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Review
. 2025 Dec;12(1):2545167.
doi: 10.1080/20450885.2025.2545167. Epub 2025 Aug 28.

Personalized therapies in advanced BRAFV600-mutated melanoma: review based on 3 case reports of the REMINISCENCE project

Christoffer Gebhardt  1 , Dirk Debus  2 , Peter Rohrer  3 , Katharina C Kähler  4 , Lukas Koch  3 , Patrick Terheyden  5 , Van Anh Nguyen  6
Affiliations
Review

Personalized therapies in advanced BRAFV600-mutated melanoma: review based on 3 case reports of the REMINISCENCE project

Christoffer Gebhardt et al. Melanoma Manag. 2025 Dec.

Abstract

The management of advanced, unresectable, or metastatic BRAFV600-mutated melanoma is complex, particularly regarding therapy sequencing with targeted therapies (TT) and immune checkpoint inhibitors (ICI). The REMINISCENCE project aimed to enhance individualized therapy approaches by analyzing case reports of patients undergoing encorafenib and binimetinib (EB) therapy. This report discusses three melanoma patients with brain metastases treated in Germany and Austria, emphasizing personalized treatment strategies in BRAFV600-mutated melanoma, particularly when both ICI and TT are available. The timing for transitioning between therapies remains contentious, with many patients experiencing disease progression during or after adjuvant therapy. Findings from clinical trials like DREAMseq, SECOMBIT, EBIN, and ImmunoCobiVem may not directly apply to this evolving clinical landscape due to the impact of prior therapies on the tumor microenvironment. The variations in trial designs further complicate sequencing strategies. Emerging methods, such as early circulating tumor DNA (ctDNA)-guided approaches, present potential pathways for personalized treatment. Ongoing research into sequencing therapy is crucial for improving clinical outcomes. To determine the most effective treatment sequences based on individual medical histories, genetic profiles, and treatment goals, there is an urgent need for prospective biomarker-driven clinical trials.

Keywords: BRAF-mutated melanoma; Oncology; clinical practice; real-world data; sequencing in melanoma treatment; targeted therapies.

Plain language summary

Why was the study undertaken?There is only limited data on multimorbid real-world patients who are often excluded from clinical trials and the best sequence for these patients, including targeted therapies (TT) and immunotherapies (ICI) remains unclear.The REMINISCENCE project aimed to collect exemplary single case reports of advanced real-world melanoma patients with a therapy sequence including ongoing or completed encorafenib and binimetinib (EB) therapy as a basis for scientific discussions.What does this study add?This report describes and discusses treatment sequences and outcomes in exemplary real-world cases of multimorbid patients with progression during ICI treatment or with preexisting autoimmune disease, rapidly progressing disease, and/or brain metastasis.Treatment decisions are discussed in the context of the new ESMO 2024 melanoma guidelines, literature, and ongoing research.An outlook on the latest study results for sequencing is given and discussed.What are the implications of this study for disease understanding and/or clinical care?Real-world sequencing efficacy data in multimorbid patients with asymptomatic and symptomatic brain metastasis, with preexisting autoimmune disease, and patients with high tumor burden and rapidly progressing disease are presented.The best sequence for each patient is based on patient characteristics, medical history and a careful benefit-risk assessment.As TT has shown quick responses even in frail patients with high tumor burden, while ICI showed slow but long-lasting benefits for BRAF-mut patients, future approaches will investigate run-in phases with TT and early switches (without progression) to ICI.

