Abstract
Radical cystectomy is the most commonly used definitive local treatment for muscle-invasive bladder cancer (MIBC), yet it carries substantial perioperative complication risk, alongside major changes in urinary and sexual function. Chemoradiotherapy (CRT) is used as a bladder-sparing alternative but is usually reserved for small, solitary tumors. Highly active systemic induction therapy could enable bladder preservation for patients with more advanced tumors and reduce recurrence risk. We previously demonstrated high activity of preoperative ipilimumab (3 mg kg−1) plus nivolumab in patients with stage III MIBC. Given this high activity, the single-arm, multicenter phase 2 INDIBLADE trial aimed to provide effective bladder-sparing treatment to patients with stage II/III (cT2-4aN0-2, n = 50) MIBC, using induction ipilimumab (3 mg kg−1) plus nivolumab followed by CRT. After a median follow-up of 28.7 months, the primary endpoint of estimated 2-year bladder-intact event-free survival (BI-EFS) was met at 78% (95% confidence interval (CI): 0.67−0.9, P < 0.001). Secondary endpoints included overall survival, safety and the predictive value of circulating tumor DNA (ctDNA). Two-year overall survival was 96% (95% CI: 0.91−1). Grade 3−4 immune-related adverse events occurred in 24% of patients; grade 3−4 CRT-related adverse events occurred in 7% of patients. Absence of detectable ctDNA after induction immunotherapy was associated with BI-EFS (hazard ratio 8.3, 95% CI: 1.38−50.36, P = 0.02). In conclusion, our results show that induction combination immunotherapy followed by CRT is an effective bladder-sparing treatment in MIBC, and response can be monitored by ctDNA. ClinicalTrials.gov identifier: NCT05200988.
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Data availability
To minimize the risk of patient reidentification, anonymized patient-level clinical data will be made available upon scientifically sound request for academic use only and within the confinements of the patient informed consent and European Data Protection Regulation. Data access can be obtained via the Netherlands Cancer Institute’s scientific repository at repository@nki.nl, which will contact the corresponding author (M.S.v.d.H.). Requests will be answered within 4 weeks. Requests will subsequently be reviewed by the institutional review board of the Netherlands Cancer Institute. A data access agreement must be signed between the researcher and the Netherlands Cancer Institute upon approval.
Code availability
No custom code or mathematical algorithm was specifically developed for this study. Software and packages used in the analyses can be found in the Methods or in the Reporting Summary.
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Acknowledgements
We thank, first and foremost, all patients and their families who participated in the INDIBLADE trial and the medical and supporting staff of the University Medical Center Utrecht, the Erasmus Medical Center and the Netherlands Cancer Institute involved in the care of study patients. We thank H. Schrijver for trial management; Y. Wijnands and K. Snapper for data management; H. Hoogenhout for trial support; and J. P. E. Lagendijk on behalf of the patients advisory committee. We thank the Core Facility of Molecular Pathology and Biobanking at the Netherlands Cancer Institute (A. Broeks, S. Cornelissen and L. Braafs) and the Genomics Core Facility (C. van Steenis and W. Brugman). The INDIBLADE trial was supported by a grant from the KWF Dutch Cancer Society (grant 13226; M.S.v.d.H.). Research at the Netherlands Cancer Institute is supported by institutional grants from the Dutch Ministry of Health, Welfare and Sport and the KWF Dutch Cancer Society. Bristol Myers Squibb provided study drugs and funding for the trial (CA209-6JG; M.S.v.d.H.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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M.S.v.d.H. conceived the INDIBLADE study. M.S.v.d.H., E.E.S., B.W.G.v.R., B.B.M.S., D.G.J.R., R.P.M., J.L.B., M.F., J.L.N., T.N.B. and S.B. contributed to the study design. C.F.S., J.J.J.M. and M.S.v.d.H. wrote and amended the protocol. C.F.S., J.J.J.M. and M.S.v.d.H. were responsible for coordination and logistics of the trial. D.G.J.R. was the principal investigator for the Erasmus Medical Center. B.B.M.S. was the principal investigator for the University Medical Center Utrecht. M.S.v.d.H. was the principal investigator for the study overall and for the Netherlands Cancer Institute. J.J.J.M., C.F.S., B.W.G.v.R., L.S.M., T.N.B., J.M.d.F., J.C.K.v.d.M., J.L.B., M.F., R.P.M., J.L.N., E.E.S., D.G.J.R., B.B.M.S. and M.S.v.d.H. were involved in recruitment and management of study patients. M.L.v.M. was involved in collection, storage and processing of clinical samples. S.B. carried out the clinical statistical analyses and wrote the statistical analysis plan. C.H., S.K.C., S.S. and A.C.E. carried out plasma sample and WES data processing and subsequent ctDNA analyses. J.J.J.M. and M.S.v.d.H. drafted the manuscript. L.S.M., B.W.G.v.R., J.M.d.F., T.N.B., R.P.M., J.L.B., E.E.S., B.B.M.S., D.G.J.R., C.H., S.S. and C.F.S. made important contributions to the final manuscript. All authors reviewed, amended and approved the final manuscript. All authors personally vouch for the adherence to protocol and the accuracy of the reported data.
