Adjuvant Nivolumab Provides Sustained DFS Benefit, Favors OS in Muscle-Invasive Urothelial Cancer

Adjuvant therapy with nivolumab (Opdivo) continued to prolong disease-free survival (DFS), non–urothelial tract recurrence-free survival (NUTRFS), and distant metastasis–free survival (DMFS) vs placebo and, for the first time, showed a favorable trend in overall survival (OS) in the intention-to-treat (ITT) and PD-L1–positive populations of patients with high-risk, muscle-invasive urothelial cancer (MIUC), according to extended follow-up data from the phase 3 CheckMate 274 trial (NCT02632409) presented at the 2024 European Association of Urology Annual Meeting.¹

With median follow-up of 36.1 months and 37.1 months in the ITT and PD-L1–positive populations, respectively, DFS continued to favor nivolumab vs placebo (ITT: HR, 0.71; 95% CI, 0.58-0.86; PD-L1–positive: HR, 0.52; 95% CI, 0.37-0.72). The median DFS with nivolumab (n = 353) and placebo (n = 356) in the ITT population was 22.0 months (95% CI, 18.8-36.9) and 10.9 months (95% CI, 8.3-15.2), respectively. The median DFS in the PD-L1–positive population was 52.6 months (95% CI, 25.8–not evaluable [NE]) and 8.4 months (95% CI, 5.6-17.9) with nivolumab (n = 140) and placebo (n = 142), respectively.

The 24- and 36-month DFS rates in the ITT population were 48.4% and 45.0%, respectively, with nivolumab vs 38.8% and 34.9% with placebo. In the PD-L1–positive population, the 24- and 36-month DFS rates were 60.3% and 56.9%, respectively, with nivolumab vs 37.6% and 33.3% with placebo.¹

Per the statistical design of the trial, OS was tested using a hierarchical procedure in the ITT and PD-L1–positive populations. OS data from the present analysis are from preplanned interim analyses for the ITT and PD-L1–positive populations.

With median follow-up of 36.1 months and 23.4 months in the ITT and PD-L1–positive populations, respectively, interim OS data favored nivolumab vs placebo (ITT: HR, 0.76; 95% CI, 0.61-0.96; PD-L1–positive: HR, 0.56; 95% CI, 0.36-0.86). A trend for OS benefit with nivolumab was also seen in prespecified patient subgroups within the ITT population.

The median OS in the ITT population was 69.5 months (95% CI, 58.1-NE) with nivolumab vs 50.1 months (95% CI, 38.2-NE) with placebo. In the PD-L1–positive population the median OS was not reached (NR) in either arm. In the ITT population, the 24- and 36-month OS rates were 76.1% and 65.6%, respectively, with nivolumab vs 70.1% and 58.1% with placebo. In the PD-L1–positive population the 24- and 36-month OS rates were 81.9% and 71.3%, respectively, with nivolumab vs 68.4% and 56.6% with placebo.

“Despite standard-of-care radical cystectomy with or without neoadjuvant cisplatin-based chemotherapy, a significant number of patients with MIUC experience disease recurrence within 3 years of surgery. Nivolumab became a standard of care adjuvant treatment for patients with high-risk MIUC after radical surgery, based on the initial results from the phase 3 CheckMate 274 trial,” Matthew Galsky, MD, professor of medicine, director of Genitourinary Medical Oncology, codirector of the Center of Excellence for Bladder Cancer, and associate director for Translational Research at The Tisch Cancer Institute at Mount Sinai in New York, New York, said in a presentation.^1,2

CheckMate 274 was a phase 3, randomized, double-blind, multicenter study that evaluated adjuvant nivolumab vs placebo in patients with high-risk MIUC. Eligible patients had ypT2 to ypT4a or ypN+ MIUC and had received neoadjuvant cisplatin-based chemotherapy. Patients with pT3 to pT4a or pN+ MIUC without prior neoadjuvant cisplatin-based chemotherapy must have been unfit for or refused adjuvant cisplatin-based chemotherapy. Radical surgery had to have occurred within the past 120 days, and patients must have maintained disease-free status within 4 weeks of randomization.¹

Patients were randomly assigned 1:1 to 240 mg of intravenous (IV) nivolumab every 2 weeks or IV placebo every 2 weeks for up to 1 year.

The primary end points were DFS in all randomly assigned patients (ITT population) and in all randomly assigned patients with tumor PD-L1 expression of at least 1%. Secondary end points included NUTRFS and OS. DMFS and safety served as exploratory end points.

