Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma
Open accessAbstract
BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).
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“Though, tumour inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility [85].”
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- Authors
- Bajorin, D. F., Witjes, J. A., Gschwend, J. E., Schenker, M., Valderrama, B. P., Tomita, Y., Bamias, A., Lebret, T., Shariat, S. F., Park, S. H., Ye, D., Agerbaek, M., Enting, D., McDermott, R., Gajate, P., Peer, A., Milowsky, M. I., Nosov, A., Neif Antonio, J., Tupikowski, K., Toms, L., Fischer, B. S., Qureshi, A., Collette, S., Unsal-Kacmaz, K., Broughton, E., Zardavas, D., Koon, H. B., & Galsky, M. D.
- Affiliations
- University of Vienna (AT)
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) — all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) — both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, ...
- University of North Carolina at Chapel Hill (US)
- ORCID
- Bajorin, Dean F.
- Witjes, J. Alfred
- Gschwend, Jürgen E.
- Schenker, Michael
- Valderrama, Begoña P.
- Tomita, Yoshihiko
- Bamias, Aristotelis
- Shariat, Shahrokh F.
- Park, Se Hoon
- Ye, Dingwei
- Enting, Deborah
- McDermott, Ray
- Gajate, Pablo
- Milowsky, Matthew I.
- Tupikowski, Krzysztof
- Collette, Sandra
- Broughton, Edward
- Galsky, Matthew D.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-06-03
- Volume
- 384
- Issue
- 22
- Pages
- 2102-2114
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC8215888
- OpenAlex
- W3163995648
- Cited by
- 1,065
- References
- 34
- Citations by year
- 2026: 173 · 2025: 226 · 2024: 240 · 2023: 219 · 2022: 166 · 2021: 40 · 2013: 1
- FWCI
- 158.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- HAL (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Bristol Myers Squibb
- ONO Pharmaceutical Company
- Topics
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Surgery › Urinary and Genital Oncology Studies
- Keywords
- muscle-invasive urothelial carcinoma, nivolumab, adjuvant immunotherapy, PD-L1 expression, disease-free survival, recurrence-free survival, radical cystectomy, immune checkpoint inhibitors, bladder cancer, cisplatin-based neoadjuvant chemotherapy, progression-free survival, overall survival, adverse events
- MeSH terms
- Antineoplastic Agents, Immunological, Nivolumab, Adult, Aged, Aged, 80 and over, Urinary Bladder Neoplasms, Carcinoma, Transitional Cell, Double-Blind Method, Female, Humans, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Placebos, Quality of Life, Chemotherapy, Adjuvant, Disease-Free Survival, Intention to Treat Analysis, B7-H1 Antigen
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