Patients with muscle-invasive urothelial carcinoma (MIUC) and muscle-invasive bladder cancer (MIBC) experienced increased disease-free survival (DFS) after radical surgery with nivolumab (Opdivo) compared with placebo. bottom. 3 The CheckMate 274 trial (NCT02632409) was presented at the 2023 American Urological Association Annual Meeting.1
“In this patient population, which represents the most common tumor site among CheckMate 274 patients, the benefits of DFS were evident regardless of tumor PD-L1 expression levels,” Matthew Milowsky, MD, FASCO, co -director, Urologic Oncology Program, UNC Lineberger Comprehensive Cancer Center at Chapel Hill, said in a data presentation. “These results further support nivolumab as the standard of care for high-risk MIUC and MIBC after radical resection.” is.”
Median follow-up for patients with MIBC and PD-L1 ≥1% was 34.5 months (range 0.0 to 75.3) and 36.7 months (range 0.0 to 75.3), respectively.
After 3 years, a median sustained DFS benefit of 22.0 months (95% CI, 18.8-36.9) was observed in the nivolumab group compared to 10.9 months (95% CI, 18.8-36.9) in the therapeutic placebo group. 8.3-15.2). (ITT) population (HR, 0.71; 95% CI, 0.58–0.86, median 25.6 months (95% CI, 19.2-41.8) vs. 8.5 months (95% CI, 7.3-13.7), MIBC patient population) ( HR, 0.63; 95% CI, 0.51–0.78).
This DFS benefit was also seen in patients with PD-L1 ≥1% in the ITT patient population, median 52.6 months (95% CI, 25.8 – not evaluable) [NE]) vs. 8.4 months (95% CI, 5.6–17.9), respectively (HR, 0.52; 95% CI, 0.37–0.72) and the MIBC patient population (median, 52.6 months) [95% CI, 39.5-NE] versus 8.3 months [95% CI, 4.7–15.2], respectively; HR, 0.44. 95% CI, 0.30–0.63).
Additionally, nivolumab produced a sustained DFS effect compared to placebo, even in patients with <1% MIBC and PD-L1 (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 demonstrated an ongoing non-urothelial tract recurrence-free survival (NUTRFS) benefit in the ITT population compared to placebo (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 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).
Furthermore, the benefit of nivolumab versus placebo for distant metastasis-free survival (DMFS) was maintained at 3 years of follow-up, with a median of 47.1 months (95% CI, 26.5-NE) vs. 28.7 months ( 95% CI, 16.6-47.8), ITT population (HR, 0.74; 95% CI, 0.60-0.92), respectively, and median 41.8 months (95% CI, 25.6-55.3) vs. 19.4 months (95%) CI , 11.4-34.4) (HR, 0.70; 95% CI, 0.55-0.89).
Finally, the time from randomization to disease progression after subsequent systemic anticancer therapy, initiation of a second subsequent systemic anticancer therapy, or death (PFS2) was also evaluated using nivolumab was improved in the ITT population compared to placebo (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 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 magnitudes of benefit for DFS, NUTRFS, and DMFS were generally stable in both populations,” Milowsky said.
He added that safety in the MIBC patient population was consistent with previous data in the ITT population and no new safety signals were identified.
CheckMate 274 Trial
“Despite curative resection, patients with MIUC remain at high risk of fatal metastatic recurrence, with most recurrences occurring within two to three years after surgery,” explained Milowsky.
Therefore, in a phase 3, multicenter, double-blind, randomized controlled trial, 709 patients with high-risk MIUC who underwent radical surgery received either intravenous nivolumab 240 mg (n = 353) or placebo. Randomly assigned at :1. (n = 356) every 2 weeks for up to 1 year.2
Primary inclusion criteria included ypT2-ypT4a or ypN-positive MIUC receiving neoadjuvant cisplatin chemotherapy. pT3-pT4a or pN-positive MIUC No prior neoadjuvant cisplatin chemotherapy, ineligible/refusing adjuvant cisplatin chemotherapy; definitive surgery within the previous 120 days; disease-free within 4 weeks of randomization.
Patients were stratified by tumor PD-L1 status, neoadjuvant cisplatin-based chemotherapy, and lymph node status.
DFS in the ITT population and patients with PD-L1 expression levels ≥1% served as primary endpoints. Secondary endpoints were NUTRFS, disease-specific survival, and overall survival. Exploratory endpoints included DMFS, PFS2 and safety.
Median follow-up was 36.1 months (range, 0.0 to 75.3) and 37.1 months (range, 0.0 to 75.3) for the ITT and PD-L1 >1% populations, respectively.
With a minimum follow-up of 11.0 months (median, 23.3 months), treatment with nivolumab was associated with 20.8 months (95% CI, 16.5-27.6) and 10.8 months (95% CI, 8.3-13.9 ) induced median DFS. in the placebo arm. Overall, 74.9% of nivolumab-treated patients were alive and disease-free at his 6 months compared with 60.3% of placebo-treated patients (HR, 0.70; 98.22% CI, 0.55- 0.90; P. < .001), in the ITT population the proportions were 74.5% and 55.7%, respectively, and in patients with PD-L1 expression levels ≥1% (HR, 0.55; 98.72% CI, 0.35–0.85; P. < .001).
Additionally, the median extra-urothelial relapse-free survival in the ITT population was 22.9 months (95% CI, 19.2-33.4) with nivolumab and 13.7 months (95% CI, 8.4-20.3) with placebo, 77.0. % and 62.7%, respectively, were alive and relapse-free at 6 months (HR, 0.72; 95% CI, 0.59-0.89). Among patients with PD-L1 expression levels ≥1%, 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 greater occurred in 17.9% of patients in the nivolumab group and 7.2% of patients in the placebo group.
“Nivolumab has become the standard of care for patients with high-risk MIUC after radical resection based on the results of the CheckMate 274 trial,” said Dr. Milowsky. “At a minimum follow-up of 11.0 months, we observed improvements in his DFS, NUTRFS, and DMFS with nivolumab compared with placebo in a subpopulation of patients with muscle-invasive bladder cancer.”
1. Milowsky M, Galsky MD, Bajorin DF, et al. Long-term follow-up results of patients with muscle-invasive bladder cancer in the CheckMate 274 trial. J Urol2023;209(4):e1189. Doi:10.1097/JU.0000000000003361.08
2. Bajorin DF, Witjes JA, Gschwend JE, other adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med2021;384(22):2102-2114. doi:10.1056/NEJ Moa2034442