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

Eva Ellebaek; Michael Weichenthal; Iva Gavrilova; Nethanel Asher; Patrick Terheyden; Jochen Utikal; Amina Jalovčić Suljeviić; Claudia Pföhler; Igor Stojkovski; Rudolf Alexander Herbst; Selma Ugurel; Christina Ruhlmann; Alfonso Berrocal; Margarita Majem; Branko Dujovic; Viktor Šabarić; Tomislav Duvancic; Ainara Soria; Marco Donia; Henrik Schmidt; Rasmus B. Friis; Alexander Gerasimov; Gergana Shalamanova-Deleva; Ahmed Kontilev; Shaked Lev-Ari; Ronnie Shapira; Luisa Piccin; Alessandro Minisini; Berna C. Özdemir; Pawel Teterycz; Anna Mariuk-Jarema; Dimitrios Ziogas; Amalia Anastasopoulou; Dimitra Stefanou; Lourdes Gutiérrez; Christoffer Gebhardt; Reinhard Dummer; Axel Hauschild; Peter Mohr; Imke von Wasielewski; Friedegund Meier; John Haanen; Inge Marie Svane; Paolo A. Ascierto; Joanna Mangana; Piotr Rutkowski; Helen Gogas; Lars Bastholt; Dirk Schadendorf

doi:10.1016/j.ejcskn.2025.100773

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

Eva Ellebaek, Michael Weichenthal^*, Iva Gavrilova, Nethanel Asher, Patrick Terheyden, Jochen Utikal, Amina Jalovčić Suljeviić, Claudia Pföhler, Igor Stojkovski, Rudolf Alexander Herbst, Selma Ugurel, Christina Ruhlmann, Alfonso Berrocal, Margarita Majem, Branko Dujovic, Viktor Šabarić, Tomislav Duvancic, Ainara Soria, Marco Donia, Henrik SchmidtRasmus B. Friis, Alexander Gerasimov, Gergana Shalamanova-Deleva, Ahmed Kontilev, Shaked Lev-Ari, Ronnie Shapira, Luisa Piccin, Alessandro Minisini, Berna C. Özdemir, Pawel Teterycz, Anna Mariuk-Jarema, Dimitrios Ziogas, Amalia Anastasopoulou, Dimitra Stefanou, Lourdes Gutiérrez, Christoffer Gebhardt, Reinhard Dummer, Axel Hauschild, Peter Mohr, Imke von Wasielewski, Friedegund Meier, John Haanen, Inge Marie Svane, Paolo A. Ascierto, Joanna Mangana, Piotr Rutkowski, Helen Gogas, Lars Bastholt, Dirk Schadendorf

^*Corresponding author af dette arbejde

Abstract

Background: Randomised trials recently showed that sequencing of first-line (1 L) immune checkpoint inhibitor (ICI) and second-line (2 L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAF^V600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2 L BRAF/MEKi are limited as the combination was developed for 1 L use, lacking estimates for the impact of prior ICI. Methods: This retrospectively study analysed 2343 patients from the EUMelaReg registry with BRAF^V600-mutated melanoma who received BRAF/MEKi either as 2 L after failing 1 L ICI (n = 654) or as 1 L treatment (n = 1689). 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). Results: Patients in the 2 L cohort achieved outcomes from start of treatment at least equivalent to the matched 1 L 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 2 L BRAF/MEKi compared to 1 L. Median OS from start of 2 L (17.2 months) or 1 L (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. Conclusion: This study further supports the recommended sequencing of ICI as 1 L and BRAF/MEKi as 2 L therapy for patients with BRAF^V600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

Originalsprog	Engelsk
Artikelnummer	100773
Tidsskrift	EJC Skin Cancer
Vol/bind	4
Antal sider	11
DOI	https://doi.org/10.1016/j.ejcskn.2025.100773
Status	Udgivet - jan. 2026

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10.1016/j.ejcskn.2025.100773Licens: CC BY-NC-ND

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Ellebaek, E., Weichenthal, M., Gavrilova, I., Asher, N., Terheyden, P., Utikal, J., Suljeviić, A. J., Pföhler, C., Stojkovski, I., Herbst, R. A., Ugurel, S., Ruhlmann, C., Berrocal, A., Majem, M., Dujovic, B., Šabarić, V., Duvancic, T., Soria, A., Donia, M., ... Schadendorf, D. (2026). 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. EJC Skin Cancer, 4, Artikel 100773. https://doi.org/10.1016/j.ejcskn.2025.100773

