Adjuvant Nivolumab Shows Sustained DFS Benefit in High-Risk Bladder Cancer

"The improvements demonstrated in patients with MIBC provide additional support for adjuvant nivolumab as a standard of care for high-risk muscle-invasive urothelial carcinoma, including muscle-invasive bladder cancer after radical surgery, and regardless of prior neoadjuvant chemotherapy,” Matthew I. Milowsky, MD, FASCO.

A sustained improvement in disease-free survival (DFS) occurred among patients with muscle-invasive bladder cancer (MIBC) who received adjuvant nivolumab (Opdivo) vs placebo, according to post hoc analysis data from the phase 3 CheckMate-274 trial (NCT02632409) presented at the 2025 ASCO Genitourinary Cancer Symposium.¹

In all randomized patients with MIBC, the median DFS was 25.6 months (95% CI, 19.2-41.8) with nivolumab (n = 353) vs 8.5 months (95% CI, 7.3-13.7) with placebo (n = 356; HR, 0.63; 95% CI, 0.51-0.78). The 24-month DFS rates in the respective arms were 50.5% and 35.9%; at 36 months, these rates were 46.8% and 32.0%. The median follow-up in the intention-to-treat (ITT) population was 36.1 months; in the MIBC population, the median follow-up was 34.5 months.

In patients with MIBC who previously received neoadjuvant chemotherapy, the median DFS with nivolumab (n = 279) was 19.6 months (95% CI, 15.6-48.2) vs 8.3 months (95% CI, 5.6-11.2) with placebo (n = 281; HR, 0.58; 95% CI, 0.43-0.79). In patients with MIBC who had not previously received neoadjuvant chemotherapy, the median DFS was 25.9 months (95% CI, 19.2-51.5) with nivolumab vs 13.7 months (95% CI, 7.8-22.1) with placebo (HR, 0.69; 95% CI, 0.50-0.94).

Data from the interim overall survival (OS) analysis indicated that in all patients with MIBC, the median OS was not reached (NR; 95% CI, 45.0-not estimable [NE]) vs 39.9 months (95% CI, 29.8-52.1) with placebo (HR, 0.70; 95% CI, 0.55-0.90). The 24- and 36-month OS rates in the nivolumab arm were 75.3% and 64.2%, respectively; in the placebo arm, these rates were 66.2% and 53.7%, respectively.

In all randomized patients with MIBC and a tumor PD-L1 expression of at least 1%, the median OS with nivolumab was again NR (95% CI, NE-NE) vs 37.6 months (95% CI, 26.9-NE) with placebo (HR, 0.48; 95% CI, 0.29-0.77). Those with MIBC who received prior neoadjuvant chemotherapy adjuvant nivolumab experienced a median OS of 55.2 months (95% CI, 41.8-NE) vs 40.2 months (95% CI, 28.8-53.7) with placebo (HR, 0.74; 95% CI, 0.53-1.03). Those with MIBC without prior neoadjuvant chemotherapy experienced a median OS that was NR (95% CI, 40.7-NE) with nivolumab vs 37.7 months (95% CI, 28.7-65.2) with placebo (HR, 0.67; 95% CI, 0.47-0.95).

“The improvements demonstrated in patients with MIBC provide additional support for adjuvant nivolumab as a standard of care for high-risk muscle-invasive urothelial carcinoma [MIUC,] including MIBC after radical surgery, and regardless of prior neoadjuvant chemotherapy,” Matthew I. Milowsky, MD, FASCO, said in a presentation of the data. “Of note, subcutaneous nivolumab was approved for multiple indications,² including as adjuvant therapy for MIUC by the FDA late last year, and might provide an alternative for patients across tumors.”

Milowsky is The George Gabriel and Frances Gable Villere Distinguished Professor of Bladder and Genitourinary Cancer Research, co-leader of the University of North Carolina (UNC) Lineberger Clinical Research Program, section chief of Genitourinary Oncology, and co-director of the Urologic Oncology Program at UNC School of Medicine in Chapel Hill.

The randomized, double-blind, multicenter, phase 3 CheckMate-274 trial enrolled patients with ypT2 to ypT4a or ypN-positive MIUC who had neoadjuvant chemotherapy.¹ Those with pT3a to pT4a or pN-positive MIUC without previously neoadjuvant chemotherapy who were not eligible for or refused adjuvant cisplatin chemotherapy were also included. Patients underwent radical surgery within the past 120 days and had to be free of disease within 4 weeks of undergoing randomization.

