Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG.

Autor:	Franklin C; Department of Dermatology and Venereology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany cindy.franklin@uk-koeln.de.; Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Cologne, Germany., Mohr P; Department of Dermatology, Elbe-Kliniken Buxtehude, Buxtehude, Germany., Bluhm L; Department of Dermatology, Elbe-Kliniken Buxtehude, Buxtehude, Germany., Meier F; Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden and, Skin Cancer Center at the University Cancer Center Dresden and National Center for Tumor Diseases (NCT), Dresden, Germany., Garzarolli M; Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden and, Skin Cancer Center at the University Cancer Center Dresden and National Center for Tumor Diseases (NCT), Dresden, Germany., Weichenthal M; Department of Dermatology, Skin Cancer Center, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany., Kähler K; Department of Dermatology, Skin Cancer Center, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany., Grimmelmann I; Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hanover, Germany., Gutzmer R; Department of Dermatology, Muehlenkreiskliniken Minden and Ruhr University Bochum, Minden, Germany., Utikal J; Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany., Terheyden P; Department of Dermatology, University of Lübeck and Schleswig-Holstein University Hospital, Campus Lübeck, Lübeck, Germany., Herbst R; Department of Dermatology, HELIOS Klinikum Erfurt, Erfurt, Germany., Haferkamp S; Department of Dermatology, University Hospital Regensburg, Regensburg, Germany., Pfoehler C; Department of Dermatology, Saarland University Medical School, Homburg, Homburg/Saar, Germany., Forschner A; Department of Dermatology, University Hospital Tübingen, Tübingen, Germany., Leiter U; Department of Dermatology, University Hospital Tübingen, Tübingen, Germany., Ziller F; Department of Dermatology, DRK Hospital Chemnitz-Rabenstein, Chemnitz, Germany., Meiss F; Department of Dermatology and Venereology, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany., Ulrich J; Department of Dermatology and Skin Cancer Center, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, Germany., Kreuter A; Department of Dermatology, Venereology and Allergology, Helios St. Elisabeth Klinik Oberhausen, University Witten-Herdecke, Oberhausen, Germany., Gebhardt C; Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Welzel J; Department of Dermatology and Allergology, University Hospital Augsburg, Augsburg, Germany., Schilling B; Department of Dermatology and Venereology, University Hospital Würzburg, Würzburg, Germany., Kaatz M; Department of Dermatology, SRH Wald-Klinikum Gera, Gera, Germany., Scharfetter-Kochanek K; Department of Dermatology and Venereology, University Hospital Ulm, Ulm, Germany., Dippel E; Department of Dermatology, Ludwigshafen Medical Center, Ludwigshafen, Germany., Nashan D; Department of Dermatology, Hospital of Dortmund, Dortmund, Germany., Sachse M; Skin Cancer Center, Department of Dermatology, Klinikum Bremerhaven Reinkenheide, Bremerhaven, Germany., Weishaupt C; Department of Dermatology, University Hospital of Muenster, Muenster, Germany., Löffler H; Department of Dermatology, SLK-Kliniken Heilbronn, Heilbronn, Germany., Gambichler T; Department of Dermatology, Ruhr-University Bochum, Bochum, Germany., Loquai C; Department of Dermatology, Klinikum Bremen-Ost, Gesundheit Nord gGmbH, Bremen, Germany.; Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Heinzerling L; Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany., Grabbe S; Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Debus D; Department of Dermatology, Nuremberg General Hospital, Paracelsus Medical University, Nuremberg, Germany., Schley G; Department of Dermatology and Venereology, Helios Klinikum Schwerin, Schwerin, Germany., Hassel JC; National Center for Tumor Diseases (NCT), Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany., Weyandt G; Department of Dermatology and Allergology, Hospital Bayreuth, Bayreuth, Germany., Trommer M; Department of Radiation Oncology and Cyberknife Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Lodde G; Department of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, Germany., Placke JM; Department of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, Germany., Zimmer L; Department of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, Germany., Livingstone E; Department of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, Germany., Becker JC; Department of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, Germany.; Translational Skin Cancer Research, German Cancer Consortium (DKTK), Deutsches Krebsforschungszentrum, Heidelberg, Germany., Horn S; Department of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, Germany.; Rudolf-Schönheimer-Institute of Biochemistry, Medical Faculty of the University Leipzig, Leipzig, Germany., Schadendorf D; Department of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, Germany., Ugurel S; Department of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, Germany.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Apr; Vol. 11 (4).
DOI:	10.1136/jitc-2022-005828
Abstrakt:	Background: Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy. Methods: Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS). Results: Of 1704 patients, 916 were BRAF wild-type (BRAF wt ) and 788 were BRAF V600 mutant (BRAF mut ). Median follow-up time after start of 1L-therapy was 40.4 months. BRAF wt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAF mut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAF mut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAF mut patients. In BRAF wt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAF wt patients. For BRAF mut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK. Conclusions: In BRAF mut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAF wt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1. Competing Interests: Competing interests: All authors declare no conflicts of interest affecting this study. Conflicts of interest outside the submitted work are as following: CF has been on the advisory board or has received honoraria from Bristol Myers Squibb, Immunocore and Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. LB received honoraria from Amgen, Bristol-Myers Squibb and Sun Pharma. FriM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. KK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. IG declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. RG: Invited speaker: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Advisory board: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, MerckSerono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. JU is on the advisory board or has received travel support from: Amgen, BMS, GSK, Immunocore, Leo Pharma, MSD, Novartis, Pierre Fabre, Sanofi, Roche. JU has received research support from Novartis; speakers and advisory board honoraria. PT has been on the advisory board or has received honoraria from Almirall, Bristol-Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera, and 4SC and received travel grants from Bristol Myers Squibb, and Pierre Fabre. RH reports speakers and advisory board honoraria from Bristol-Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma outside the submitted work. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD and CeGaT, outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie. FZ declares speakers and advisory board honoraria and/or travel support from BMS, MSD, Roche, Novartis, Pierre Fabre and Sanofi Aventis. FraM (Frank Meiss) served as a consultant and/or has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and MSD. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre and travel support from Novartis, Roche, BMS and Pierre Fabre. AK reports receiving lecture fees and fees for serving on advisory boards from MSD Sharp & Dohme, Almirall, Infectopharm, and Boehringer Ingelheim. JW has been on the advisory board, received honoraria and/or travel grants from Bristol Myers Squibb, Novartis, MSD, and Pierre Fabre. TG has received speakers and/or advisory board honoraria and travel support from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono. CL has received speaker’s fees, advisory board honoraria and travel reimbursements from Merck, MSD, Roche, Almirall Hermal, Biontech, Sanofi, Sun Pharma, Kyowa Kirin, Immonocore, BMS, Pierre Fabre, Novartis. LH has received consultancy and speaker fees from Amgen, Biome Dx, BMS, Curevac, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi and SUN. SG has been on the advisory board and/or has received travel support from Bristol Myers Squibb, MSD, Sun Pharma and Novartis and received research support from Novartis and Pierre Fabre. DD has been on the advisory board or has received honoraria from BMS, Kyowa Kirin, MSD, Novartis, Pierre Fabre, Sanofi and received travel grants from Boehringer, Mylan, Pfizer. GS has received honoraria from BMS. GL has received travel support from Sun Pharma. LZ served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Amgen, Pierre Fabre, Sunpharma, Sanofi and Novartis. EL served as consultant and/or has received honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sunpharma and travel support from Medac, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis. JCB received speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group received research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. DS declares relevant financial activities (Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, Sandoz). SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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