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Adjuvant therapy with nivolumab (Opdivo, “nivo”) continues to show disease-free survival (DFS) and overall survival (OS) benefits compared with placebo among patients with muscle-invasive bladder cancer (MIBC), in a new post hoc analysis of CheckMate 274 data.

Patients enrolled in the Checkmate 274 trial included those who had stage II to IVa muscle invasive urothelial cancer (MIUC) following neoadjuvant chemotherapy, or those with stage III to IVa MIUC tumors or positive lymph node MIUC who had not received neoadjuvant chemotherapy and were not eligible for or had refused cisplatin-based chemotherapy. All patients had undergone radical surgery within the past 120 days and were disease free within 4 weeks of randomization.

Previously reported results, at a median follow-up of about 20 months, showed that the study met its primary endpoint, showing significant prolongation of DFS in the intention-to-treat population (all randomized patients), with nivolumab at 21 months vs placebo at 10.9 months (hazard ratio [HR], 0.70; P < .001), as reported by Medscape Medical News. When the analysis considered only patients with tumors expressing programmed death-1 protein ligand-1 (PD-L1) ≥ 1%, the median DFS was even higher, not reached vs 10.8 months (HR, 0.53; P < .001).

In the post hoc analysis, the benefit of adjuvant nivolumab was seen both in patients with MIBC who had previously received neoadjuvant chemotherapy and those who had not, and in patients with tumors expressing PD-L1. Matthew I. Milowsky, MD, of the University of North Carolina School of Medicine, Chapel Hill, North Carolina, presented these and other findings of Checkmate 274 at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium (GUCS) 2025 in San Francisco, California.

“Overall survival data from interim analyses favor adjuvant nivo over placebo in patients with MIBC and patients with MIBC tumor PD-L1 ≥ 1%” and no new safety signals were identified since the previous analyses, he said.

“These results provide additional support for adjuvant nivo as a standard of care for high-risk MIUC including MIBC after radical surgery,” he said in an oral abstract session at the meeting.

A total of 709 patients were enrolled in CheckMate 274, including 353 patients (of whom 140 patients had PD-L1 ≥ 1%) who were randomly assigned to take nivolumab 240 mg every 2 weeks, and 356 patients (with 142 patients with PD-L1 ≥ 1%) who were randomized to placebo. All patients had pathologic evidence of urothelial cancer at high risk for recurrence and Eastern Cooperative Oncology Group performance status ≤ 1.

Updated MIBC Data

At ASCO GU 2025, Milowsky reported the results of the post hoc analysis of the endpoints of DFS in the subgroup of all randomized patients with MIBC, and in patients with MIBC according to prior neoadjuvant chemotherapy status, as well as interim OS among all patients with MIBC. He also described OS according to PD-L1 tumor expression and prior neoadjuvant chemotherapy status in patients with MIBC. The longest patient follow-up was out to 6.5 years.

Among all patients with MIBC randomized in the trial — 279 of whom had been assigned to nivolumab and 281 randomized to placebo — the median DFS was 25.6 months with nivolumab vs 8.5 months with placebo. This translates into an HR for disease progression with nivolumab of 0.63, and a CI indicating statistical significance.

DFS was also improved with nivolumab among patients who had received nedoadjuvant chemotherapy (median, 19.6 months vs 8.3 months) and those who had not (median, 25.9 months vs 13.7 months, respectively).

The interim analysis of OS at 6 years of follow-up showed that the median OS with nivolumab was not reached compared with 39.9 months with placebo, translating into a statistically significant HR favoring nivolumab of 0.70.

Similarly, after 54 months of follow-up for patients with MIBC tumors expressing at least 1% PD-L1, the median OS had not been reached for patients who received nivolumab compared with 37.6 months for patients with MIBC who had lower or no PD-L1 expression on tumors.

The analysis of OS by neoadjuvant chemotherapy status showed a median OS of 55.2 months for patients with neoadjuvant chemotherapy exposure who received nivolumab vs 40.2 months for those who received placebo; this difference was not statistically significant, however.

Among patients with MIBC without prior neoadjuvant chemotherapy, the median OS was not reached with nivolumab vs 37.7% months with placebo, and this difference was statistically significant (HR, 0.67).

Treatment-related adverse events graded ≥ 3 occurred in 17% of patients assigned to nivolumab vs 6% randomized to placebo. Treatment-related events leading to discontinuation occurred in only 2% and 1% of patients, respectively.

Biomarkers Needed to Prevent Over-Treatment

Invited discussant Elizabeth Plimack, MD, MS, deputy director of the Fox Chase Cancer Center at Temple Health in Philadelphia, said that the absolute DFS and OS benefits seen with nivolumab in patients with resected high-risk MIBC compare favorably with adjuvant regimens used to treat other cancers.

She noted, however, that biomarkers are needed to prevent over-treatment with nivolumab of patients whose disease has not recurred within 3 years and are therefore likely to be cured and to determine which patients need the extra protection against disease recurrence that nivolumab offers.

“The conundrum is, with the patient sitting in front of us in clinic, we don’t know which category they’ll fall into,” she said.

Circulating tumor DNA (ctDNA) can help to determine “is adjuvant treatment needed? Is the patient in front of us cured already, or is she destined to recur?” Plimack said, “whereas PD-L1 asks the question will adjuvant treatment work? In a patient destined to recur, will a treatment change their outcome.”

She noted that, as previously reported by Medscape Medical News, ctDNA could help to predict which patients with resected MIUC would be likely to benefit from adjuvant immunotherapy with a different immune checkpoint inhibitor, atezolizumab (Tecentriq), as demonstrated in the ImVigor010 trial.

In that trial, ctDNA-positive patients derived the largest benefit from adjuvant treatment, whereas ctDNA-negative patients derived little benefit.

“We would love to see these data from CheckMate 274, and I wonder if benefit might be seen in both groups in this positive trial,” she said.

Plimack also said that while it’s “good news” that patients who had received neoadjuvant chemotherapy also benefited from adjuvant nivolumab, she was disappointed that only 15% of patients in the study received this standard-of-care therapy.

This study was supported by Bristol-Myers Squibb. Milowsky disclosed stock ownership with Gilead Sciences, Merck, and Pfizer; receiving institutional research funding from BMS and others; and financial relationships with Elsevier, Medscape Medical News, Prime Education, and Research to Practice. Plimack disclosed a consulting/advisory role for 23andMe, Abbvie, Adaptimmune, Astellas Pharma, AstraZeneca, Aura, Biosceince, BMS/Medarex, Eisai, EMD Serono, Merck, Pfizer, Seagen, Signatera, and Synthekine; and receiving institutional research funding from BMS, Merck Sharp & Dohme, and Pfizer.