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. 2025 May 2:220:115339.
doi: 10.1016/j.ejca.2025.115339. Epub 2025 Mar 7.

Immune checkpoint inhibition in metastatic or non-resectable melanoma after failure of adjuvant anti-PD-1 treatment. A EUMelaReg real-world evidence study

Michael Weichenthal  1 , Eva Ellebaek  2 , Joanna Mangana  3 , Nethanel Asher  4 , Iva Gavrilova  5 , Lidija Kandolf  6 , Selma Ugurel  7 , Axel Hausschild  8 , Friedegund Meier  9 , Ulrike Leiter  10 , Elisabeth Livingstone  7 , Christoffer Gebhardt  11 , Ralf Gutzmer  12 , Christina H Ruhlmann  13 , Louise Mahncke-Guldbrandt  14 , Charlotte A Haslund  15 , Sylwia Kopec  16 , Paweł Teterycz  17 , Marc Bender  18 , Wilfried Poudroux  19 , Eva Muñoz-Couselo  20 , Miguel-Angel Berciano-Guerrero  21 , Gergana Shalamanova  22 , Danielle K DePalo  23 , Jasmina Marić Brozić  24 , Vanna Chiarion-Sileni  25 , Anna Arance  26 , Dimitrios Ziogas  27 , Caroline Robert  28 , Anthonie Obik van de Velde  29 , Awa Aminata Gassama  30 , Ronnie Shapira  31 , Guy BenBetzalel  31 , Shirly Grynberg  31 , Egle Ramelyte  32 , Fabio Bertoldo  3 , Valerio DelPrete  3 , Caroline Gaudy-Marqueste  33 , Peter Mohr  34 , Reinhard Dummer  3 , Paolo A Ascierto  35 , Helen Gogas  27 , Enrique Espinosa  36 , Celeste Lebbé  37 , Piotr Rutkowski  16 , John Haanen  38 , Dirk Schadendorf  7 , Inge Marie Svane  2 ; EUMelaReg Consortium Members
Affiliations
Free article

Immune checkpoint inhibition in metastatic or non-resectable melanoma after failure of adjuvant anti-PD-1 treatment. A EUMelaReg real-world evidence study

Michael Weichenthal et al. Eur J Cancer. .
Free article

Abstract

Background: Adjuvant immune checkpoint inhibition (ICI) with anti-PD-1 antibodies in high-risk resected melanoma has been shown to improve recurrence-free survival. It is unclear whether prior adjuvant anti-PD-1 therapy is associated with altered response to subsequent ICI treatment in the metastatic setting.

Methods: Using data from the European Melanoma Registry (EUMelaReg), we analyzed the efficiency of first-line (1L) ICI in non-resectable or metastatic melanoma after failure from prior adjuvant anti-PD-1 treatment. Both single-agent anti-PD-1 and combined anti-PD-1/CTLA-4 (Ipi/Nivo) 1L regimes were included in the analysis. We identified 389 patients receiving 1L ICI with prior adjuvant anti-PD-1 treatment. The control population was selected from a pool of 3390 PD-1-naive cases by 1:1 matching for the type of 1L ICI and various prognostic factors. As outcome measure, overall remission rates (ORR) were calculated and progression-free survival (PFS) was evaluated by Kaplan-Meier and Cox regression analysis.

Results: Out of 389 patients, 303 (77.9 %) received Ipi/Nivo and 86 (22.1 %) anti-PD-1 in 1L. ORR was significantly lower in pre-treated patients (31.4 %) as compared to anti-PD-1 naive patients (48.8 %; p < 0.0001). Kaplan-Meier analysis showed significantly shorter median PFS for pre-treated patients. This applied to both anti-PD-1 and Ipi/Nivo treatment. Patients with early recurrence from adjuvant treatment (during or up to 12 weeks after end of treatment) showed lower ORR (28.5 %) and shorter PFS (3.1 months) than those who recurred later (37.7 % and 6.1 months, respectively).

Conclusions: Patients with metastatic melanoma, previously exposed to anti-PD-1 ICI in the adjuvant setting showed significantly lower ORR and shorter PFS to 1L ICI with either Ipi/Nivo or single-agent anti-PD-1 retreatment.

Keywords: Adjuvant treatment; Immunotherapy; Melanoma; Resistance.

