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Adjuvant nivolumab led to a significant improvement in disease-free survival compared with placebo in patients with high-risk muscle-invasive urothelial carcinoma following radical surgery, irrespective of PD-L1 expression level.
Adjuvant nivolumab (Opdivo) led to a significant improvement in disease-free survival (DFS) compared with placebo in patients with high-risk muscle-invasive urothelial carcinoma following radical surgery, irrespective of PD-L1 expression level, according to findings from the phase 3 CheckMate 274 trial (NCT02632409) that were published in the New England Journal of Medicine.
At a median follow-up of 20.9 months in the nivolumab arm and 19.5 months in the placebo arm, the median DFS was 20.8 months (95% CI, 16.5-27.6) in patients who received nivolumab (n = 353) vs 10.8 months (95% CI, 8.3-13.9) in patients who received placebo (n = 356) in the intention-to-treat (ITT) population. The 6-month DFS rates were 74.% (95% CI, 69.9%-79.2%) vs 60.3% (95% CI, 54.9%-65.3%), respectively (HR, 0.70; 98.22% CI, 0.55-0.90; P <.001). The 12-month DFS rates were 62.8% (95% CI, 57.3%-67.8%) vs 46.6% (95% CI, 41.1%-51.9%), respectively.
In patients with a PD-L1 expression level of 1% or more, the 6-month DFS rate was 74.5% (95% CI, 66.2%-81.1%) with nivolumab (n = 140) vs 55.7% (95% CI, 46.8%-63.6%) with placebo (n = 142; HR, 0.55; 98.72% CI, 0.35-0.85; P <.001). The 12-month DFS rates were 67.2% (95% CI, 58.4%-74.5%) vs 45.9% (95% CI, 37.1%-54.2%), respectively.
“The CheckMate 274 trial showed a significant and clinically meaningful benefit of adjuvant systemic immunotherapy as compared with placebo, both in the ITT population and in patients with a PD-L1 expression level of 1% or more,” wrote lead study author Dean F. Bajorin, MD, and co-authors, in the study publication.
In a phase 3, multicenter, double-blind, randomized, controlled trial, patients with muscle-invasive urothelial carcinoma who had undergone radical surgery were randomized 1:1 to receive 240 mg of intravenous nivolumab or placebo every 2 weeks for up to 1 year.
Prior neoadjuvant cisplatin-based chemotherapy was allowed. The primary end points were DFS among all patients (ITT population) and among patients with a PD-L1 expression level of 1% or more.
RFS outside the urothelial tract was a secondary end point. Distant metastasis-free survival (DMFS), safety, adverse effect (AE) profile, and health-related quality of life were exploratory end points.
Patients had a mean age of 65.3 years (range, 30-92) in the nivolumab arm and 65.9 years (range, 42-88) in the placebo arm. The majority of patients in the nivolumab and placebo arms were male, at 75.1% and 77.2%, respectively.
Most patients were White in the nivolumab arm (74.8%) and placebo arm (76.4%) and had an ECOG performance status of 0, at 63.5% and 62.1%, respectively.
The tumor origin at initial diagnosis was the urinary bladder in 79.0% of patients in the nivolumab arm and 78.9% in the placebo arm, and the time from initial diagnosis to randomization was less than 1 year in 92.1% and 91.0% of patients, respectively.
Approximately 40% of patients in both arms had a PD-L1 expression level of at least 1% by interactive voice-response system.
Less than half of patients had received prior neoadjuvant cisplatin therapy in the nivolumab and placebo arms, at 43.3% and 43.5%, respectively. The pathological tumor stage and nodal stage at resection was pT3,4N– in 44.8% and 44.7% of patients, respectively. The pathological tumor stage at resection was pT3 in over half of patients in the nivolumab and placebo arms, at 58.4% and 57.3%, respectively. In terms of nodal status at resection, N0 or NX with less than 10 nodes removed was reported in 26.6% of patients in the nivolumab arm vs 27.8% of patients in the placebo arm.
