Longer follow-up shows improved DFS with nivolumab in high-risk muscle-invasive urothelial carcinoma

Treatment with nivolumab (Opdivo) continued to induce improved disease-free survival (DFS) among patients with high-risk muscle-invasive urothelial carcinoma (MIUC) following radical surgery, regardless of previous treatment with neoadjuvant chemotherapy, nodal involvement, or PD-L1 status, according to extended follow-up from the phase 3 Checkmate 274 trial (NCT02632409) presented at the 22nd Annual Meeting of the Society of Urologic Oncology.¹

Matthew Galsky, MD

“With longer follow-up, nivolumab continued to demonstrate a clinically meaningful improvement in disease-free survival versus placebo for patients with high-risk muscle invasive urothelial cancer after radical surgery. This disease-free survival benefit was observed in both the intent to treat [ITT] population and in the subset of patients with tumors harboring high levels of PD-L1 expression, a disease-free survival benefit with nivolumab was observed in most pre-specified clinical subgroups,” Matthew Galsky, MD, professor of medicine (hematology and medical oncology); director of genitourinary medical oncology; co-director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute; and associate director for translational research at The Tisch Cancer Institute at Mount Sinai, said during a virtual presentation of the poster.

The randomized, double-blind, multicenter phase 3 CheckMate 274 trial enrolled a total of 709 patients with high-risk MIUC, originating in the bladder, ureter, or renal pelvis, including 353 in the ITT nivolumab group (PD-L1 ≥1%, n = 140) and 356 in the placebo group (PD-L1 ≥1%, n = 142). Additionally, 140 patients in the nivolumab arm and 142 in the placebo arm had a PD-L1 expression of 1% or more.²

Patients were randomized 1:1 and stratified based on PD-L1 expression, pathological nodal status, and treatment with a neoadjuvant cisplatin-based chemotherapy. A dose of 240 mg of nivolumab or placebo was administered every 2 weeks intravenously for up to a year or until disease recurrence or trial discontinuation.

The primary end point of the study was DFS for all patients in the ITT population, as well as those with a PD-L1 expression of 1% or greater. The key secondary end point was NUTRFS in the ITT population and in patients with PD-L1 ≥1%. Moreover, DMFS was an exploratory end point. DFS was also evaluated in prespecified subgroups.

To be eligible for the trial, the high-risk population of patients with MIUC who had previously undergone radical surgery needed to have undergone radical surgery with or without cisplatin-based chemotherapy within 120 days prior to randomization, and were required to have an ECOG performance status of 0 or 1.

Following a previous minimum follow-up in the ITT population of 5.9 months, DFS was significantly improved with nivolumab, compared with placebo, both in the ITT population (HR, 0.70; 98.22% CI, 0.55-0.90; P <.001) and in the population with tumor PD-L1 expression ≥1% (HR, 0.55; 98.72% CI, 0.35-0.85; P < .001). The safety profile of nivolumab was consistent with that observed in previous trials.

Following an additional follow-up of 5 months, which included a minimum follow-up in the intention-to-treat (ITT) population of 11 months (median follow-up in the nivolumab vs placebo group, 24.4 months vs 22.5 months, respectively) and 11.4 months in the PD-L1 ≥1% group (median follow-up in the nivolumab vs placebo group, 25.5 months vs 22.4 month), DFS benefit with nivolumab was maintained.

With the longer follow-up, the anti-PD-1 antibody demonstrated improved DFS, compared with placebo, in the ITT nivolumab and placebo groups (22.0 months vs 10.9 months, respectively), as well as in the PD-L1 ≥1% groups (not reached [NR] vs 8.4 months). DFS probability at 12 months was 63.5% with nivolumab and 46.9% with placebo in ITT patients, and 67.6% vs 46.3%, respectively, among patients with PD-L1 ≥1%.

In the subgroup analysis, improved DFS was observed with nivolumab, compared with placebo, for those in subgroups including age (<65: HR, 0.73; 95% CI, 0.53-1.01), sex (female: HR, 0.77, 95% CI, 0.50-1.17), ECOG performance status (1: HR, 0.79; 95% CI, 0.56-1.12), nodal status (N0/x with <10 nodes removed: HR, 0.85; 95% CI, 0.57-1.27), use of prior cisplatin-based chemotherapy (No: HR, 0.90; 95% CI, 0.68-1.18), and PD-L1 status (<1%: HR, 0.82; 95% CI, 0.63-1.05).

At 12 months, non-urothelial tract recurrence-free survival (NUTRFS) probabilities were also improved with nivolumab, versus placebo, in both the ITT (65.8% vs 50.6%, respectively) and PD-L1 ≥1% (69.2% vs 47.1%) populations. The median NUTRFS in the ITT was 26.0 months [95% CI, 19.5-41.1] vs 13.7 months [95% CI, 8.4-20.0]; HR, 0.71; 95% CI, 0.58-0.88), respectively, and placebo (NR [95% CI, 25.8-not estimable (NE)] vs 10.8 months [95% CI, 5.7-20.7]; HR, 0.54; 95% CI, 0.39-0.77) groups was also improved with nivolumab.

Similarly, median distant metastasis-free survival (DMFS) was also improved with nivolumab, compared with placebo, in both the ITT (41.1 months [95% CI, 26.0-NE] vs 29.3 months [95% CI, 15.2-NE], respectively; HR, 0.73; 95% CI, 0.58-0.92) and PD-L1 ≥1% groups (NR [95% CI, 26.0-NE] vs 20.7 months [95% CI, 10.8-NE]; HR, 0.60; 95% CI, 0.41-0.88).

In terms of time to response, the median among the nivolumab and placebo groups, respectively, were 25.8 months (95% CI, 19.6-NE) and 11.1 months (95% CI, 8.3-19.4) in the ITT population, and NR (95% CI, 25.8-NE) and 10.9 months (95% CI, 5.8-22.2) in the PD-L1 ≥1% population.

Galsky added that subsequent systemic therapy was received by 30% of patients on the nivolumab arm and 37.6 patients on the placebo arm.

The median duration of therapy was 10.1 months (range, 0-12.5) in the nivolumab group, compared with 8.6 months (range, 0-12.6) in the placebo group.

“These results support adjuvant nivolumab as a standard of care for patients with high-risk muscle-invasive urothelial cancer after radical resection,” Galsky said.

Reference

1. Galsky MD, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the phase 3 Checkmate 274 trial of adjuvant nivolumab in patients who underwent surgery for high-risk muscle-invasive urothelial carcinoma. Presented at: SUO 22nd Annual Meeting; December 1-3, 2021; Orlando, Florida. Poster 175.

2. 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.