Discontinuation of combo immunotherapy and outcome of patients with melanoma brain metastases

BACKGROUND: Nivolumab plus ipilimumab (COMBO) is the standard treatment for asymptomatic melanoma brain metastases (MBM), but current guidelines do not provide specific recommendations for treatment discontinuation in responding patients. This study aimed to evaluate outcomes after COMBO discontinuation within 24 months and the role of continuing treatment beyond 24 months. METHODS: Patients with MBM treated with COMBO who discontinued treatment within 24 months for reasons other than disease progression or continued beyond this time point were retrieved. Overall survival (OS), objective response, progression-free survival (PFS) and toxicities were analyzed. RESULTS: 465 patients were included: 392 discontinued COMBO within 24 months, while 73 continued beyond 24 months. Treatment was discontinued due to complete response (CR, n=47), partial response (PR, n=45), stable disease (SD, n=12), toxicity after SD (n=59), toxicity after CR (n=99), or toxicity after PR (n=130). At multivariable analysis, the line of treatment (>first vs first: HR 2.65 (1.62-4.32)), the immune-related adverse events (irrespective of anti-tumor necrosis factor-alpha) (HR 0.18 (0.07-0.42)); COMBO discontinuation after CR (HR 0.15 (0.05-0.40)), or PR (HR 0.08 (0.03-0.26)), as well as stopping due to toxicity after CR (HR 0.14 (0.07-0.27)) or PR (HR 0.51 (0.32-0.82)), were associated with OS. Notably, at a median follow-up of 51 months (IQR 31-70), patients with CR/PR who discontinued COMBO within 24 months had PFS and OS comparable to those who continued treatment beyond this time point. 4-year OS exceeded 83% in patients discontinuing COMBO after CR, PR, or toxicity following CR, compared with 66.4% in those discontinuing due to toxicity after PR; median PFS was not reached in the former groups but was 18.6 months in the toxicity after PR group. CONCLUSION: Discontinuation of COMBO within 24 months appears safe in patients with CR and in selected cases of PR, with no survival disadvantage versus prolonged therapy.

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Journal
Journal for ImmunoTherapy of Cancer
Published
2026-05-01
DOI
https://doi.org/10.1136/jitc-2026-015063
Primary Topic
Brain Metastases and Treatment
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article
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article

Discontinuation of combo immunotherapy and outcome of patients with melanoma brain metastases

Michele Del Vecchio, Alice Indini, Marco Tucci, Martina Ubaldi et al.
Journal for ImmunoTherapy of Cancer
Brain Metastases and Treatment
article

Discontinuation of combo immunotherapy and outcome of patients with melanoma brain metastases

Michele Del Vecchio, Alice Indini, Marco Tucci, Martina Ubaldi, Ryan J. Sullivan, R Dummer, Patricio Serra-Bellver, Alexander Maxwell Menzies, Barbara Merelli, Maria Chiara Sergi, Marie-Lena Rasch, Michele Guida, Francesco Spagnolo, Ernesto Rossi, P. Lorigan, Caroline Robert, Monica F. Chen, Iris Dirven, E. Muñoz-Couselo, Tobias Peres, Aleigha Lawless, Thomas Carter, Ana Arance, K Suijkerbuijk, Katharina Kähler, Paul Nathan, Lisa Zimmer, Mario Mandalà, Hildur Helgadottir, Elisabeth Livingstone, Bart Neyns, Diana Giannarelli, Derek Effiom, Pietro Quaglino, Roberta Depenni, Georgina V Long, Douglas B. Johnson, James Larkin, Michael Postow, Maria Grazia Vitale, Paolo A Ascierto, Ines Pires da Silva, Anna Maria Di Giacomo, Teresa Amaral, Axel Hauschild
article en

Abstract

BACKGROUND: Nivolumab plus ipilimumab (COMBO) is the standard treatment for asymptomatic melanoma brain metastases (MBM), but current guidelines do not provide specific recommendations for treatment discontinuation in responding patients. This study aimed to evaluate outcomes after COMBO discontinuation within 24 months and the role of continuing treatment beyond 24 months. METHODS: Patients with MBM treated with COMBO who discontinued treatment within 24 months for reasons other than disease progression or continued beyond this time point were retrieved. Overall survival (OS), objective response, progression-free survival (PFS) and toxicities were analyzed. RESULTS: 465 patients were included: 392 discontinued COMBO within 24 months, while 73 continued beyond 24 months. Treatment was discontinued due to complete response (CR, n=47), partial response (PR, n=45), stable disease (SD, n=12), toxicity after SD (n=59), toxicity after CR (n=99), or toxicity after PR (n=130). At multivariable analysis, the line of treatment (>first vs first: HR 2.65 (1.62-4.32)), the immune-related adverse events (irrespective of anti-tumor necrosis factor-alpha) (HR 0.18 (0.07-0.42)); COMBO discontinuation after CR (HR 0.15 (0.05-0.40)), or PR (HR 0.08 (0.03-0.26)), as well as stopping due to toxicity after CR (HR 0.14 (0.07-0.27)) or PR (HR 0.51 (0.32-0.82)), were associated with OS. Notably, at a median follow-up of 51 months (IQR 31-70), patients with CR/PR who discontinued COMBO within 24 months had PFS and OS comparable to those who continued treatment beyond this time point. 4-year OS exceeded 83% in patients discontinuing COMBO after CR, PR, or toxicity following CR, compared with 66.4% in those discontinuing due to toxicity after PR; median PFS was not reached in the former groups but was 18.6 months in the toxicity after PR group. CONCLUSION: Discontinuation of COMBO within 24 months appears safe in patients with CR and in selected cases of PR, with no survival disadvantage versus prolonged therapy.

Journal for ImmunoTherapy of CancerVol. 14(5)
University of Siena (IT), Università Cattolica del Sacro Cuore (IT), Champalimaud Foundation (PT), University of Modena and Reggio Emilia (IT), Royal Marsden NHS Foundation Trust (GB), Memorial Sloan Kettering Cancer Center (US), Karolinska University Hospital (SE), Vrije Universiteit Brussel (BE), Utrecht University (NL), Cornell University (US), University of Perugia (IT), Institut Gustave Roussy (FR), Agostino Gemelli University Polyclinic (IT), University of Manchester (GB), University Medical Center Utrecht (NL), Ospedale San Paolo (IT), Institut de Cancérologie Strasbourg (FR), University Hospital of Zurich (CH), Ospedale Papa Giovanni XXIII (IT), Mount Vernon Cancer Centre (GB), University Hospital Schleswig-Holstein (DE), Hospital Clínic de Barcelona (ES), Federico II University Hospital (IT), Melanoma Institute Australia (AU), Universitair Ziekenhuis Brussel (BE), Vall d'Hebron Hospital Universitari (ES), Department of Medical Sciences (BY), Istituto Tumori Bari (IT), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Mass General Brigham (US), National Cancer Research Institute (GB), University of Turin (IT), University of Bari Aldo Moro (IT), University of Duisburg-Essen (DE), University of Tübingen (DE), Vanderbilt University Medical Center (US), University of Lübeck (DE)
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