ESMO 2025: Adjuvant Nivolumab versus Placebo for High-Risk Muscle Invasive Urothelial Carcinoma: 5-Year Efficacy and ctDNA Results from CheckMate 274

(UroToday.com) The 2025 ESMO annual meeting featured a urothelial carcinoma proffered paper session and a presentation by Dr. Matthew Galsky discussing 5-year efficacy and ctDNA results from CheckMate 274 assessing adjuvant nivolumab versus placebo for high-risk muscle invasive urothelial carcinoma. Despite standard of care, radical cystectomy with or without neoadjuvant cisplatin-based chemotherapy, a significant number of patients with muscle invasive urothelial carcinoma experience disease recurrence within 3 years of surgery.

The phase 3 CheckMate 274 trial of adjuvant nivolumab versus placebo in patients with high-risk muscle invasive urothelial carcinoma after radical surgery met the primary endpoints of improvement in disease free survival with nivolumab versus placebo in intent to treat patients and patients with tumor PD-L1 expression ≥ 1%.¹ Importantly, efficacy improvements were continued at the 3-year follow-up,² and interim overall survival also favored nivolumab versus placebo. At the 2025 ESMO annual meeting, Dr. Galsky and colleagues reported extended 5-year follow-up results and exploratory ctDNA data.

Patients in CheckMate 274 were randomized 1:1 to nivolumab 240 mg IV every 2 weeks or placebo for ≤ 1 year of adjuvant treatment. Patients had radical surgery ± neoadjuvant chemotherapy and were at high risk of recurrence. The primary endpoints were disease free survival in the intent to treat patients and patients with PD-L1 ≥ 1%; overall survival and disease specific survival were secondary endpoints. Analysis of ctDNA was an exploratory endpoint:

A total of 709 patients (nivolumab, n = 353; placebo, n = 356) were randomized. With a median follow-up of 43.4 months, improvement in disease free survival was observed with nivolumab versus placebo in all randomized patients (HR 0.74, 95% CI 0.61-0.90) and PD-L1 ≥ 1% (HR 0.58, 95% CI 0.42-0.79) patients:

Specific to patients with muscle invasive bladder cancer, improvement in disease free survival was also observed with nivolumab versus placebo in all randomized patients (HR 0.66, 95% CI 0.53-0.81) and PD-L1 ≥ 1% (HR 0.50, 95% CI 0.36-0.72) patients:

Furthermore, among patients with muscle invasive bladder cancer, improvement in disease free survival was observed with nivolumab versus placebo in patients receiving neoadjuvant chemotherapy (HR 0.63, 95% CI 0.47-0.84) and for those who did not receive neoadjuvant chemotherapy (HR 0.70, 95% CI 0.52-0.95) patients:

Improvement in overall survival (interim analysis) was observed with nivolumab versus placebo in all randomized patients (although not statistically significant; HR 0.83, 95% CI 0.67-1.02) and PD-L1 ≥ 1% (HR 0.63, 95% CI 0.44-0.90) patients:

Among muscle invasive bladder cancer patients, there was a significant overall survival benefit with nivolumab versus placebo in all randomized patients (HR 0.73, 95% CI 0.58-0.91) and PD-L1 ≥ 1% (HR 0.51, 95% CI 0.35-0.76) patients:

For disease specific survival, nivolumab versus placebo was improved in all randomized patients (HR 0.79, 95% CI 0.62-1.00) and PD-L1 ≥ 1% (HR 0.57, 95% CI 0.37-0.87) patients:

Overall, 133/709 patients (18.8%) had evaluable cycle 1 day 1 ctDNA results, and 54/133 (40.6%) patients were ctDNA positive. Patients with undetectable ctDNA showed a >10 fold longer median disease free survival (HR 0.30, 95% CI 0.18-0.48), as well as an improved overall survival (HR 0.44, 95% CI 0.25-0.76) compared to those with a detectable ctDNA:

Within the ctDNA detectable subgroup, nivolumab improved median disease free survival (HR 0.35, 95% CI 0.18-0.66) and overall survival (HR 0.41, 95% CI 0.20-0.83) versus placebo. Additionally, despite a small number of samples analyzed, the trend of improvement for disease free survival and overall survival is evident in patients with detectable ctDNA:

No new safety signals were observed since the previous database lock, as patients have been off of treatment for at least 4 years:

Dr. Galsky concluded his presentation discussing 5-year efficacy and ctDNA results from CheckMate 274 with the following take home points:

With extended 5 years minimum follow-up in CheckMate 274, adjuvant nivolumab continued to show disease free survival benefits versus placebo, and median overall survival and median disease specific survival were longer with nivolumab versus placebo in both the all randomized and PD-L1 ≥ 1% muscle invasive urothelial carcinoma populations
In patients with muscle invasive bladder cancer, nivolumab was associated with disease free survival benefits and showed a trend toward overall survival benefit regardless of prior cisplatin exposure
In exploratory post hoc ctDNA analyses, nivolumab improved disease free survival and overall survival by more than 2-fold and 1.5-fold, respectively, versus placebo within the ctDNA-detectable subgroup
- However, conclusions are limited due to the small sample size
No new safety signals were observed since the previous database lock, as patients have been off treatment for at least 4 years
Subcutaneous nivolumab has been shown to provide clinical equipoise to standard IV dosing and may provide an alternative for patients across various tumors
These results provide additional support for adjuvant nivolumab as a standard of care for high-risk muscle invasive urothelial carcinoma after radical resection, potentially providing an opportunity for curative outcome

Presented by: Matthew D. Galsky, MD, Icahn School of Medicine, Mount Sinai, New York, NY

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 European Society of Medical Oncology (ESMO) Annual Congress held in Berlin, Germany, between September 17^th and 21^st.

References:

Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114.
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 Jan;43(1):15-21.

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