegund Meier; Edgar Dippel; Michael Weichenthal; Annette Paschen; Elisabeth Livingstone; Lisa Zimmer; Dirk Schadendorf; Eva Hadaschik; Selma Ugurel; Klaus G Griewank Journal: Eur J Cancer Date: 2021-11-04 Impact factor: 10.002
Authors: Reinhard Dummer; Celeste Lebbé; Victoria Atkinson; Mario Mandalà; Paul D Nathan; Ana Arance; Erika Richtig; Naoya Yamazaki; Caroline Robert; Dirk Schadendorf; Hussein A Tawbi; Paolo A Ascierto; Antoni Ribas; Keith T Flaherty; Neha Pakhle; Catarina D Campbell; Daniel Gusenleitner; Aisha Masood; Jan C Brase; Eduard Gasal; Georgina V Long Journal: Nat Med Date: 2020-10-05 Impact factor: 53.440