Efficacy of combined BRAF-MEK inhibitor second-line therapy in patients with non-resectable or metastatic BRAFV600-positive melanoma after prior immunotherapy: A retrospective EUMelaReg multicenter study

<h2>Abstract</h2><h3>Background</h3> Randomised trials recently showed that sequencing of first-line (1L) immune checkpoint inhibitor (ICI) and second-line (2L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in <i>BRAF</i><sup>V600</sup>-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2L BRAF/MEKi are limited as the combination was developed for 1L use, lacking estimates for the impact of prior ICI. <h3>Methods</h3> This retrospectively study analysed 2,343 patients from the EUMelaReg registry with <i>BRAF</i><sup>V600</sup>-mutated melanoma who received BRAF/MEKi either as 2L after failing 1L ICI (n=654) or as 1L treatment (n=1,689). Patients with prior adjuvant ICI or BRAF/MEKi were excluded. Prognostic imbalances between the two groups were adjusted using 1:1 inverse propensity score matching. Key efficacy outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and time on treatment (TOT). <h3>Results</h3> Patients in the 2L cohort achieved outcomes from start of treatment at least equivalent to the matched 1L BRAF/MEKi cohort. Kaplan-Meier estimates demonstrated longer median PFS (8.4 vs 7.7 months; p=0.01) and longer median TOT (7.8 vs 6.2 months; p=0.002) for patients treated with 2L BRAF/MEKi compared to 1L. Median OS from start of 2L (17.2 months) or 1L (16.0 months) BRAF/MEKi was similar (p=0.73) despite inherent bias from differing index dates. ORR among both groups (56.4% vs 53.5%; p=0.32) was equal. <h3>Conclusion</h3> This study further supports the recommended sequencing of ICI as 1L and BRAF/MEKi as 2L therapy for patients with <i>BRAF</i><sup>V600</sup>-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

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Journal
EJC Skin Cancer
Published
2025-12-24
DOI
https://doi.org/10.1016/j.ejcskn.2025.100773
Primary Topic
Melanoma and MAPK Pathways
Type
article
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article

Efficacy of combined BRAF-MEK inhibitor second-line therapy in patients with non-resectable or metastatic BRAFV600-positive melanoma after prior immunotherapy: A retrospective EUMelaReg multicenter study

Paweł Teterycz, Patrick Terheyden, D. Ziogas, Rudolf Alexander Herbst et al.
EJC Skin Cancer
Melanoma and MAPK Pathways
article

Efficacy of combined BRAF-MEK inhibitor second-line therapy in patients with non-resectable or metastatic BRAFV600-positive melanoma after prior immunotherapy: A retrospective EUMelaReg multicenter study

Paweł Teterycz, Patrick Terheyden, D. Ziogas, Rudolf Alexander Herbst, Christoffer Gebhardt, Anna Mariuk-Jarema, Michael Weichenthal, Gergana Shalamanova-Deleva, Eva Ellebæk, Christina H. Bruvik Ruhlmann, Rasmus Blechingberg Friis, Iva Gavrilova, Inge Marie Svane, Axel Hausschild, Viktor Šabarić, Dimitra Stefanou, Selma Ugurel, Shaked Lev‐Ari, Alfonso Berrocal, M. Donia, Ainara Soria, Amalia Anastasopoulou, J Utikal, Igor Stojkovski, Luisa Piccin, Alessandro Marco Minisini, Berna C. Özdemir, Margarita Majem, Dirk Schadendorf, B. Dujović, Claudia Pföhler, Lourdes Gutiérrez, Ronnie Shapira, Lars Bastholt, Tomislav Duvančić, Alexander Gerasimov, Ahmed Kontilev, Helen Gogas, Reinhard Dummer, Friedegund Meier, John Haanen, Peter Mohr, Henrik Schmidt, Joanna Mangana, Nethanel Asher, Paolo Antonio Ascierto, Amina Jalovčić Suljeviić, Piotr Rutkowski, Imke von Wasielewski
article en

Abstract

<h2>Abstract</h2><h3>Background</h3> Randomised trials recently showed that sequencing of first-line (1L) immune checkpoint inhibitor (ICI) and second-line (2L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in <i>BRAF</i><sup>V600</sup>-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2L BRAF/MEKi are limited as the combination was developed for 1L use, lacking estimates for the impact of prior ICI. <h3>Methods</h3> This retrospectively study analysed 2,343 patients from the EUMelaReg registry with <i>BRAF</i><sup>V600</sup>-mutated melanoma who received BRAF/MEKi either as 2L after failing 1L ICI (n=654) or as 1L treatment (n=1,689). Patients with prior adjuvant ICI or BRAF/MEKi were excluded. Prognostic imbalances between the two groups were adjusted using 1:1 inverse propensity score matching. Key efficacy outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and time on treatment (TOT). <h3>Results</h3> Patients in the 2L cohort achieved outcomes from start of treatment at least equivalent to the matched 1L BRAF/MEKi cohort. Kaplan-Meier estimates demonstrated longer median PFS (8.4 vs 7.7 months; p=0.01) and longer median TOT (7.8 vs 6.2 months; p=0.002) for patients treated with 2L BRAF/MEKi compared to 1L. Median OS from start of 2L (17.2 months) or 1L (16.0 months) BRAF/MEKi was similar (p=0.73) despite inherent bias from differing index dates. ORR among both groups (56.4% vs 53.5%; p=0.32) was equal. <h3>Conclusion</h3> This study further supports the recommended sequencing of ICI as 1L and BRAF/MEKi as 2L therapy for patients with <i>BRAF</i><sup>V600</sup>-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

EJC Skin CancerVol. 4
Military Medical Academy (RS), University Hospital Centre Zagreb (HR), Universität Hamburg (DE), German Cancer Research Center (DE), National and Kapodistrian University of Athens (GR), Heidelberg University (DE), Tokuda Hospital (BG), Rabin Medical Center (IL), University Hospital of Bern (CH), Medical University Plovdiv (BG), Odense University Hospital (DK), Hospital de Sant Pau (ES), University Hospital Heidelberg (DE), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), The Netherlands Cancer Institute (NL), Christian-Albrechts-Universität zu Kiel (DE), Medizinische Hochschule Hannover (DE), University Hospital of Zurich (CH), Mercy University Hospital (IE), University Clinic of Traumatology (AT), University Hospital St. Ivan Rilski (BG), Hospital Universitario Puerta de Hierro Majadahonda (ES), University Medical Center Hamburg-Eppendorf (DE), Istituto Oncologico Veneto (IT), Clinical Center University of Sarajevo (BA), University Hospital Schleswig-Holstein (DE), Essen University Hospital (DE), University Cancer Center Hamburg (DE), Ospedale Santa Maria della Misericordia di Udine (IT), Hospital General Universitario De Valencia (ES), Klinikum Bielefeld (DE), Elbe Kliniken Stade-Buxtehude (DE), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Sisters of Mercy of the Americas (US), PHI University Psychiatric Clinic - Skopje (MK), Helios Klinikum Erfurt (DE), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Hospital Universitario Ramón y Cajal (ES), University Hospital Carl Gustav Carus (DE), Technische Universität Dresden (DE), Saarland University (DE), University of Lübeck (DE)
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Good health and well-being
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Melanoma and MAPK Pathways
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