Long Term Disease Free Survival Benefits with Adjuvant OPDIVO® in Urothelial Carcinoma

SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 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 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-analyses 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, as well as adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection.

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. The mean age was 65.3 years and both treatment groups were well balanced. 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 NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival (DMFS), Overall Survival and Safety.

The authors in this publication reported the DFS outcomes, with 5 additional months of follow up, in all randomized patients. Patients with high-risk, muscle-invasive urothelial carcinoma continued to experience clinically meaningful improvements in Disease Free Survival (DFS), with a median DFS of 22.0 months among those receiving OPDIVO® (95% CI, 17.7-36.9) compared with 10.9 months (95% CI, 8.3-14.0) among those receiving placebo (HR=0.70; 95% CI, 0.57-0.85). The DFS probability at 12 months was 63.5% with OPDIVO® versus 46.9% with placebo. The DFS benefit was even more significant in patients with PD-L1 expression of 1% or more and was Not Reached in the OPDIVO® group versus 8.4 months in the placebo group (HR, 0.53; 95% CI, 0.38-0.75). The DFS probability at 12 months was 67.6% with OPDIVO® versus 46.3% with placebo. The DFS benefits was observed with OPDIVO® among most subgroups analyzed, including age, sex, ECOG PS, nodal status and use of prior Cisplatin-based chemotherapy.

NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival (DMFS) were also improved with OPDIVO® when compared to placebo, both in all randomized patients, as well as patients with PD-L1 expression of 1% or more.

It was concluded that with longer follow up, OPDIVO® continued to show clinically meaningful improvement in Disease Free Survival among patients with high-risk muscle-invasive urothelial carcinoma, when compared to placebo, both in all randomized patients, as well as patients with PD-L1 expression of 1% or more. OPDIVO® also improved NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival when compared to Placebo. The authors added that these results support adjuvant OPDIVO® as a Standard of Care for high risk muscle-invasive urothelial carcinoma patients after radical surgery.

Galsky M, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the CheckMate 274 trial of adjuvant nivolumab in patients after surgery for high-risk muscle-invasive urothelial carcinoma. J Urol. 2022;207(suppl 5):e183. doi:10.1097/JU.0000000000002536.01