Nivolumab Maintains DFS Benefit in MIUC and MIBC After Radical Surgery

Matthew Milowsky, MD, FASCO

Nivolumab (Opdivo) following radical surgery continued to display a benefit in disease-free survival (DFS) in patients with muscle-invasive urothelial carcinoma (MIUC) and muscle-invasive bladder cancer (MIBC), according to extended follow-up from the phase 3 CheckMate 274 trial (NCT02632409) presented at the 2023 American Urological Association Annual Meeting.¹

“In this patient population representing the most common tumor site among patients in CheckMate 274, DFS benefit was evident regardless of tumor PD-L1 expression level,” Matthew Milowsky, MD, FASCO, co-director, Urologic Oncology Program, UNC Lineberger Comprehensive Cancer Center, said in a presentation of the data. “These results further support nivolumab as a standard of care for high-risk MIUC and MIBC after radical resection.”

Median follow-up among patients with MIBC and those with PD-L1 ≥ 1% was 34.5 months (range, 0.0-75.3) and 36.7 months (range, 0.0-75.3), respectively.

After 3 years, continued disease-free survival (DFS) benefit was observed with a median of 22.0 months (95% CI, 18.8-36.9) in the nivolumab arm, vs 10.9 months (95% CI, 8.3–15.2) with placebo in the intent-to-treat (ITT) population (HR, 0.71; 95% CI, 0.58–0.86, and a median of 25.6 months (95% CI, 19.2-41.8) vs 8.5 months (95% CI, 7.3-13.7), in the MIBC patient population (HR, 0.63; 95% CI, 0.51–0.78).

This DFS benefit was also seen among patients with PD-L1 ≥ 1% in the ITT patient population (median, 52.6 months [95% CI, 25.8–NE] vs 8.4 months [95% CI, 5.6–17.9], respectively; HR, 0.52; 95% CI, 0.37-0.72), and in the MIBC patient population (median, 52.6 months [95% CI, 39.5-NE] vs 8.3 months [95% CI, 4.7–15.2], respectively; HR, 0.44; 95% CI, 0.30-0.63).

Further, nivolumab induced continued DFS benefit in patients with MIBC and PD-L1 < 1% as well, compared with placebo (median, 18.3 months [95% CI, 14.1–22.4] vs 9.7 months [95% CI, 7.4-16.6], respectively; HR, 0.74; 95% CI, 0.56-0.97).

Similarly, treatment with nivolumab, vs placebo, demonstrated continued non-urothelial tract recurrence-free survival (NUTRFS) benefit in the ITT population (median, 25.9 months [95% CI, 19.4-44.0] vs 13.7 months [95% CI, 8.4-20.3], respectively; HR, 0.72; 95% CI, 0.59-0.88) and the MIBC population (median, 25.8 months [95% CI, 19.2–44.0] vs 9.6 months [95% CI, 7.6-13.8], respectively; HR, 0.64; 95% CI, 0.52-0.80).

In addition, the benefit of nivolumab, vs placebo, on distant metastasis-free survival (DMFS) was endured in the 3-year follow-up, with a median of 47.1 months (95% CI, 26.5-NE) vs 28.7 months (95% CI, 16.6-47.8), respectively, in the ITT population (HR, 0.74; 95% CI, 0.60-0.92), and a median of 41.8 months (95% CI, 25.6-55.3) vs 19.4 months (95% CI, 11.4-34.4) in the MIBC group (HR, 0.70; 95% CI, .55-0.89).

Lastly, the time from randomization to disease progression after subsequent next-line systemic anticancer therapy, start of second subsequent next-line systemic anticancer therapy, or death (PFS2) was also improved with treatment using nivolumab, vs placebo, in the ITT population (median, 61.2 months [95% CI, 44.0–NE] vs 47.1 months [95% CI, 29.4–65.2], respectively; HR, 0.79; 95% CI, 0.63–0.98) and the MIBC group (median, 55.4 [95% CI, 40.1–NE] vs 30.0 months [95% CI, 24.8–47.1], respectively; HR, 0.70; 95% CI, 0.55–0.89).

“The magnitude of DFS, NUTRFS, and DMFS benefit was generally stable over time in both populations,” Milowsky said.

He added that safety in the MIBC patient population was consistent with previous data in the ITT population, with no new safety signals identified.

CheckMate 274 trial

“Despite radical resection, patients with muscle-invasive urothelial carcinoma remain at high risk for lethal metastatic recurrence, with most recurrences occurring within 2 to 3 years after surgery,” Milowsky explained.

Therefore, in the phase 3, multicenter, double-blind, randomized, controlled trial, 709 patients with high-risk MIUC who had undergone radical surgery were randomized 1:1 to receive either 240 mg nivolumab intravenously (n = 353) or placebo (n = 356) every 2 weeks for up to 1 year.²

Key inclusion criteria included ypT2-ypT4a or ypN-positive MIUC who had neoadjuvant cisplatin chemotherapy; pT3-pT4a or pN-positive MIUC without prior neoadjuvant cisplatin chemotherapy and not eligible for/refused adjuvant cisplatin chemotherapy; radical surgery within the past 120 days; and disease-free status within 4weeks of randomization.

Patients were stratified by tumor PD-L1 status, prior neoadjuvant cisplatin-based chemotherapy, and nodal status.

DFS among the ITT population and patients with PD-L1 expression levels of 1% or more served as the primary end point. Secondary end points were NUTRFS, disease specific survival, and overall survival. Exploratory end points included DMFS, PFS2, and safety.

Median follow-up for the ITT population and those with PD-L1 greater than 1% was 36.1 months (range, 0.0–75.3) and 37.1 months (range, 0.0–75.3), respectively.

At minimum follow-up of 11.0 months (median, 23.3 months) treatment with nivolumab induced a median DFS of 20.8 months (95% CI, 16.5-27.6) in the ITT population, and 10.8 months (95% CI, 8.3-13.9) in the placebo arm. Overall, 74.9% of patients treated with nivolumab were alive and disease-free at 6 months, compared with 60.3% of patients treated with placebo (HR, 0.70; 98.22% CI, 0.55-0.90; P < .001) in the ITT population, while rates were 74.5% and 55.7%, respectively, in patients with PD-L1 expression levels of 1% or more (HR, 0.55; 98.72% CI, 0.35-0.85; P < .001).

In addition, median survival free from recurrence outside the urothelial tract was 22.9 months (95% CI, 19.2-33.4) with nivolumab, vs 13.7 months (95% CI, 8.4-20.3) with placebo in the ITT population, with 77.0% and 62.7%, respectively, alive and free from recurrence at 6 months (HR, 0.72; 95% CI, 0.59-0.89). In patients with a PD-L1 expression level of 1% or more, the rates were 75.3% and 56.7%, respectively (HR, 0.55; 95% CI, 0.39-0.79).

Treatment-related adverse events of grade 3 or higher occurred in 17.9% of patients in the nivolumab group and 7.2% of patients in the placebo group.

“Nivolumab became a standard of care for patients with high-risk MIUC after radical resection on the basis of results from the CheckMate 274 trial,” Milowsky said. “With a minimum follow-up of 11.0 months, improvements in DFS, NUTRFS, and DMFS with nivolumab versus placebo were observed in the subpopulation of patients with muscle-invasive bladder cancer.”

References

1. Milowsky M, Galsky MD, Bajorin DF, et al. Results from the extended follow-up in patients with muscle-invasive bladder cancer in the CheckMate 274 trial. J Urol. 2023;209(4):e1189.

2. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021;384:2102-2114. doi:10.1056/NEJMoa2034442