Prior results showed that with median follow-up of 20.9 months for nivolumab and 19.5 months for placebo, nivolumab led to improved DFS in the ITT (HR, 0.70; 98.22% CI, 0.55-0.90; P <.001) and PD-L1–positive (HR, 0.55; 98.72% CI, 0.35-0.85; P <.001) populations, meeting the primary end points of the study.³

Additional results from the present analysis demonstrated continued NUTRFS and DMFS benefit with nivolumab vs placebo in both the ITT and PD-L1–positive populations. With respect to NUTRFS, the median values in the ITT population were 25.9 months (95% CI, 19.4-44.0) with nivolumab vs 13.7 months (95% CI, 8.4-20.3) with placebo (HR, 0.72; 95% CI, 0.59-0.88). In the PD-L1–positive population, the median NUTRFS was 52.6 months (95% CI, 29.7-NE) with nivolumab vs 8.4 months (95% CI, 5.6-20.0) with placebo (HR, 0.53; 95% CI, 0.38-0.74).¹

In the ITT population, the median DMFS was 47.1 months (95% CI, 26.5-NE) with nivolumab vs 28.7 months (95% CI, 16.6-47.8) with placebo (HR, 0.74; 95% CI, 0.60-0.92). In the PD-L1–positive population, the median DMFS was NR (95% CI, 44.0-NE) with nivolumab vs 20.7 months (95% CI, 10.6-NE) with placebo (HR, 0.58; 95% CI, 0.40-0.84).

Notably, a wider separation between the Kaplan-Meier curves was seen in the PD-L1–positive population in both landmark analyses for NUTRFS and DMFS. In terms of NUTRFS in the ITT population, the 24- and 36-month rates were 51.6% and 47.5%, respectively, with nivolumab vs 42.2% and 38.3% with placebo. In the PD-L1–positive population, the 24- and 36-month rates were 62.7% and 57.4%, respectively, with nivolumab vs 38.3% and 34.8% with placebo. Regarding DMFS in the ITT population, the 24- and 26-month rates were 57.8% and 53.9%, respectively, with nivolumab vs 51.2% and 47.0% with placebo. In the PD-L1–positive population, the 24- and 36-month rates were 66.4% and 61.7%, respectively, with nivolumab vs 48.6% and 44.2% with placebo.

Regarding safety, no new signals were seen. Treatment-related adverse effects (TRAEs) and TRAEs leading to discontinuation were more common with nivolumab (TRAEs: any grade, 79%; grade ≥3, 18%; TRAEs leading to discontinuation: any grade, 14%; grade ≥3, 7%) vs placebo (TRAEs: any grade, 56%; grade ≥3, 7%; TRAEs leading to discontinuation: any grade, 2%; grade ≥3, 1%).

The most common AEs that occurred in at least 5% of patients in either arm in order of frequency were pruritus, fatigue, diarrhea, rash, increased lipase, hypothyroidism, increased amylase, hyperthyroidism, nausea, asthenia, decreased appetite, increased blood creatinine, maculopapular rash, and arthralgia. Most nivolumab-related events were mild, and most grade 3 or greater events occurred in approximately 1% of patients, although 5% and 4% of patients in the nivolumab arm experienced grade 3 or greater lipase increase and amylase increase, respectively.

“These results provide additional support for adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection, potentially providing an opportunity for a curative outcome,” Galsky concluded.

Follow-up for OS is ongoing because the prespecified statistical boundary for significance was not met at this time.

Disclosures: Dr Galsky reported advisory board/consultant for AbbVie, Alligator Bioscience, Analog Devices, ARS Pharmaceuticals, Asieris Pharmaceuticals, AstraZeneca, Basilea Pharmaceutica, Bicycle Therapeutics, Bristol Myers Squibb, Curis, Daiichi Sankyo, Dragonfly Therapeutics, EMD Serono, Fujifilm, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Numab Therapeutics, Pfizer, Rappta Therapeutics, SeaGen, UroGen Pharma, and Veracyte.

References

1. Galsky MD, Alfred Witjes J, Gschwend JE, et al. Extended follow-up from CheckMate 274 including the first report of overall survival outcomes. Presented at: 2024 European Association of Urology Annual Meeting; April 5-8, 2024; Paris, France.
2. US Food and Drug Administration approves Opdivo (nivolumab) for the adjuvant treatment of patients with high-risk urothelial carcinoma. News release. Bristol Myers Squibb. August 20, 2021. Accessed April 16, 2024. https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Approves-Opdivo-nivolumab-for-the-Adjuvant-Treatment-of-Patients-with-High-Risk-Urothelial-Carcinoma/default.aspx
3. 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