A total of 351 patients in the nivolumab arm vs 348 in the placebo arm received at least 1 dose of the trial regimen. The median duration of exposure was 8.8 months (range, 0-12.5) in the nivolumab arm vs 8.2 months (range, 0-12.6) in the placebo arm.
Additional results indicated that the median recurrence-free survival (RFS) outside the urothelial tract in the ITT population was 22.9 months with nivolumab (95% CI, 19.2-33.4) vs 13.7 months with placebo (95% CI, 8.4-20.3).
The 6-month RFS rates outside the urothelial tract were 77.0% (95% CI, 72.1%-81.1%) and 62.7% (95% CI, 57.3%-67.6%), respectively (HR, 0.72; 95% CI, 0.59-0.89). The 12-month RFS rates were 65.1% (95% CI, 59.6%-70%) and 50.4% (95% CI, 44.8%-55.7%) respectively.
Among patients with a PD-L1 expression level of 1% or more, the 6-month RFS rates were 75.3% (95% CI, 67.0%-81.7%) and 56.7% (95% CI, 47.8%-64.6%), respectively (HR, 0.55; 95% CI, 0.39-0.79). The 12-month RFS rates were 68.7% (95% CI, 60%-75.9%) and 46.7% (95% CI, 37.9%-55.1%), respectively.
DMFS also favored nivolumab in the ITT and PD-L1–positive populations. In the ITT population, the median DMFS was 40.5 months [95% CI, 22.4-not evaluable (NE)] with nivolumab vs 29.5 months with placebo (95% CI, 16.7-NE). The 6-month DMFS rates were 82.5% with nivolumab vs 69.8% with placebo (HR, 0.75; 95% CI, 0.59-0.94).
The 6-month DMFS rates were 78.7% with nivolumab vs 65.7% with placebo in the PD-L1–positive population (HR, 0.61; 95% CI, 0.42-0.90).
Additionally, according to subgroup analysis, a higher likelihood of DMFS was observed with nivolumab vs placebo, irrespective of nodal status, PD-L1 status, or use of prior neoadjuvant cisplatin-based chemotherapy.
A total of 83.6% of patients with censored data in the ITT population were still receiving study treatment at the time of the data lock in August 2020.
In terms of safety, any-grade treatment-related AEs (TRAEs) occurred in 77.5% of the patients in the nivolumab arm vs 55.5% of those in the placebo arm. Grade 3 or higher TRAEs occurred in 17.9% of patients in the nivolumab arm vs 7.2% of patients in the placebo arm. Two treatment-related deaths due to pneumonitis were reported in the nivolumab arm. Both patients began glucocorticoid treatment at the onset of pneumonitis.
The most common any-grade TRAEs in the nivolumab arm were pruritus (23.1%), fatigue (17.4%), and diarrhea (16.8%). The most common grade 3 or higher TRAEs in the nivolumab arm were elevations in the serum levels of lipase (5.1%) and amylase (3.7%), diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%).
In the ITT population, 53.3% of patients in the nivolumab arm vs 56.3% of patients in the placebo arm discontinued treatment. The most common reason for discontinuation was disease recurrence in the nivolumab and placebo arms, at 25.6% and 42.2%, respectively.
Any-grade TRAEs that led to discontinuation of the trial regimen occurred in 12.8% of the patients in the nivolumab arm vs 2.0% of those in the placebo arm. The most common TRAEs leading to nivolumab discontinuation were pneumonitis (1.7%), rash (1.1%), colitis (0.9%), and an increased alanine aminotransferase level (0.9%).
Changes from baseline in the EORTC QLQ-C30 global health status score and the EQ-5D-3L visual analogue scale score over time found no significant difference in deterioration in quality of life between patients who received nivolumab and those who received placebo in the ITT population and in patients with a PD-L1 expression level of 1% or more.
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