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. / Ellebaek, Eva; Weichenthal, Michael; Gavrilova, Iva et al.
I: EJC Skin Cancer, Bind 4, 100773, 01.2026.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Ellebaek, E, Weichenthal, M, Gavrilova, I, Asher, N, Terheyden, P, Utikal, J, Suljeviić, AJ, Pföhler, C, Stojkovski, I, Herbst, RA, Ugurel, S, Ruhlmann, C, Berrocal, A, Majem, M, Dujovic, B, Šabarić, V, Duvancic, T, Soria, A, Donia, M, Schmidt, H, Friis, RB, Gerasimov, A, Shalamanova-Deleva, G, Kontilev, A, Lev-Ari, S, Shapira, R, Piccin, L, Minisini, A, Özdemir, BC, Teterycz, P, Mariuk-Jarema, A, Ziogas, D, Anastasopoulou, A, Stefanou, D, Gutiérrez, L, Gebhardt, C, Dummer, R, Hauschild, A, Mohr, P, von Wasielewski, I, Meier, F, Haanen, J, Svane, IM, Ascierto, PA, Mangana, J, Rutkowski, P, Gogas, H, Bastholt, L & Schadendorf, D 2026, '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', EJC Skin Cancer, bind 4, 100773. https://doi.org/10.1016/j.ejcskn.2025.100773

@article{3c288b01d10d41eeb6fac61a47916675,

title = "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",

abstract = "Background: Randomised trials recently showed that sequencing of first-line (1 L) immune checkpoint inhibitor (ICI) and second-line (2 L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAFV600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2 L BRAF/MEKi are limited as the combination was developed for 1 L use, lacking estimates for the impact of prior ICI. Methods: This retrospectively study analysed 2343 patients from the EUMelaReg registry with BRAFV600-mutated melanoma who received BRAF/MEKi either as 2 L after failing 1 L ICI (n = 654) or as 1 L treatment (n = 1689). 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). Results: Patients in the 2 L cohort achieved outcomes from start of treatment at least equivalent to the matched 1 L 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 2 L BRAF/MEKi compared to 1 L. Median OS from start of 2 L (17.2 months) or 1 L (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. Conclusion: This study further supports the recommended sequencing of ICI as 1 L and BRAF/MEKi as 2 L therapy for patients with BRAFV600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.",

keywords = "BRAF inhibitor, MEK inhibitor, Melanoma, Real-world-data, Second-line",

author = "Eva Ellebaek and Michael Weichenthal and Iva Gavrilova and Nethanel Asher and Patrick Terheyden and Jochen Utikal and Suljevii{\'c}, {Amina Jalov{\v c}i{\'c}} and Claudia Pf{\"o}hler and Igor Stojkovski and Herbst, {Rudolf Alexander} and Selma Ugurel and Christina Ruhlmann and Alfonso Berrocal and Margarita Majem and Branko Dujovic and Viktor {\v S}abari{\'c} and Tomislav Duvancic and Ainara Soria and Marco Donia and Henrik Schmidt and Friis, {Rasmus B.} and Alexander Gerasimov and Gergana Shalamanova-Deleva and Ahmed Kontilev and Shaked Lev-Ari and Ronnie Shapira and Luisa Piccin and Alessandro Minisini and {\"O}zdemir, {Berna C.} and Pawel Teterycz and Anna Mariuk-Jarema and Dimitrios Ziogas and Amalia Anastasopoulou and Dimitra Stefanou and Lourdes Guti{\'e}rrez and Christoffer Gebhardt and Reinhard Dummer and Axel Hauschild and Peter Mohr and {von Wasielewski}, Imke and Friedegund Meier and John Haanen and Svane, {Inge Marie} and Ascierto, {Paolo A.} and Joanna Mangana and Piotr Rutkowski and Helen Gogas and Lars Bastholt and Dirk Schadendorf",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2026",

month = jan,

doi = "10.1016/j.ejcskn.2025.100773",

language = "English",

volume = "4",

journal = "EJC Skin Cancer",

issn = "2772-6118",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - Efficacy of combined BRAF-MEK inhibitor second-line therapy in patients with non-resectable or metastatic BRAFV600-positive melanoma after prior immunotherapy

