MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma - An evaluation of the multicenter prospective skin cancer registry ADOREG.

Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30-40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2-2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4-7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2-20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Valerie Glutsch has received honoraria from Bristol-Myers Squibb (BMS) and reports travel support from Novartis, Pierre Fabre Pharmaceuticals, BMS, Merck Sharp & Dohme (MSD), Sanofi Genzyme and SUN Pharmaceuticals Industries outside the submitted work. Anne Zaremba reports receiving travel support from Novartis, Sanofi Genzyme and BMS, outside the submitted work. Patrick Schummer has received honoraria from BMS, an institutional research grant from Novartis and reports travel support from Novartis, Lilly, Abbvie, Sanofi-Aventis and BMS, outside the submitted work. Peter Mohr declares research support from BMS, Novartis and MSD; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, BMS, MSD, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre Pharma, Sanofi Genzyme, Sun Pharma and Roche, and travel support from BMS, MSD, Novartis and Pierre Fabre. Imke Grimmelmann declares speakers and advisory board honoraria from Almirall Hermal, BMS, MSD, Novartis, Pierre Fabre Pharma, Sanofi Genzyme, Sun Pharma and Roche. Ralf Gutzmer has received honoraria for lectures (personally): Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, Sun Pharma, Sanofi, Pierre-Fabre. Honoraria for advice (personally): BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, Merck Serono, Pfizer, Immunocore. Research grants (to institution): Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, Sun Pharma, Sanofi, Almirall Hermal. Support for meeting participation: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. Friedegund Meier has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre Pharma and research funding from Novartis and Roche. Claudia Pföhler has received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, Sun Pharma, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO, outside the submitted work. Michael Max Sachse reports speakers honoraria from Novartis and advisory board honoraria from Sanofi Genzyme. Frank Meiss served as consultant and/or has received honoraria from Novartis, Roche, BMS, MSD, Pierre Fabre Pharma, Sanofi Genzyme and travel support from Novartis, Sun Pharma and Bristol-Myers Squibb, outside the submitted work. Andrea Forschner is on the advisory board or has received speaker's honoraria or travel support for congress participation from BMS, MSD, Novartis, Pierre Fabre Pharma, Roche. Institutional research support: BMS. Sebastian Haferkamp is on the advisory board or has received honoraria from Pierre Fabre Pharma, Amgen, Novartis, Roche, BMS and MSD, research funding from BMS and Novartis and travel support from Novartis, Roche, BMS, Pierre Fabre Pharma, MSD and Amgen, outside the submitted work. Julia Welzel has received speakers fees from MSD and Pierre Fabre Pharma. Patrick Terheyden declares honoraria from BMS, Novartis, MSD, Pierre Fabre Pharma, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera; travel support from BMS and Pierre Fabre Pharma, outside the submitted work. Rudolf Herbst reports speakers and advisory board honoraria from BMS, Immunocore, Novartis, Pierre Fabre, Roche and Sun Pharma outside the submitted work. Jochen Utikal is on the advisory board or has received honoraria and travel support from Amgen, BMS, GlaxoSmithKline, Immuncore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre Pharma, Roche, outside the submitted work. Carsten Weishaupt is on the advisory board or has received honoraria and travel support from Amgen, BMS, Curevac, MSD, Novartis, Pierre Fabre Pharma, Roche and Sanofi. Alexander Kreuter reports speakers and advisory board honoraria from MSD, Böhringer Ingelheim, Infectopharm, Sanofi, MSD, and Abbvie. Pia Duecker is on the advisory board or has received honoraria from BMS, Novartis, Roche, Sanofi, MSD, and Pierre Fabre Pharma. Dirk Debus reports grants, personal fees, or non-financial support from Amgen, BMS, Kyowa Kirin, MSD, Mylan, Novartis, Pfizer, Pierre Fabre Pharma, Roche, and Sanofi. Dirk Schadendorf reports grants, personal fees and non-financial support from BMS, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Novartis, non-financial support from Regeneron, personal fees from Sanofi, personal fees and non-financial support from MSD, personal fees and non-financial support from Amgen, personal fees and non-financial support from 4SC, personal fees and non-financial support from Merck Serono, personal fees from Array, personal fees and non-financial support from Pierre Fabre Pharma, personal fees and non-financial support from Philogen, personal fees and non-financial support from Incyte, personal fees from Pfizer, outside the submitted work. Selma Ugurel reports research support from BMS and Merck Serono, speakers and advisory board honoraria from BMS, MSD, Merck Serono, Novartis and Roche and travel support from BMS and MSD, and Pierre Fabre Pharma, outside the submitted work. Anja Gesierich reports personal fees from BMS, MSD, is on advisory boards of BMS, Novartis, MSD, Pierre Fabre Pharma, Pfizer, Roche and Sanofi, travel support from BMS, MSD, Novartis and Roche, outside the submitted work. Bastian Schilling is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Incyte, Novartis, Roche, BMS and MSD, research funding from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb and MSD and travel support from Novartis, Roche, Bristol-Myers Squibb, Pierre Fabre Pharma, MSD and Amgen, outside the submitted work. All other authors declare no conflicts of interest.