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Conflict of interest statement

Declaration of Competing Interest M. Weichenthal: consulting/advisory roles: Merck Sharp & Dohme, Roche, Novartis, Bristol Myers and Squibb, Sun Pharma, Sanofi, Pierre Fabre. Honoraria: Merck Sharp & Dohme, Roche, Novartis, Bristol Myers and Squibb, Sanofi. Research funding: institutional funding from Merck Sharp & Dohme, Bristol Myers and Squibb, Novartis, 4SC, Innate Pharma. E. Ellabaek: honoraria: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre. Travel/accommodations/expenses: Pierre Fabre, Merck Sharp & Dohme J. Mangana: consultant/advisory roles: Merck/Pfizer, Merck Sharp & Dohme, Novartis, Roche, Pierre Fabre, Amgen, Bristol Myers and Squibb. Travel/accommodations/expenses: Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb und Pierre Fabre. N. Asher: honoraria payments: Novartis, Merck Sharp & Dohme, Bristol Myers and Squibb, Medison, Taro, Sanofi. Research funding: Bristol Myers and Squibb. I. Gavrilova: consulting/advisory roles: Merck Sharp & Dohme, Bristol Myers and Squibb, Pierre Fabre, Medison. Honoraria: Roche, Novartis, Merck Sharp & Dohme, Bristol Myers and Squibb, Sanofi, Merck, Pierre Fabre, Medison. Speaker’s bureau: Roche, Novartis, Merck Sharp & Dohme, Bristol Myers and Squibb, Sanofi, Merck, Pierre Fabre, Medison. Travel/accommodations/expenses: Merck Sharp & Dohme, Bristol Myers and Squibb, Pierre Fabre L. Kandolf: consulting/advisory roles: Merck Sharp & Dohme, Bristol Myers and Squibb, Novartis, Immunocore. Speaker’s bureau: Merck Sharp & Dohme, Bristol Myers and Squibb, Roche, Novartis, Janssen, Immunocore, Abbvie. Honoraria: Merck Sharp & Dohme, Bristol Myers and Squibb, Roche, Novartis, Janssen, Immunocore, Abbvie. Travel/accommodations/expenses: Merck Sharp & Dohme, Bristol Myers and Squibb, Janssen. S. Ugurel: consulting/advisory roles: Bristol Myers and Squibb, Merck Sharp & Dohme, Merck, Novartis. Honoraria payments: Almirall, Bristol Myers and Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sun Pharma. Travel/accommodations/expenses: Pierre-Fabre, Sun Pharma. Research funding: Bristol Myers and Squibb, Merck. A. Hausschild: Consulting/advisory roles: Bristol Myers and Squibb, Merck Pfizer, Merck Sharp & Dohme/Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Immunocore, Replimune, Seagen, IO Biotech, Dermagnostix, Incyte, NeraCare, Highlight Therapeutics, Iovance. Honoraria payments: Amgen, Bristol Myers and Squibb, Merck Pfizer, Merck Sharp & Dohme/Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Immunocore, Replimune, Seagen, IO Biotech, Dermagnostix, Incyte, NeraCare, Highlight Therapeutics, Huya Biosciences, Kyowa Kirin, Iovance. Research funding: Bristol Myers and Squibb, Merck Pfizer, Merck Sharp & Dohme/Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma. Stocks/shares: Melagenix F. Meier: has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol Myers and Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche. U. Leiter: research support: Merck Sharp & Dohme. Consulting fees and honoraria: Sun Pharma, Sanofi (personal and institutional), Merck Sharp & Dohme (personal and institutional), Novartis, Roche, Almirall Hermal. Support for attending meeting from Sun Pharma and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, Merck Sharp & Dohme, Novartis, Roche, Almirall Hermal, outside the submitted work. E. Livingstone: Consulting/advisory roles: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma, Takeda. Honoraria payments: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sunpharma, Takeda. Travel/accommodations/expenses: Pierre-Fabre, Sunpharma. C. Gebhardt: Consulting/advisory roles: Beiersdorf, BioNTech, Bristol-Myers Squibb, Immunocore, Merck Sharp & Dohme, Novartis, Pierre-Fabre Pharma, Roche, Sanofi Genzyme, SUN Pharma, Sysmex Travel/accommodations/expenses: Bristol-Myers Squibb, Pierre Fabre Pharma, SUN Pharma. Speaker’s bureau: Almirall, Bristol-Myers Squibb, Immunocore, Janssen, Merck Sharp & Dohme, Novartis, Onkowissen, Pierre-Fabre Pharma, Regeneron, Roche, Sanofi Genzyme, SUN Pharma. Honoraria payments: