Nivolumab: First Adjuvant Immunotherapy to Show Survival Benefit in High-Risk Muscle-Invasive Urothelial Cancer

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Adjuvant therapy with nivolumab, an anti–PD-1 immune checkpoint inhibitor, after radical surgery improved disease-free survival in high-risk muscle-invasive urothelial cancer regardless of PD-L1 status, according to the results of the CheckMate 274 randomized phase III trial presented at the 2021 Genitourinary Cancers Symposium.1

In the intent-to-treat population of CheckMate 274, disease-free survival was 21 months in patients who received nivolumab vs about half that—10.9 months—for those assigned to placebo, a 30% reduction in recurrence or death favoring nivolumab (P < .001).

In the PD-L1–positive (≥ 1%) population, the disease-free survival benefit with nivolumab was even more robust, with median disease-free survival not reached for the nivolumab-treated patients compared with 10.8 months with placebo, representing a 47% reduction in risk of recurrence or death favoring nivolumab (P < .001).

Dean F. Bajorin, MD

Dean F. Bajorin, MD

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with muscle-invasive urothelial carcinoma,” stated lead author Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center in New York City. “These results support nivolumab monotherapy as a new standard of care in the adjuvant setting in high-risk muscle-invasive urothelial cancer after surgery.”


Radical cystectomy is the standard of care in muscle-invasive urothelial cancer of the bladder, ureter, and renal pelvis. Although neoadjuvant cisplatin is an option, patients may be ineligible or refuse this surgery, and adjuvant therapy is not currently recommended for patients previously treated with neoadjuvant therapy. Some patients who do not receive neoadjuvant therapy may be offered adjuvant cisplatin-based therapy, but there is little evidence to support this approach in muscle-invasive urothelial cancer.

“Prior to this study, no immune checkpoint inhibitor has shown efficacy as adjuvant therapy in patients with muscle-invasive urothelial cancer at high risk of recurrence after radical surgery,” Dr. Bajorin told listeners.

Although overall survival data are immature in the current study, the disease-free survival curves are clearly separate for both the intent-to-treat and PD-L1–positive populations. “We think, based on those disease-free survival curves, this will translate into an overall survival benefit,” Dr. Bajorin noted.

Study Details

The multicenter, double-blind, phase III CheckMate 274 trial randomly assigned 709 patients with high-risk muscle-invasive urothelial cancer to receive either nivolumab (240 mg every 2 weeks) or placebo for up to a year. Stratification factors included PD-L1 status (< 1% or ≥ 1%), prior neoadjuvant cisplatin-based chemotherapy, and nodal status. Co-primary endpoints were disease-free survival in the intent-to-treat and PD-L1 populations.

Most patients had bladder tumors (79%), with the remaining having tumors of the upper tract; 40% had PD-L1–positive disease, and 43% had previously received neoadjuvant therapy.

Minimum follow-up was 5.9 months; median follow-up of both the nivolumab and the placebo groups was around 21 months. Treatment discontinuations were reported in 53.3% of the nivolumab group and 56.3% of the placebo group, most commonly due to recurrent disease.

Subgroup analyses of the intent-to-treat group showed that the disease-free survival benefit was driven by patients with tumors of the urinary bladder, with a 38% improvement with nivolumab, and no benefit was observed for those with tumors of the renal pelvis or ureter. “This is hypothesis-generating,” Dr. Bajorin said. Patients who had already received neoadjuvant therapy fared better with nivolumab than those without preoperative chemotherapy. Treatment still favored nivolumab in the PD-L1–negative (< 1%) population, with an 18% improvement over placebo.


  • CheckMate 274 showed that adjuvant therapy with nivolumab following radical surgery improved disease-free survival in high-risk muscle-invasive bladder cancer regardless of PD-L1 status.
  • This is the first adjuvant immunotherapy to show a survival benefit in this setting.

Nivolumab also improved non–urothelial tract recurrence-free survival, a secondary endpoint, in both populations, with a median 24.6 months compared with 13.7 months with placebo in the intent-to-treat population, a 28% improvement, and a median not reached vs 10.9 months, respectively, in the PD-L1–positive group, a 46% improvement.

For the exploratory endpoint of distant metastasis–free survival, nivolumab improved outcomes in both the intent-to-treat (35 vs 29 months, respectively) and PD-L1 populations (not reached vs 21.2 months, respectively).

Adverse Events

Toxicity was slightly worse in the nivolumab arm, with the most common adverse events of pruritus, fatigue, diarrhea, and rash.

Overall, grade ≥ 3 adverse events were reported in 42.7% of nivolumab-treated patients vs 36.8% with placebo, but treatment-related grade ≥ 3 adverse events occurred in 17.9% vs 7.2%, respectively. Discontinuation of treatment for toxicity occurred in 14% of patients in the nivolumab arm compared with 2.3% of those on placebo.

Quality-of-life outcomes, as measured by the European Organisation for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire (QLQ-C30), were similar between the two study arms in both the intent-to-treat and PD-L1 populations.

“There was no deterioration in quality of life in either of the study arms,” Dr. Bajorin said. 

Publisher's Note: This article was originally published in the April 10, 2021 issue of The ASCO Post.

DISCLOSURE: The study was funded by Bristol Myers Squibb. Dr. Bajorin has received honoraria from Merck Sharp & Dohme; has served as a consultant or advisor to Dragonfly Therapeutics, Fidia Farmaceutici SpA, Hoffmann–LaRoche, and Merck; has received institutional research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck, Novartis, and Seattle Genetics/Astellas; and has been reimbursed for travel, accommodations, or other expenses by Merck and Roche/Genentech.


1. Bajorin DF, Witjes JA, Gschwend J, et al: First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). 2021 Genitourinary Cancers Symposium. Abstract 391. Presented February 12, 2021.

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