Participants were randomized 1:1 to receive intravenous (IV) nivolumab or placebo at 240 mg every 2 weeks. They received adjuvant treatment for up to 1 year. Stratification factors included tumor PD-L1 status (≥1% vs <1% or indeterminate), prior receipt of neoadjuvant chemotherapy (yes vs no), or nodal status.

The primary end points of the trial were DFS in all randomized patients and in the subset of patients with a tumor PD-L1 expression of at least 1%. Data showed that adjuvant nivolumab significantly improved DFS vs placebo in patients with high-risk MIUC post–radical surgery with or without cisplatin-based neoadjuvant chemotherapy.³ Extended follow-up data with a median of 3 years indicated that nivolumab continued to improve DFS vs placebo in all randomized patients , those with PD-L1 expression of at least 1%, and those with MIBC.⁴ The first report of OS outcomes showed that survival favored nivolumab vs placebo in all randomized patients and the subset of patients with a PD-L1 expression of at least 1%.

For the post-hoc analysis shared at ASCO GU, the key end points were DFS in all randomized patients with MIBC and in those with MIBC according to previous neoadjuvant chemotherapy, and OS in all randomized patients with MIBC, those with MIBC and a tumor PD-L1 expression of 1% or higher, and those with MIBC according to prior neoadjuvant chemotherapy.¹

Milowsky said that baseline clinical and demographic characteristics were generally well balanced between the arms. “[They] were largely consistent between the ITT and MIBC populations. About 80% of patients in CheckMate-274 had bladder tumor origin. Of those patients with MIBC, about 50% received prior neoadjuvant chemotherapy and about 40% had tumor PD-L1 positivity.”

Additional efficacy data indicated that in patients with MIBC who received prior neoadjuvant chemotherapy, the 24-month DFS rates with nivolumab and placebo were 48.9% vs 33.2%, respectively; the 36-month rates were 46.5% vs 28.9%, respectively. In patients with MIBC who had not received prior neoadjuvant chemotherapy, the 24-month DFS rates in the nivolumab and placebo arms were 52.1% vs 38.8%, respectively; the 36-month DFS rates were 46.9% vs 35.4%, respectively.

In all patients with MIBC and a tumor PD-L1 expression of at least 1%, the 24-month OS rate with nivolumab was 82.6% vs 67.4% with placebo; the respective 36-month rates were 71.8% and 52.0%. In those with MIBC and prior neoadjuvant chemotherapy, the 24-month OS rates with nivolumab and placebo were 73.6% vs 63.2%, respectively; the 36-month rates were 64.5% and 53.4%, respectively. In those with MIBC without prior neoadjuvant chemotherapy, the 24-month OS rate with nivolumab was 77.1% vs 69.4% with placebo; the respective OS rates at 36 months were 63.8% vs 53.9%.

“Safety in patients with MIBC was consistent with previous data in ITT patients, and no new safety signals were identified,” Milowsky concluded.

Disclosures: Milowsky disclosed stock ownership with regard to Gilead Sciences, Merck, and Pfizer. Research funding was received from Accuray, Acrivon Therapeutics, Alliance for Clinical Trials in Oncology, Alliance Foundation Trials, ALX Oncology, Arvinas, Astellas Pharma, Bristol-Myers Squibb, Clovis Oncology, Flare Therapeutics, G1 Therapeutics, Genentech, Hoosier Cancer Research Network, Loxo/Lilly, Merck, Mirati Therapeutics, Novartis, OncoC4, PCCTC, Roche, and Seagen. Other relationships include Elsevier, Medscape, Prime Education, and Research to Practice. Uncompensated relationships include G1 Therapeutics and Loxo/Lilly.

References

1. Milowsky MI, Galsky MD, Witjes JA, et al. Adjuvant nivolumab vs placebo for high-risk muscle-invasive urothelial carcinoma: additional efficacy outcomes including overall survival in patients with muscle-invasive bladder cancer from CheckMate-274. J Clin Oncol. 2025;43(suppl 5):658. doi:10/1200/JCO.2025.43.5_suppl.658
2. FDA approves nivolumab and hyaluronidase-nvhy for subcutaneous injection. FDA. December 27, 2024. Accessed February 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-and-hyaluronidase-nvhy-subcutaneous-injection
3. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. doi:1056/NEJMoa2034442
4. Galsky MD, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab in high-risk muscle-invasive urothelial carcinoma: Expanded efficacy from CheckMate 274. J Clin Oncol. 2025;43(1):15-21. doi:10.1220/JCO.24.00340