Beiersdorf, BioNTech, Bristol-Myers Squibb, Immunocore, Merck Sharp & Dohme, Novartis, Pierre-Fabre Pharma, Regeneron, Sanofi Genzyme, SUN Pharma, Sysmex. Research funding: Novartis, Regeneron, Sanofi Genzyme. Stocks/shares: Dermagnostix, Dermagnostix R&D. R. Gutzmer: Consulting/advisory roles: Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Amgen, Merck-Serono, SUN Pharma, Pierre-Fabre, Sanofi/Regeneron, 4SC, Sanofi, Immunocore; Delcath (to person). Honoraria payments: Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Amgen, Merck-Serono, SUN, Pierre-Fabre, Sanofi, 4SC, Sanofi, Immunocore; Delcath (to person) Travel/accommodations/expenses: Pierre Fabre, SUN Pharma and Boehringer Ingelheim (to person). Research funding: institutional funding from SUN Pharma, Amgen, Sanofi/Regeneron, Merck-Serono, Kyowa-Kirin, Almirall-Hermal. C. H. Ruhlmann: honoraria: Bristol Myers and Squibb, Merck Sharp & Dohme, Helsinn Healthcare SA, Pharmanovia, Astellas Pharma. Research funding: institutional funding from Helsinn Healtcare SA and Novo Nordisk Foundation. LMahncke-Guldbrandt: Honoraria payments: Bristol Meyer Squibb. C. A. Haslund: Consulting/advisory roles: AstraZeneca. Honoraria payments: GSK and Bristol Myers Squibb. S. Kopec: Travel/accommodations/expenses: Pierre Fabre. P. Teterycz: Travel/accommodations/expenses: Pierre-Fabre. E. Munoz-Couselo: Consulting/advisory roles: Immunocore, Merck-Serono, Regeneron, Replimune, Sanofi, Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre. Speaker’s bureau: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi. Honoraria payments: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi. Travel/accommodations/expenses: Merck Sharp & Dohme, Novartis. Research funding: institutional funding from Bristol Myers and Squibb, Merck Sharp & Dohme. E. Berciano-Guerro: Consulting/advisory roles: Bristol Myers and Squibb, Merck Sharp & Dohme, Pierre Fabre, Novartis, Eisai, Novartis, Ipsen, Lilly. Speaker’s bureau: Bristol Myers and Squibb, Merck Sharp & Dohme, Pierre Fabre, Novartis, Eisai, Novartis, Ipsen, Lilly. Research funding: Novartis. G. Shalamanova: Consulting/advisory roles: MSD, BMS, Roche, Novartis and Merck. Honoraria: MSD, BMS, Roche, Novartis, Merck. J. Maric Brozic: Consulting/advisory roles: Merck Sharp & Dohme, Novartis. Speaker’s bureau: Merck Sharp & Dohme, Roche, Novartis, Abbvie, Bristol Myers and Squibb. Honoraria payments: Merck Sharp & Dohme, Bristol Myers and Squibb, Roche, Novartis, Abbvie. Travel/accommodations/expenses: Merck Sharp & Dohme, Novartis, Roche. V. Chiaron-Sileni: Consulting/advisory roles: Immunocore, Pierre-Fabre. Travel/accommodations/expenses: Pierre-Fabre, Sanofi A. Arance: Consulting/advisory roles: Bristol Myers and Squibb, Merck Sharp & Dohme, Pierre Fabre, Biontech. Speaker’s bureau: Bristol Myers and Squibb, Merck Sharp & Dohme, Pierre Fabre; Novartis. Travel/accommodations/expenses: Bristol Myers and Squibb, Merck Sharp & Dohme, Pierre Fabre. Research funding: institutional funding from Bristol Myers and Squibb, Merck Sharp & Dohme, Pierre Fabre, Novartis. D. Ziogas: Consulting/advisory roles: Roche, Winmedica. Honoraria payments: Amgen, Astra-Zeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Genesis, Gilead, Ipsen, Pierre Fabre. C. Robert: Consulting/advisory roles: Novartis, Roche, Merck, Merck Sharp & Dohme, Bristol Myers and Squibb, Regeneron, AstraZeneca, Pierre Fabre. Stocks/shares: Ribonexus. R. Shapira: Honoraria: Novartis, BMS, MSD, Roche, Astra-Zeneca. G. BenBetzalel: consulting/advisory roles: NucleAI. Honoraria: Novartis, BMS, MSD, Medison. S. Grynberg: Honoraria payments: Merck Sharp & Dohme, Medison, Novartis, Bristol Myers and Squibb, Sanofi, Merk Serono. E. Ramelyte: Consultant/advisory board (project focused)/Speaker’s bureau: Sanofi, Pierre Fabre, Bristol Meyers and Squibb, Eli Lilly, Leo Pharma, Merck Sharp & Dohme. Travel/congress support: Sanofi, Pierre Fabre, Kyowa Kirin, Galderma, Bristol Meyers and Squibb V. DelPrete: Honoraria payments from educational collaboration/projects from Novartis, Pierre Fabre, Merck Sharp & Dohme. C. Gaudy-Marqueste: Consulting/advisory roles/Honoraria