T2 - A retrospective EUMelaReg multicenter study

AU - Ellebaek, Eva

AU - Weichenthal, Michael

AU - Gavrilova, Iva

AU - Asher, Nethanel

AU - Terheyden, Patrick

AU - Utikal, Jochen

AU - Suljeviić, Amina Jalovčić

AU - Pföhler, Claudia

AU - Stojkovski, Igor

AU - Herbst, Rudolf Alexander

AU - Ugurel, Selma

AU - Ruhlmann, Christina

AU - Berrocal, Alfonso

AU - Majem, Margarita

AU - Dujovic, Branko

AU - Šabarić, Viktor

AU - Duvancic, Tomislav

AU - Soria, Ainara

AU - Donia, Marco

AU - Schmidt, Henrik

AU - Friis, Rasmus B.

AU - Gerasimov, Alexander

AU - Shalamanova-Deleva, Gergana

AU - Kontilev, Ahmed

AU - Lev-Ari, Shaked

AU - Shapira, Ronnie

AU - Piccin, Luisa

AU - Minisini, Alessandro

AU - Özdemir, Berna C.

AU - Teterycz, Pawel

AU - Mariuk-Jarema, Anna

AU - Ziogas, Dimitrios

AU - Anastasopoulou, Amalia

AU - Stefanou, Dimitra

AU - Gutiérrez, Lourdes

AU - Gebhardt, Christoffer

AU - Dummer, Reinhard

AU - Hauschild, Axel

AU - Mohr, Peter

AU - von Wasielewski, Imke

AU - Meier, Friedegund

AU - Haanen, John

AU - Svane, Inge Marie

AU - Ascierto, Paolo A.

AU - Mangana, Joanna

AU - Rutkowski, Piotr

AU - Gogas, Helen

AU - Bastholt, Lars

AU - Schadendorf, Dirk

PY - 2026/1

Y1 - 2026/1

N2 - Background: Randomised trials recently showed that sequencing of first-line (1 L) immune checkpoint inhibitor (ICI) and second-line (2 L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAFV600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2 L BRAF/MEKi are limited as the combination was developed for 1 L use, lacking estimates for the impact of prior ICI. Methods: This retrospectively study analysed 2343 patients from the EUMelaReg registry with BRAFV600-mutated melanoma who received BRAF/MEKi either as 2 L after failing 1 L ICI (n = 654) or as 1 L treatment (n = 1689). 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). Results: Patients in the 2 L cohort achieved outcomes from start of treatment at least equivalent to the matched 1 L 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 2 L BRAF/MEKi compared to 1 L. Median OS from start of 2 L (17.2 months) or 1 L (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. Conclusion: This study further supports the recommended sequencing of ICI as 1 L and BRAF/MEKi as 2 L therapy for patients with BRAFV600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

AB - Background: Randomised trials recently showed that sequencing of first-line (1 L) immune checkpoint inhibitor (ICI) and second-line (2 L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAFV600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2 L BRAF/MEKi are limited as the combination was developed for 1 L use, lacking estimates for the impact of prior ICI. Methods: This retrospectively study analysed 2343 patients from the EUMelaReg registry with BRAFV600-mutated melanoma who received BRAF/MEKi either as 2 L after failing 1 L ICI (n = 654) or as 1 L treatment (n = 1689). 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). Results: Patients in the 2 L cohort achieved outcomes from start of treatment at least equivalent to the matched 1 L 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 2 L BRAF/MEKi compared to 1 L. Median OS from start of 2 L (17.2 months) or 1 L (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. Conclusion: This study further supports the recommended sequencing of ICI as 1 L and BRAF/MEKi as 2 L therapy for patients with BRAFV600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

KW - BRAF inhibitor

KW - MEK inhibitor

KW - Melanoma

KW - Real-world-data

KW - Second-line

UR - http://www.scopus.com/inward/record.url?scp=105027470223&partnerID=8YFLogxK

U2 - 10.1016/j.ejcskn.2025.100773

DO - 10.1016/j.ejcskn.2025.100773

M3 - Journal article

AN - SCOPUS:105027470223

SN - 2772-6118

VL - 4

JO - EJC Skin Cancer

JF - EJC Skin Cancer

M1 - 100773

ER -

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

Abstract

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