Abstract
Background
Ipilimumab+nivolumab (IPINIVO) can induce durable responses in advanced melanoma, but many patients experience progression at some point. It is currently unknown to what extent these patients benefit from IPINIVO rechallenge. This study describes efficacy and safety of IPINIVO rechallenge.
Methods
Data from advanced melanoma patients rechallenged with IPINIVO after previous ipilimumab-containing treatment were retrieved from the nationwide Dutch Melanoma Treatment Registry. Patient characteristics, responses, survival, and safety were analyzed.
Results
Among 3.759 patients receiving ipilimumab-containing treatment, 73 received rechallenge IPINIVO. 41 received IPINIVO, 32 ipilimumab monotherapy (IPI) as initial therapy. Objective response to rechallenge IPINIVO was seen in 36.1% (initial IPINIVO) and 40.0% (initial IPI) of patients. Median progression-free survival after rechallenge was 2.8 months (initial IPINIVO) and 5.6 months (initial IPI), but reached 18.4 months for responders to rechallenge therapy. Grade ≥3 immune-related adverse events occurred in 40.5% (initial IPINIVO) and 38.7% (initial IPI) of patients. Objective responses to initial and rechallenge treatment were discordant in 48.6% (initial IPINIVO) and 53.3% (initial IPI) of patients. Fifteen patients (20.5%) responded to rechallenge therapy but not to initial treatment.
Conclusions
Rechallenge IPINIVO after previous ipilimumab-based therapy had a considerable response rate, acceptable safety profile, and potential for a durable response.
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Data availability
The datasets generated during and/or analyzed during this study are not publicly available due to privacy regulations in the Netherlands. Requests for data sharing can be addressed to the corresponding author.
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Acknowledgements
We thank all physicians and data managers who registered patient data in the Dutch Melanoma Treatment Registry.
Funding
The Dutch Institute for Clinical Auditing foundation received a start-up grant from governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002) for the Dutch Melanoma Treatment Registry (DMTR). The DMTR is structurally funded by Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis and Roche Pharma. Roche Pharma stopped funding in 2019 and Pierre Fabre started funding in 2019. For this work no funding was granted.
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Contributions
EJD: conceptualization, methodology, formal analysis, data interpretation, writing original draft, review and editing, data collection, project administration. HHN: conceptualization, data interpretation, writing original draft, review and editing, data collection, project administration. AJME: data interpretation, review and editing, data collection, project administration. MJB: data interpretation, review and editing, data collection, project administration. MB: data interpretation, review and editing, data collection, project administration. AMK: data interpretation, review and editing, data collection. MMR: data interpretation, review and editing, data collection. CB: data interpretation, review and editing. MJBA: data interpretation, review and editing, data collection, project administration. FWPJB: data interpretation, review and editing, data collection, project administration. CUB: data interpretation, review and editing, data collection, project administration. WAMB: data interpretation, review and editing, data collection, project administration. JWBG: data interpretation, review and editing, data collection, project administration. GAPH: data interpretation, review and editing, data collection, project administration. DP: data interpretation, review and editing, data collection, project administration. RSR: data interpretation, review and editing, data collection, project administration. AMS: data interpretation, review and editing, data collection, project administration. GV: data interpretation, review and editing, data collection, project administration. MWJMW: data interpretation, review and editing, data collection, project administration. EK: data interpretation, review and editing, data collection, project administration. JBH: data interpretation, review and editing, data collection, project administration. AAMV: data interpretation, review and editing, data collection, project administration. KPMS: conceptualization, data interpretation, review and editing, data collection, project administration, supervision.
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Competing interests
HHN has advisory/consultancy relations with Bayer, Roche, Johnson&Johnson, and Illumina. AJME has advisory/consultancy relations with Amgen, Bristol Myers Squibb, Ipsen Biopharmaceuticals, Janssen-Cilag BV, Merck, Merck Sharp & Dohme, Novartis, Pfizer Canada and Pierre Fabre Pharmaceuticals. He received a research grant from Bristol-Myers Squibb, paid to institution. CB received research grants from Philips, Bracco, Sensius, all paid to institution. CUB has advisory/consultancy relations with Bristol Myers Squibb, Roche, Merck and Third Rock Ventures. He received research grants from 4SC, Bristol Myers Squibb, Roche, Merck, NanoString Technologies, all paid to institution. He received an individual research grant from Third Rock Ventures. He is co-founder of Signature Oncology and Imagene BV, and has a pending patent (Patent number WO 2021/177822 A1). GAPH received research grants from Bristol-Myers Squibb and Seerave, all paid to institution. DP has advisory/consultancy relations with Novartis and Pierre Fabre Pharmaceuticals. She received a travel grant from Pierre Fabre Pharmaceuticals. EK has advisory/consultancy relations with Delcath, Immunocore and Lilly, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis, and Pierre-Fabre. Not related to current work and paid to institute. JBH has advisory/consultancy relations with AZ, BioNTech, CureVac, Eisai, Ipsen, Instil Bio, Iovance Bio, MSD, Novartis, Neogene Therapeutics, Roche, Sanofi, Sastra Cell Therapy, Third Rock Ventures, and T-Knife. He received research grants from Amgen, BioNTech, Bristol Myers Squibb, Novartis, Sastra Cell Therapy. He is editor-in-Chief of ESMO Immmuno-Oncology & Technology (IOTECH). AAMV has advisory/consultancy relations with Bristol-Myers Squibb, MSD, Sanofi, Merck, Pierre Fabre, Novartis, Pfizer, Roche, Eisai and Ipsen. KPMS has advisory/consultancy relations with AbbVie, and Sairopa. She received research grants from Bristol-Myers Squibb, Genmab, Philips, Pierre Fabre, and Tigatx, all paid to institution. She does data and safety monitoring for Sairopa. No other competing interests were reported.
Ethics approval and consent to participate
This study was performed in accordance with the Declaration of Helsinki. In compliance with Dutch regulations, research with DMTR data was approved by the medical ethical committee (METC Leiden University Medical Center, 2013) not to be subject to the Medical Research Involving Human Subjects Act, thereby waiving the requirement for informed consent.
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van Dijk, E.J., Nienhuis, H.H., van den Eertwegh, A.J.M. et al. Rechallenge of ipilimumab and nivolumab in advanced melanoma patients after previous ipilimumab-based therapy. Br J Cancer 133, 66–75 (2025). https://doi.org/10.1038/s41416-025-03027-z
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DOI: https://doi.org/10.1038/s41416-025-03027-z