payments/ Travel/accommodations/expenses: Pierre Fabre, Bristol Myers and Squibb, Merck Sharp & Dohme. P. Mohr: consulting/advisory roles: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sun Pharma. Speaker’s bureau: Novartis, Roche, Bristol Myers and Squibb, Merck Sharp & Dohme, Sanofi, Sun Pharma, Pierre Fabre. Honoraria: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sun Pharma Advanced Research Company. Travel/accommodations/expenses: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sun Pharma. Research funding: institutional funding from Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis Deutschland LTd. R. Dummer: intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, T3 Pharma, MaxiVAX SA, Pfizer and Simcere outside the submitted work. P. A. Ascierto: consultant/advisory role: Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Medicenna, Bio-Al Health, ValoTX, Replimune, Bayer, Erasca, Philogen, Biontech, Anaveon. Research funding: institutional funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Travel/accommodations/expenses: Pfizer, Bio-Al Health, Replimune, Merck Sharp & Dohme, Pierre Fabre. H. Gogas: consulting/advisory roles: Bristol-Myers Squibb, Merck Sharp & Dohme Oncology, Pierre Fabre, Sanofi/Regeneron. Honoraria: Bristol-Myers Squibb, Merck Sharp & Dohme Oncology, Pierre Fabre, Sanofi/Regeneron. Travel/accommodations/expenses: Merck Sharp & Dohme, Pfizer, Sanofi. Research funding: institutional funding from Bristol-Myers Squibb, Roche, Merck Sharp & Dohme Oncology, Amgen, Novartis, Iovance Biotherapeutics. E. Espinosa: Consulting/advisory roles: Merck Sharp & Dohme. Honoraria payments: Bristol Myers and Squibb, Immunocore, Merck Sharp & Dohme, Pierre Fabre, Novartis. Travel/accommodations/expenses: Pierre Fabre. C. Lebbe: Consulting/advisory roles/Speaker’s bureau/Honoraria payments: Bristol Myers and Squibb, Merck Sharp & Dohme, PFO immunocore. Travel/accommodations/expenses: PFO. Research funding: Bristol Myers and Squibb PFO. P. Rutkowski: Consulting/advisory boards: Novartis, Blueprint Medicines, Bristol-Myers Squibb, Pierre Fabre, MSD, Amgen, Philogen, Astra-Zeneca. Honoraria: Bristol-Myers Squibb, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, Merck. Speakers’ bureau: Pfizer, Novartis, Pierre Fabre. Travel/accommodations/expenses: Orphan Europe, Pierre Fabre. Research funding: institutional funding from Novartis, Roche, Bristol-Myers Squibb, Pierre Fabre. J. Haanen: Consulting/advisory boards: Achilles Tx, AZ, BioNTech, Bristol Myers and Squibb, CureVac, GSK, Immunocore, Instil Bio, Iovance Bio, Merck Serono, Molecular Partners, Merck Sharp & Dohme, Neogene Tx, Novartis, Pfizer, Roche, Serono, Sastra Cell Therapy, Scenic, T-knife. TRV. Stock options: Neogene Tx, Sastra Cell Therapy. Grant support: Amgen, Asher Bio, BioNTech, Bristol Myers and Squibb, Novartis, Sastra Cell Therapy D. Schadendorf: consulting/advisory roles: Astra-Zeneca, Daiichi Sankyo, Erasca, Haystack, Anaevon, Immatics, Immunocore, InFlarX, Innovent, Merck-Serono, Nektar, Neracare, NoviGenix, PamGene, Philogen, Pfizer, Regeneron, BioNTech, Replimune, Roche, Sanofi, Seagen, UltimoVacs, Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sun Pharma. Honoraria: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sun Pharma. Travel/accommodations/expenses: Pierre-Fabre. Research funding: institutional funding from Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche and Pfizer. I.M. Svane: consulting/advisory roles: Astra-Zeneca, Daiichi Sankyo, Erasca, Haystack, Anaevon, Immatics, Immunocore, InFlarX, Innovent, Merck-Serono, Nektar, Neracare, NoviGenix, PamGene, Philogen, Pfizer, Regeneron, BioNTech, Replimune, Roche, Sanofi, Seagen, UltimoVacs, Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sun Pharma. Honoraria: Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sun Pharma. Travel/accommodations/expenses: Pierre Fabre. Research funding: institutional funding from Bristol Myers and Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche and Pfizer. All other authors declared no conflict of interest.

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