Clinical trialPhase 3Bladder cancer

Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma

N Engl J Med · 2021709 patients (353 nivolumab, 356 placebo)

Bajorin DF, Witjes JA, Gschwend JE, et al. N Engl J Med. 2021. 384:2102-2114

Study type: Clinical trial
Study name: CheckMate 274
Phase: Phase 3
Design: Multicentre, double-blind, placebo-controlled randomised trial (1:1 randomisation)
Sample size: 709 patients (353 nivolumab, 356 placebo)
Source: N Engl J Med · 2021
Trial registration: NCT02632409

In plain words

After surgery to remove the bladder (or the ureter and kidney), some patients have a high risk of the cancer coming back because of how far the tumour had spread in the surgical specimen. In this study, one year of treatment with the immunotherapy drug nivolumab nearly doubled the time without disease (median about 21 months versus 11 months). At 5 years of follow-up this benefit lasted, and patients in the nivolumab group lived longer on median, but this difference in overall survival was not yet statistically certain. Serious side effects occurred in about 1 in 6 patients.

Key results

20.8 vs 10.8 months

Median disease-free survival (intention to treat)

HR 0.70 (98.22% CI 0.55–0.90); P<0.001

74.5% vs 55.7%

Alive and disease-free at 6 months (PD-L1 ≥1%)

HR 0.55 (98.72% CI 0.35–0.85); P<0.001

21.9 vs 11.0 months

Median disease-free survival with a minimum of 5 years of follow-up

HR 0.74 (0.61–0.90); in PD-L1 ≥1%: 55.5 vs 8.4 months, HR 0.58 (Galsky et al., Ann Oncol 2026)

75.0 vs 50.1 months

Median overall survival with a minimum of 5 years of follow-up

HR 0.83 (95% CI 0.67–1.02); not statistically significant (Galsky et al., Ann Oncol 2026)

17.9% vs 7.2%

Treatment-related grade 3 or higher adverse events

Two treatment-related deaths due to pneumonitis in the nivolumab group

Drugs in this study:Nivolumab (Opdivo)

Dose and schedule cards

Adjuvant nivolumab (CheckMate 274)

High-risk invasive urothelial carcinoma within 120 days after radical surgery: ypT2 to ypT4a or ypN+ after neoadjuvant cisplatin; or pT3 to pT4a or pN+ without it in patients ineligible for or declining adjuvant cisplatinOn the page “Bladder cancer” · Muscle-invasive cancer (MIBC): after cystectomy (adjuvant)

Drug	Dose	Route	Schedule
Nivolumab	240 mg (or 480 mg)	IV infusion over 30 minutes	Every 2 weeks (480 mg: every 4 weeks)

Cycle length: Every 14 days (or 28 days)
Duration: Until recurrence or toxicity, up to 1 year

Per the FDA label and the CheckMate 274 trial. FDA approval applies regardless of PD-L1 expression, whereas EMA approval is limited to tumour-cell PD-L1 expression of 1% or higher.

On the page “Bladder cancer” · Muscle-invasive cancer (MIBC): after cystectomy (adjuvant)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Nivolumab

Nivolumab 240 mg IV over 30 minutes every 2 weeks, for a maximum of 1 year or until recurrence or unacceptable toxicity. FDA-label equivalent: 240 mg every 2 weeks or 480 mg every 4 weeks for up to 1 year.

2Placebo

IV placebo over 30 minutes every 2 weeks, for a maximum of 1 year.

Source of the regimen details: Full text of the paper (PMC8215888) and the FDA label for OPDIVO (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

709 patients with muscle-invasive urothelial carcinoma (bladder, ureter or renal pelvis) who had undergone radical surgery with negative margins (R0) within 120 days before randomisation and were at high risk of recurrence: ypT2 to ypT4a or ypN+‎ after neoadjuvant cisplatin; or pT3 to pT4a or pN+‎ without neoadjuvant cisplatin in patients who were ineligible for or declined adjuvant cisplatin. ECOG 0 or 1; disease-free on imaging within 4 weeks before treatment; active autoimmune disease and HBV/HCV infection were exclusion criteria.

Endpoints

Primary endpoints: disease-free survival in all patients (intention-to-treat population) and in patients with tumour PD-L1 expression of 1% or more. Secondary endpoint: non-urothelial-tract recurrence-free survival. Overall survival was a key secondary endpoint in later updates.

Safety and side effects

Treatment-related grade 3 or higher adverse events occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. The most common severe treatment-related events with nivolumab were raised serum lipase (5.1%) and amylase (3.7%), as well as diarrhoea, colitis and pneumonitis (0.9% each). Two treatment-related deaths due to pneumonitis were reported. No new safety findings were seen at 5-year follow-up.

Clinical significance and place in guidelines

On 19 August 2021 the FDA approved nivolumab for adjuvant treatment of patients with urothelial carcinoma at high risk of recurrence after radical surgery, regardless of PD-L1 expression; EMA approval is only for tumours with tumour-cell PD-L1 expression of 1% or more. The EAU 2025 guideline recommends offering adjuvant nivolumab to selected patients with pT3/4 and/or pN+‎ disease who are ineligible for or decline adjuvant cisplatin chemotherapy (strong recommendation). At 5-year follow-up the disease-free survival benefit was durable, and an exploratory ctDNA analysis suggested that the benefit is seen mainly in patients with detectable ctDNA after surgery (this finding needs confirmation).

Limitations

Patients with upper urinary tract tumours were also included (about 20%); the primary endpoint was disease-free survival, and the improvement in overall survival was not statistically confirmed by 5-year follow-up; the ctDNA analysis is post hoc and exploratory.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.