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Multicenter Study
. 2025 Feb 14:16:1536642.
doi: 10.3389/fimmu.2025.1536642. eCollection 2025.

Presence of brain metastasis differentially impacts long-term survival after first-line therapy in melanoma depending on BRAF mutation status

Jan-Malte Placke  1   2 , Luisa Sophie Rajcsanyi  3   4   5 , Rudolf Herbst  6 , Patrick Terheyden  7 , Jochen Utikal  8   9   10 , Claudia Pföhler  11 , Alexander Kreuter  12 , Peter Mohr  13 , Ralf Gutzmer  14 , Michael Weichenthal  15 , Friedegund Meier  16 , Carola Berking  17 , Ulrike Leiter  18 , Johanna Seier  1 , Frederik Krefting  1 , Alpaslan Tasdogan  1   2 , Georg C Lodde  1 , Elisabeth Livingstone  1 , Lisa Zimmer  1 , Alexander Roesch  1   2 , Klaus Griewank  1 , Dirk Schadendorf  1   2 , Selma Ugurel  1   2
Affiliations
Multicenter Study

Presence of brain metastasis differentially impacts long-term survival after first-line therapy in melanoma depending on BRAF mutation status

Jan-Malte Placke et al. Front Immunol. .

Abstract

Background: Modern therapeutic strategies have significantly improved the prognosis of advanced melanoma patients. Predictive factors of therapy response include serum LDH; however, predictive markers for long-term survival are currently largely lacking.

Patients and methods: Patients diagnosed with stage IV melanoma (AJCCv8) of cutaneous origin or unknown primary were identified from the prospective multicenter German Dermatologic Cooperative Oncology Group (DeCOG) skin cancer registry ADOREG. Baseline characteristics were compared between patient groups with short-term versus long-term survival. Statistical analysis included ROC analysis and multinomial regression analysis.

Results: Of 3066 stage IV melanoma patients entered into the ADOREG between 05/2014 and 06/2021, 395 were identified for this study, of whom 301 (76.2%) survived ≤1 year, and 94 (23.8%) survived ≥5 years after stage IV diagnosis. The median follow-up time was 6 months (range 0-129 months). Regarding the baseline characteristics, only elevated serum LDH (P <0.001) was found to be independently predicting survival ≤1 year. Type of first-line therapy, immune checkpoint inhibition (ICI) versus BRAF/MEK targeted therapy (TT), was not predictive of long-term survival ≥5 years. For survival ≤1 year, the presence of brain metastases at treatment start was an independent predictor in BRAF-mutated patients regardless if they received TT (N=113; P=0<0.001) or ICI (N=69; P=0.015), but not in BRAF-wildtype patients who received ICI (N=161; P=0.47).

Conclusions: Low serum LDH independently predicts long-term survival of stage IV melanoma patients in every subgroup of treatment type and BRAF status. Brain metastasis has a negative impact on long-term survival in BRAF-mutated, but not in BRAF-wildtype patients. Investigation of molecular features of brain metastases in BRAF-mutated vs. BRAF-wildtype melanomas may lead to new insights in tumor biology and may yield new therapeutic approaches.

Keywords: BRAF; brain metastases; immune checkpoint inhibitor (ICI); long-term survival; melanoma; targeted therapy.

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Conflict of interest statement

J-MP served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis and received travel support from Bristol-Myers Squibb, Pierre Fabre, Novartis and Therakos. RH is employee of Helios Kliniken GmbH. PT has received honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin and Biofrontera; and travel support from Bristol-Myers Squibb and Pierre Fabre. JU received honoraria speaker honoraria or honoraria as a consultant and travel support from Bristol-Myers Squibb, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi/Regeneron, Sunpharma outside the submitted work. CP received honoraria speaker honoraria or honoraria as a consultant and travel support from Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO, outside the submitted work. AK served as a speaker and/or consultant and/or advisory board for MSD, AbbVie, Boehringer Ingelheim, Janssen, and Sanofi. PR declares research support from Bristol Myers Squibb, Merck Sharp & Dohme and Novartis; speakers and advisory board honoraria from Bristol Myers Squibb, Beiersdorf, Merck Sharp & Dohme, Pierre Fabre, Sun Pharma, Immunocore, Sanofi and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Sun Pharma, and Pierre Fabre, outside the submitted work. RG received honoraria as speaker from BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi/Regeneron, Pierre-Fabre, as advisory board member from BMS, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi/Regeneron, Pierre-Fabre, 4SC, MerckSerono, Pfizer, Immunocore, Delcath, for meeting support from SUN, Pierre-Fabre, Boehringer Ingelheim and for research projects to institution from Amgen, Merck-Serono, SUN Pharma, Sanofi/Regeneron, Kyowa-Kirin, Almirall-Hermal. MW received grants from Bristol-Myers Squibb and Merck Sharp & Dohme, consulting fees from Merck Sharp & Dohme, Immunocore and Novartis, lecture honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme and Pierre-Fabre, and advisory board honoraria from Merck Sharp & Dohme. CB has received speaker’s fees or/and advisor’s honoraria by Almirall-Hermal, Novartis, Roche, BMS, MSD, Delcath, Pierre Fabre, Regeneron, Sanofi, and Immunocore. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche. UL reports relevant financial activities research support from Merck Sharp and Dohme; speakers and advisory board honoraria from Merck Sharp and Dohme, Novartis and Roche, Sanofi Aventis and travel support from Sun Pharma. GL received travel support from Sun Pharma, Pierre Fabre, research funding from Novartis. FK received travel support for participation in congresses and/or speaker honoraria from Novartis, Lilly, Bristol-Myers Squibb, Janssen, Pierre Fabre, Almirall, and Boehringer Ingelheim outside of the present publication. EL served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre- Fabre, Sunpharma and Novartis, outside the submitted work. LS served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. AR reports grants from Novartis, Bristol Myers Squibb and Adtec; personal fees from Merck Sharp & Dohme; and nonfinancial support from Amgen, Roche, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb and Teva. DS reports partial financial support from Bristol Myers Squibb for the conduct of this study and drug supply nivolumab and ipilimumab support; grants or contracts from Amgen, Array/Pfizer, Bristol-Myers Squibb, MSD, Novartis and Roche; consulting fees from 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi and Sun Pharma; support for attendings meetings or travel support from Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre and Sanofi; participation on drug safety monitoring or advisory boards for 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and SunPharma; leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaReg. 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, and Merck Sharp & Dohme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic presentation of the study flow.
Figure 2
Figure 2
Multivariate analysis of baseline clinical parameters on long-term versus short-term survival after 1L therapy in stage IV melanoma patients. Forest plots show multivariate evaluation of clinical parameters associated with long-term OS ≥5 years versus short-term OS ≤1 year in melanoma patients who received ICI or TT (A), BRAF-wildtype patients who received ICI (B), BRAF-mutant patients who received ICI (C), and BRAF-mutant patients who received TT (D).
Figure 3
Figure 3
Impact of clinical parameters on long-term versus short-term survival after 1L therapy in stage IV melanoma patients by univariate analysis. (A) The heatmap shows the univariate evaluation of clinical parameters associated with long-term OS ≥5 years versus short-term OS ≤1 year depending on therapy type and BRAF status. Pie charts show the impact of (B) serum LDH, and (C) presence of brain metastasis on long-term OS ≥5 years versus short-term OS ≤1 year in BRAF-wildtype patients (top, green) who received ICI versus BRAF-mutant patients who received ICI or TT (bottom, purple).
See this image and copyright information in PMC

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