SUMMARY: The American Cancer Society estimates that in the United States for 2021, about 83,730 new cases of bladder cancer will be diagnosed and approximately 17,200 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Even though radical cystectomy is considered the standard of care for patients with localized Muscle Invasive Bladder Cancer (MIBC), two large randomized trials and two meta-analysis have shown greater survival benefit with neoadjuvant Cisplatin-based combination chemotherapy for patients with MIBC, compared to surgery alone. However, not all patients with MIBC benefit from neoadjuvant Cisplatin based therapy, with only 25-50% attaining a pathologic response. More than 50% of patients with MIBC or regional lymph node involvement will develop metastatic disease following radical cystectomy. There is presently no clear consensus with regards to the routine use of adjuvant Cisplatin-based chemotherapy. Further, not all patients are eligible for adjuvant or neoadjuvant Cisplatin-based chemotherapy.
OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® has been shown to have antitumor activity in patients with metastatic urothelial carcinoma who had previously received platinum treatment, and is presently approved by the FDA for this patient group.
CheckMate 274 is a multicenter, double-blind, randomized, Phase III trial conducted to evaluate the efficacy and safety of adjuvant OPDIVO®, as compared with placebo, in patients with muscle-invasive urothelial carcinoma following radical surgery (with or without previous neoadjuvant Cisplatin-based combination chemotherapy). A total of 709 patients with muscle-invasive urothelial carcinoma who had undergone radical surgery were randomly assigned in a 1:1 ratio to receive either OPDIVO® 240 mg as a 30-minute IV infusion (N=353) or placebo (N=356), every 2 weeks for up to 1 year. To be eligible, patients must have had radical surgery (R0, with negative surgical margins), with or without neoadjuvant Cisplatin-based chemotherapy. Patients must have had pathological evidence of urothelial carcinoma (originating in the bladder, ureter or renal pelvis) with a high risk of recurrence defined as follows: pathological stage of pT3, pT4a, or pN+ and patients not eligible for or declined adjuvant Cisplatin-based combination chemotherapy, patients who had not received neoadjuvant Cisplatin-based chemotherapy, and pathological stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant Cisplatin. Both treatment groups were well balanced and approximately 40% of patients in both treatment groups had PD-L1 expression of 1% or more and 43% of patients had received previous neoadjuvant cisplatin therapy. The two Primary endpoints were Disease Free Survival (DFS) among all the patients, and among patients with a tumor Programmed Death-Ligand 1 (PD-L1) expression level of 1% or more. Secondary endpoints included Survival free from recurrence outside the urothelial tract, Overall Survival and Safety. The median follow up was 20.9 months among patients who received OPDIVO® and 19.5 months among those who received placebo.
The median DFS was 20.8 months in the OPDIVO® group and 10.8 months in the placebo group in the intention-to-treat population, which was nearly double that with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with OPDIVO® and 60.3% with placebo, in the intention-to-treat population (HR for disease recurrence or death=0.70; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage who were alive and disease-free at 6 months was 74.5% with OPDIVO® and 55.7% with placebo, in the Intention-to-Treat Population (HR=0.55; P<0.001). The subgroup analysis showed that there was a higher probability of DFS with OPDIVO® than with placebo, and this benefit was observed regardless of nodal status, PD-L1 status, or use or nonuse of previous neoadjuvant Cisplatin-based chemotherapy.
The median survival free from recurrence outside the urothelial tract, in the intention-to-treat population, was 22.9 months among patients who received OPDIVO® and 13.7 months with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77% with OPDIVO® and 62.7% with placebo (HR for recurrence outside the urothelial tract or death=0.72). Among those with a PD-L1 expression level of 1% or more, the percentage who were alive and free from recurrence outside the urothelial tract at 6 months was 75.3% and 56.7%, respectively (HR=0.55). Grade 3 or higher toxicities were noted in 17.9% of patients in the OPDIVO® group and 7.2% of patients in the placebo group.
It was concluded that among patients with high risk muscle-invasive urothelial carcinoma who had undergone radical surgery with curative intent, adjuvant treatment with OPDIVO® significantly improved Disease Free Survival, compared to placebo, in both intention-to-treat population and among patients with a PD-L1 expression level of 1% or more.
Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. Bajorin DF, Witjes JA, Gschwend JE, et al. N Engl J Med 2021;384:2102-2114.