Updated Efficacy Shows Nivolumab Boosts Survival in High-Risk MIBC

Sumanta K. Pal, MD

Chair, Kidney and Bladder Cancer Disease Team

Co-director, Kidney Cancer Program

Professor

Vice Chair of Academic Affairs

Department of Medical Oncology & Therapeutics Research

City of Hope Comprehensive Cancer Center

Duarte, CA

Targeted Oncology: What was the design of the CheckMate 274 trial (NCT02632409) investigating nivolumab (Opdivo) in muscle-invasive bladder cancer (MIBC)?

Sumanta K. Pal, MD: The study included patients in 2 different disease categories. Importantly, this patient population had either T3a or T4 disease with nodal positivity, and they had not received prior neoadjuvant treatment, or they had neoadjuvant therapy and/or pathologic T2 to T4a.… These patients were randomly assigned to receive either placebo or nivolumab for a span of 1 year.¹

In this study, nivolumab was dosed every 2 weeks, which was consistent with many studies evolving at the time. There were stratification factors around PD-L1 status, prior neoadjuvant platinum-based chemotherapy, and nodal status—N1 vs N0 vs unknown nodal status or N0 with greater than 10 nodes removed.

The primary end points are important. The primary end point was disease-free survival [DFS] based on investigator assessment. There were 2 coprimary end points: one in all randomly assigned patients, and the other in patients with PD-L1 expression greater than 1%. Key secondary end points included overall survival (OS), disease-specific survival, and non-urothelial DFS.

Who was included in the overall patient population?

If you look at the baseline characteristics of the population, they were pretty typical. The median age was around 65 years in this cohort, and the majority were male, as you might anticipate. The study population was primarily White patients, with a fairly reasonable representation of Asian patients as well.

A couple of other key points: when considering the sites of disease, we often think of upper tract disease as a distinct entity. About 20% of patients in the study had a tumor of the renal pelvis or a tumor within the ureter.

Looking at PD-L1 expression greater than 1%, which was the threshold used in this study, it was present in about 40% of patients. The nodal tumor stage at the time of resection [showed] most patients were in the T3 category and potentially node-positive. This was a very high-risk population of patients.

What was the updated efficacy seen in these patients with MIBC?

The study met its primary end point. The HR for DFS was 0.71 [95% CI, 0.58-0.86], which in my mind represents a pretty marked shift in DFS. The median DFS was 22.0 months vs 10.9 months [with nivolumab vs placebo, respectively].²

This difference seems to be particularly profound in the context of patients who were PD-L1 positive. Here, the difference in DFS is 52.6 months as a median vs 8.4 months, [respectively]. This is remarkable, in my opinion. Clearly, there’s a population in both cohorts—the experimental arm and the control arm—that do well long-term. But there’s no doubt in my mind that those patients who received nivolumab seemed to fare better in terms of DFS.

The OS shows a very compelling trend toward a benefit with adjuvant nivolumab therapy, with an HR of 0.76 [95% CI, 0.61-0.96]. It clearly looks as though the confidence intervals avoid 1.0 here, and the PD-L1 positive population again seems to benefit to a greater extent.

The [investigators also looked at the] elements of non-urothelial tract recurrence-free survival. These are elements of disease that escape beyond the substance of the urothelial tract. They also showed the distant metastasis-free survival. In general, everything seems to favor nivolumab at 36 months of follow-up.

What was the toxicity profile seen in CheckMate 274?

In the nivolumab arm, about 18% of patients had grade 3/4 adverse events related to nivolumab. Elements like itching, fatigue, and diarrhea tend to top the list with these therapies.¹

DISCLOSURE: Pal has previously received travel support from Ipsen and CRISPR Therapeutics and consulting fees from Pfizer, Novartis, Genentech, Exelixis, and Bristol-Myers Squibb.

_References:

_{1. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. doi:10.1056/NEJMoa2034442}

_{2. 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;43(1):15-21. doi:10.1200/JCO.24.00340}