With longer-term follow-up, adjuvant nivolumab continued to demonstrate improved disease-free survival, non–urothelial tract recurrence–free survival, and distant metastasis–free survival vs placebo in patients with muscle-invasive urothelial carcinoma at high risk of recurrence after surgery, according to the results of the phase III CheckMate 274 trial presented at the 2023 ASCO Genitourinary (GU) Cancers Symposium.¹ The survival benefits of adjuvant nivolumab were observed in the overall population in an intent-to-treat analysis and were even more robust in patients whose tumors were PD-L1–positive (ie, PD-L1 > 1%).

At a minimum follow-up of 31.6 months, in the intent-to-treat population, median disease-free survival in the nivolumab arm was 22.0 months vs 10.9 months in the placebo arm, representing a 29% improvement favoring nivolumab. In the PD-L1–positive population, median disease-free survival was 52.6 months and 8.4 months, respectively, reflecting a 48% improvement favoring nivolumab.

The 24-month and 36-month disease-free survival rates for the nivolumab and placebo arms were 48.4% vs 38.8% and 45.0% vs 34.9%, respectively, in the intent-to-treat population. In the PD-L1 population, the corresponding rates were 60.3% vs 37.6% and 56.9% vs 33.3%, respectively.

Adjuvant nivolumab was superior to placebo across all prespecified patient subgroups, including those by age, sex, geographic region, performance status, minor histologic variance, pathologic lymph node status, and pathologic T stage.

Matthew D. Galsky, MD, FASCO

“These results further support adjuvant nivolumab as a standard of care in patients with muscle-invasive urothelial cancer at high risk for recurrence after radical surgery,” said lead study author Matthew D. Galsky, MD, FASCO, of the Icahn School of Medicine at Mount Sinai in New York.

Study Details

The randomized, double-blind, multicenter CheckMate 274 study included patients at high risk of recurrence after radical surgery and who could have had treatment with neoadjuvant cisplatin. Eligible patients underwent radical surgery within the previous 120 days and attained disease-free status within 4 weeks of randomization.

Patients were randomly assigned 1:1 to receive intravenous nivolumab at 240 mg every 2 weeks or placebo for up to 1 year. Stratification factors included tumor PD-L1 status, previous neoadjuvant cisplatin–based chemotherapy, and nodal status.

The primary endpoint was disease-free survival in the intent-to-treat and PD-L1 > 1% populations, and secondary endpoints included non–urothelial tract recurrence–free survival, disease-specific survival, and overall survival. Exploratory endpoints included distant metastasis–free survival, second progression-free survival, safety, and health-related quality of life. Stratification factors were tumor PD-L1 expression of more than 1% vs less than 1%, prior neoadjuvant cisplatin–based chemotherapy (yes or no), and nodal status (positive or negative).

At baseline, demographic and disease factors were well balanced. Median patient age was approximately 65 years, about three-quarters of patients were White, nearly 63% had an Eastern Cooperative Oncology Group performance status of 0, and 79% had a primary bladder tumor. About 40% had PD-L1–positive disease, and about 40% had received neoadjuvant cisplatin–based chemotherapy.

Key Findings

In the intent-to-treat population, median non–urothelial tract recurrence–free survival was 25.9 months with nivolumab vs 13.7 months with placebo, a 28% improvement favoring nivolumab. Among patients with PD-L1 expression of 1% or more, the corresponding rate was 52.6 months vs 8.4 months, respectively, for a 47% improvement favoring nivolumab.

The 24-month and 36-month non–urothelial tract recurrence–free survival rates in the nivolumab and -placebo groups, respectively, were 51.6% vs 42.2% and 47.5% vs 38.3%. Among those with PD-L1–positive tumors, the corresponding rates were 62.7% vs 38.3% and 57.4% vs 34.8%, respectively.

In the intent-to-treat population, median distant metastasis–free survival was 47.1 months with adjuvant nivolumab and 28.7 months with placebo, a 26% improvement favoring nivolumab. The 24-month and 36-month distant metastasis–free survival rates were 57.8% vs 51.2% and 53.9% vs 47.0%, respectively.

In patients with PD-L1–positive disease, the median distant metastasis–free survival was not reached in the nivolumab group vs 20.7 months in the placebo group, representing a 42% improvement favoring nivolumab. The 24-month and 36-month distant metastasis–free survival rates were 66.4% vs 48.6% and 61.7% vs 44.2%, respectively.

In the intent-to-treat population, median time to progressive disease on subsequent next-line therapy (ie, PFS2) was 61.2 months with nivolumab vs 47.1 months with placebo, a 21% difference favoring nivolumab. In the PD-L1–positive group, the corresponding rate was not reached for nivolumab vs 39.4 months for placebo, a 46% difference favoring nivolumab.

The 24-month and 36-month PFS2 rates with nivolumab and placebo in the intent-to-treat population were 71.4% vs 60.7% and 61.0% vs 53.8%, respectively. In the PD-L1–positive subgroup, these rates were 78.8% vs 59.3% and 70.6% vs 51.4%, respectively.

“[When examining] efficacy outcomes over time from the initial report with a minimum follow-up of 5.9 months to the current presentation with a minimum follow-up of 31.6 months, you will note that across primary, secondary, and exploratory endpoints, the effect of adjuvant nivolumab vs placebo is remarkably stable over time,” Dr. Galsky said. “It’s important to point out that this is with a fixed duration of treatment—limited to 1 year of adjuvant treatment—with sustained effects over time.”

Toxicity

Treatment-related adverse events of any grade were reported in 79% of patients in the nivolumab arm compared with 56% in the placebo arm. The rate of grade 3 or higher toxicities was 18% and 7%, respectively. The rates of treatment-related adverse events of any grade leading to discontinuation of therapy were 14% with nivolumab and 2% with placebo.

In the nivolumab arm, the most common treatment-related adverse events of any grade were pruritus (23%), fatigue (17%), and diarrhea (17%), and grade 3 or higher toxicities included lipase increase (5%) and amylase increase (4%). In the placebo arm, the most common treatment-related adverse events of any grade were fatigue (12%), pruritus (11%), and diarrhea (11%). In the placebo arm, grade 3 or higher toxicities included lipase increase (3%) and amylase increase (1%). 

DISCLOSURE: Dr. Galsky has served as a consultant or advisor to Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, RapptaTherapeutics, Alligator, Silverback, Fujifilm, Curis, Gilead, Bicycle, Asieris, AbbVie, and Analog Devices; and has received institutional research funding from Janssen, Dendreon, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, and Genentech/Roche.

REFERENCE

1. Galsky MD, Witjes AA, Gschwend JE, et al: Extended follow-up results from the CheckMate 274 trial. 2023 ASCO GU Cancers Symposium. Abstract LBA443. Presented February 17, 2023.