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Conflict of interest statement

C. Gebhardt states research support by BMS, Novartis, Pierre-Fabre, Regeneron and Sanofi, membership of the advisory board of BioNTech, BMS, Immunocore, MSD, Novartis, Pierre-Fabre, Regeneron, Sanofi, SUN Pharma, Sysmex, and honoraria by BMS, GSK, Immunocore, MSD, Novartis, Pierre-Fabre, Regeneron, Sanofi, SUN Pharma, Sysmex, he received travel expenses by BMS, Pierre-Fabre, SUN Pharma, he is board member of the DeCOG (ADO), unpaid, of the Hiege Stiftung – Die Deutsche Hautkrebsstiftung, unpaid and of the the Roggenbuck Stiftung, unpaid, additionally he is a Co-Founder of Dermagnostix and Dermagnostix R&D; D. Debus declares funding received by Pierre Fabre, consulting fees from MSD, BMS, Sanofi, Novartis, Pierre Fabre, Kyowa Kirin, SUN, honoraria from MSD, BMS, Sanofi, Novartis, Pierre Fabre, Kyowa Kirin, SUN, and meeting and travel expenses from MSD, BMS, Sanofi, Novartis, Pierre Fabre, Kyowa Kirin, SUN, Pfizer, Boehringer, Celltrion, he participated in advisory boards of MSD, BMS, Sanofi, Novartis, Pierre Fabre, Kyowa Kirin, SUN; P. Rohrer declares having received support for meeting attendance and travel expenses by Pierre Fabre; K.C. Kähler declares consulting and advisory roles with BMS, MSD, Pierre Fabre, Philogen, Sun Pharma, research funding provided by Novartis, travel, meeting attendance support and expenses by BMS, MSD, Novartis, Roche, Pierre Fabre, Sun Pharma; L. Koch declares grants for research received by Pierre Fabre, honoraria received in 2023 from Pierre Fabre for presentations and support for meeting attendance and expenses from Pierre Fabre in 2023; P. Terheyden declares consluting fees from Almirall, Biotest, Bristol-Myers Squibb, Sanofi, honoraria paid by Almirall, Bristol-Myers Squibb, L’Oréal, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera, 4SC, support for attending meetings and expenses for travel paid by Bristol Myers Squibb, Pierre Fabre; V.A. Nguyen declares consulting fees from BMS, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi, honoraria from BMS, MSD, Novartis, Pierre Fabre, Roche and meeting support and expenses provided by BMS, MSD, Novartis, Pierre Fabre, Roche, Sanofi.

Figures

Figure 1.
Figure 1.
Exemplary patient cases 1, 2, 3. Abbreviations: 1 L, First line; 2 L, Second line; AJCC, American Joint Committee on Cancer; ALT, Alanine amino transferase; AST, Aspartat amino transferase; BR: best resonse; CNS, central nervous system; CR, complete remission; EB, Encorafenib + Binimetinib; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GOT, glutamyl-oxaloacetate transaminase; GPT, glutamyl-pyruvate transaminase; IFN, Interferone; LDH, lactate dehydrogenase; PD, Progress; PR, partial remission; SRS, stereotaxis radiosurgery; T-VEC, Talimogen lapherparepvec; ULN, upper limit of normal; UNK, unknown.
See this image and copyright information in PMC

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Reference annotations

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    2. The COLUMBUS-7 study is a landmark in melanoma research because it provides long-term evidence—spanning seven years—on the effectiveness and safety of targeted therapies for patients with BRAF V600E/K-mutant metastatic melanoma.

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    2. Together with Part 1 of this guideline (this publication provides the latest diagnostic and therapy guidelines in Europe that are valid until the end of 2026.

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    2. This study by Haas et al. (2021) is a game-changer in understanding how melanoma evolves under treatment pressure.

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    2. The DREAMseq trial is a pivotal study that reshaped how clinicians approach treatment sequencing in advanced BRAF V600-mutant melanoma. It showed that treatment sequencing matter and Influences guidelines and real-world practice for managing BRAF-mutant melanoma.

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    2. The SECOMBIT trial is a cornerstone study in melanoma treatment strategy, especially for patients with BRAF V600-mutant metastatic melanoma. It explores how the sequence of therapies—immunotherapy vs. targeted therapy—can dramatically influence long-term survival.

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