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Patients with muscle invasive urothelial carcinoma who received adjuvant nivolumab experienced a longer disease-free survival compared with those who received placebo.
Adjuvant nivolumab (Opdivo) demonstrated an improved disease-free survival (DFS) over placebo in patients with muscle invasive urothelial carcinoma (MIBC), according to the results of a phase 3 clinical trial (NCT02632409) that was published in the New England Journal of Medicine.
After a median follow-up of 20.9 months (range, 0.1-48.3) in the nivolumab cohort and 19.5 months (range, 0-50.0) for patients in the placebo cohort, investigators reported a median DFS of 20.8 months (95% CI, 16.5-27.6) in the nivolumab group and 10.8 months (95% CI, 8.3-13.9)in the placebo group. At the 6-month follow-up, 74.9% of patients in the nivolumab group and 60.3% in the placebo group were alive and disease free (HR 0.70; 98.22% CI, 0.55-0.90; P< .001).
The randomized, double-blind clinical trial enrolled a total of 709 patient, including 353 in the ITT nivolumab group and 356 in the placebo group. Additionally, 140 patients in the nivolumab arm and 142 in the placebo arm had a PD-L1 expression of 1% or more.
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 trial included a high-risk population of patients with MIBC who had previously undergone radical surgery. To be eligible for the trial, patients needed to have undergone radical surgery with or without cisplatin-based chemotherapy within 120 days prior to randomization. Additionally, an ECOG performance status of 0 or 1 was required.
The primary end point of the study was DFS for all patients in the intent-to-treat (ITT) population, as well as those with a PD-L1 expression of 1% or greater. The key secondary end point was survival free from recurrence outside the urothelial tract.
Lymph nodes with urothelial carcinoma invasion was common in both groups and included 47.3% of those in the nivolumab group and 47.2% in the placebo group. Additionally, 43.3% and 43.5% of patients received neoadjuvant cisplatin-based combination therapy in both the nivolumab cohort and placebo cohort, respectively.
Notably, 53.3% and 56.3% in the nivolumab and placebo groups, respectively, discontinued treatment. The most common cause of discontinuation was disease recurrence, including 25.6% of those in the nivolumab group and 42.2% in the placebo group.
Additional findings from the study indicated that 74.5% of patients in the nivolumab arm who had a PD-L1 expression of 1% or higher were alive and disease-free at 6-months vs 55.7% of those in the placebo (HR 0.55; 98.72% CI, 0.35-0.85; P< .001). A subgroup analysis identified a higher probability of DFS following treatment with nivolumab vs placebo regardless of nodule or PD-L1 status or use or non-use of previous neoadjuvant chemotherapy. At the database lock, 83.6% of patients were still receiving nivolumab or the placebo.
Moreover, investigators reported a median survival free from recurrence outside of the urothelial tract of 22.9 months for the nivolumab ITT population (95% CI, 19.2-33.4) and 13.7 months for the placebo ITT population (95% CI, 8.4-20.3). At the 6-month follow-up, 77.0% in the nivolumab group and 62.7% in the placebo group were alive and disease free (HR 0.72; 95% CI, 0.59-0.89). Among patients who had a PD-L1 expression of 1% or more, 75.3% in the nivolumab group and 56.7% in the placebo group were alive and free from recurrence outside the urothelial tract at 6 months (HR 0.55; 95% CI, 0.39-0.79).
Treatment with nivolumab also yielded a longer median distant metastasis-free survival (MFS) of 40.5 months (95% CI, 22.4–could not be estimated), and 29.5 months for the placebo group (95% CI, 16.7–could not be estimated). Investigators also reported a 6-month distant MFS of 82.5% and 69.8% in both the nivolumab and placebo cohort, respectively (HR 0.75; 95% CI, 0.59-0.94). Those who had a PD-L1 expression of 1% or more had a 6-month distant MFS of 78.7% and 65.7% in both groups, respectively (HR 0.61; 95% CI, 0.42-0.90).
Adverse effects (AEs) occurred in 98.9% of patients who were treated with adjuvant nivolumab and 95.4% of those who received the placebo. AEs that were grade 3 or higher occurred in 42.7% of patients in the nivolumab arm and 36.8% in the placebo arm.
Treatment-related adverse effects (TRAEs) occurred in 77.5% and 55.5% of patients in both groups, respectively. TRAEs that were grade 3 or higher occurred in 17.9% in the nivolumab group and 7.2% in the placebo group. Some of the most common any grade TRAEs included pruritus (23.1% vs 11.5%), fatigue (17.4% vs 12.1%), and diarrhea (16.8% vs 10.9%). The most common TRAEs that were grade 3 or higher included increased lipase level (5.1% vs 2.6%) and increased amylase level (3.7% vs 1.4%).
In the nivolumab group, 2 patients died from pneumonitis. Additionally, 12.8% of patients in the nivolumab group and 2.0% of those in the placebo group discontinued treatment due to of TRAEs, with the most frequent being pneumonitis (1.7%), rash (1.1%), colitis (0.9%), and increased alanine aminotransferase level (0.9%).
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