A phase III randomized clinical trial called CheckMate 274 has demonstrated significant benefits of adjuvant nivolumab immunotherapy for patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after radical surgery. The study, funded by Bristol Myers Squibb, was published in the Journal of Clinical Oncology on October 11, 2024.
CheckMate 274 was a double-blind, placebo-controlled trial conducted across multiple international centers. The primary purpose was to evaluate the efficacy and safety of adjuvant nivolumab compared to placebo in patients with high-risk MIUC who had undergone radical resection. A total of 709 patients were randomized 1:1 to receive either nivolumab 240 mg intravenously every 2 weeks for up to 1 year, or placebo.
Eligible patients had either received previous neoadjuvant cisplatin-based chemotherapy (ypT2-ypT4a or ypN+) or were ineligible/declined adjuvant cisplatin-based chemotherapy (pT3-pT4a or pN+). They must have undergone radical resection within 120 days prior and been disease-free within 4 weeks of randomization. The study population included patients with tumors originating in the bladder (79%) as well as upper tract urothelial carcinoma.
The primary endpoints were disease-free survival (DFS) in the intent-to-treat (ITT) population and in patients with tumor PD-L1 expression ≥1%. Secondary endpoints included overall survival (OS), non-urothelial tract recurrence-free survival (NUTRFS), and safety. This publication reports extended follow-up results with a median of 36.1 months, as well as the first interim OS analysis.
In the ITT population, nivolumab significantly improved median DFS compared to placebo (22.0 vs 10.9 months; HR 0.71, 95% CI 0.58-0.86). The benefit was even more pronounced in patients with PD-L1 ≥1% tumors (median DFS 52.6 vs 8.4 months; HR 0.52, 95% CI 0.37-0.72). Improvements were also seen in NUTRFS and distant metastasis-free survival.
The interim OS analysis showed a 24% reduction in risk of death with nivolumab in the ITT population (HR 0.76, 95% CI 0.61-0.96) and a 44% reduction in the PD-L1 ≥1% subgroup (HR 0.56, 95% CI 0.36-0.86). Median OS was 69.5 months with nivolumab vs 50.1 months with placebo in the ITT group.
An exploratory analysis of the subset of patients with muscle-invasive bladder cancer (MIBC), which comprised 79% of the study population, showed consistent efficacy benefits with nivolumab regardless of PD-L1 status. This provides important data specific to MIBC patients.
The safety profile was consistent with previous reports of nivolumab, with no new signals identified. Grade 3-4 treatment-related adverse events occurred in 18.2% of nivolumab patients compared to 7.2% of placebo patients.
Some limitations of the study include the lack of final OS data, as the interim analysis did not cross the pre-specified boundary for statistical significance. Longer follow-up will be needed to definitively establish an OS benefit. Additionally, while improvements were seen across subgroups, the study was not powered for formal statistical comparisons in all subgroups analyzed.
The authors conclude that these extended follow-up results, including early OS trends, provide strong support for adjuvant nivolumab as a new standard of care for patients with high-risk MIUC after radical resection. They note that the 3-year follow-up is particularly clinically relevant, as most MIUC recurrences occur within this timeframe.
The potential clinical impact of these findings is substantial. Adjuvant nivolumab offers a new treatment option that could significantly delay or prevent recurrence and potentially improve survival for patients with high-risk MIUC after surgery. The fixed 1-year duration of therapy is also notable. The clear benefit in the PD-L1 ≥1% population suggests PD-L1 testing may help identify patients most likely to benefit, though improvements were seen regardless of PD-L1 status.
For medical professionals, these results establish adjuvant nivolumab as an important consideration for appropriate high-risk MIUC patients after radical resection. The data support initiating discussions about adjuvant immunotherapy with eligible patients. However, patient selection, timing of therapy initiation, and management of immune-related adverse events will be important considerations in clinical practice. Further research may help refine optimal patient selection and explore potential combinations or sequencing with other therapies.
Overall, CheckMate 274 represents a significant advance in the management of high-risk MIUC, offering new hope for improving outcomes in this aggressive disease. As longer-term data mature, the full impact of adjuvant nivolumab on survival and quality of life will become clearer. For now, these results provide a strong rationale for integrating this approach into clinical practice for appropriate patients.
References
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:10.1200/JCO.24.00340