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M.S.v.d.H. has received institutional funding from Bristol Myers Squibb to finance the INDIBLADE trial. C.H., S.K.C., S.S. and A.C.E. are all full-time employee at Natera, Inc. with stocks or options to own stocks in the company. No other author received financial support for the work reported in this paper. No medical writers were involved in drafting the manuscript. B.W.G.v.R. has received consulting fees from Cepheid and Astellas (institutional). L.S.M. received consulting fees from Johnson & Johnson and Merck (institutional). T.N.B. makes use of free-to-use server and software for research purposes from Siemens. J.M.d.F. has an advisory role for Merck and Janssen (institutional). J.C.K.v.d.M. received research support from Bayer (institutional) and received consultancy fees from Merck/Merck Sharp & Dohme, IPSEN, Jansen, Bayer, Novartis and AstraZeneca (institutional). J.L.B. received consulting fees from Bristol Myers Squibb, Janssen, AstraZeneca, Merck AG/Pfizer, Merck Sharp & Dohme, Bayer and Ismar Healthcare (institutional) and received speaker’s fees from Springer Media, Congress Care and NLC Health (personal). R.P.M. has an advisory role for Astellas, Merck and Bristol Myers Squibb (institutional) and received research support from Merck, Janssen-Cilag, Astellas and Gilead Sciences Netherlands (institutional). D.G.J.R. has an advisory role for MSD Oncology, Pfizer, Astellas, AstraZeneca, Johnson & Johnson, Merck and Gilead Sciences Netherlands (institutional) and has received research support from Merck (institutional). B.B.M.S. has an advisory role for AstraZeneca, Bristol Myers Squibb, MDS, IPSEN, Merck, Astellas and Pfizer (institutional) and has received research support from AstraZeneca, Bristol Myers Squibb, MDS, IPSEN, Merck, Astellas and Pfizer (institutional). M.S.v.d.H. has received consulting fees from Astellas, AstraZeneca, Bristol Myers Squibb, MSD Oncology, Pfizer/Seagen, Johnson & Johnson and Daiichi-Sankyo (institutional); has received research support from Bristol Myers Squibb, Roche, AstraZeneca, Seagen, 4SC and MSD Oncology (institutional); and has received travel expenses paid by Bristol Myers Squibb (institutional). All other authors have nothing to disclose.
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Extended data
Extended Data Fig. 1 Longitudinal ctDNA results.
Representation of plasma ctDNA measurements longitudinally collected at various time points (Extended Data Table 1). Scoring of ctDNA is binary, with samples classified as positive or negative. Follow up was cut-off at 24 months to improve readability.
Supplementary information
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Supplementary Tables 1 and 2, study protocol and statistical analysis plan.
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Mellema, JJ.J., Stockem, C.F., Herberts, C. et al. Ipilimumab and nivolumab followed by chemoradiotherapy as bladder-sparing treatment in muscle-invasive bladder cancer: a phase 2 trial. Nat Med (2026). https://doi.org/10.1038/s41591-026-04271-3
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DOI: https://doi.org/10.1038/s41591-026-04271-3
