FDA Grants Priority Review to Adjuvant Nivolumab for Muscle-Invasive Urothelial Carcinoma

The FDA has granted a priority review designation to a supplemental biologics license application for nivolumab (Opdivo) for use as an adjuvant treatment in patients with surgically resected, high-risk, muscle-invasive urothelial carcinoma.¹

The decision was based on data from the phase 3 CheckMate-274 trial (NCT02632409), which demonstrated that giving the PD-1 inhibitor after surgery resulted in improved disease-free survival (DFS) in this patient population.² This is the first positive phase 3 trial of an immunotherapy in this setting, according to Bristol Myers Squibb.

Results indicated that adjuvant nivolumab nearly doubled the median DFS in the intent-to-treat (ITT) population vs placebo, at 21.0 months vs 10.9 months, respectively (HR, 0.70; 98.31% CI, 0.54-0.89; P <.001). A subset of patients with PD-L1–positive disease also experienced an improvement in DFS vs placebo. The median DFS had not yet been reached in the investigative arm, while it was 10.8 months in the control arm (HR, 0.53; 98.87% CI, 0.34-0.84; P <.001).

Under the Prescription Drug User Fee Act, the FDA must make a decision on the application by September 3, 2021. If approved, the PD-1 inhibitor will be the first adjuvant immunotherapy option available to patients with this disease in the United States.

“After patients undergo surgery for muscle-invasive urothelial carcinoma, they continue to face uncertainties given the high rate of disease recurrence and the lack of safe and effective treatment options,” Dana Walker, MD, MSCE, vice president, development program lead, genitourinary cancers, at Bristol Myers Squibb, stated in a press release. “Based on the groundbreaking DFS results from CheckMate-274, we believe [nivolumab] has the potential to change the future of treatment for muscle-invasive urothelial carcinoma.”

CheckMate-274 evaluated the safety and efficacy of adjuvant nivolumab vs placebo in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery. The trial enrolled 709 patients who were randomized 1:1 to nivolumab at 240 mg once every 2 weeks (n = 353) or placebo (n = 356) for up to 1 year of adjuvant treatment.

Patients must have undergone radical surgery within 120 days with or without neoadjuvant cisplatin or that they must not have been eligible for, or declined, cisplatin-based chemotherapy. Patients also needed to be free of disease on imaging.

The primary end point of the trial was DFS in the ITT population and those with a PD-L1 expression of 1% or higher. For nivolumab, the median follow-up was 20.9 months, while it was 19.5 months for placebo. Additionally, 53.3% and 56.3% of patients in the investigative and control arms discontinued treatment, respectively. Recurrence was the most frequently cited reason for discontinuation.

In the investigative arm, 79% had their tumor of origin be urinary bladder carcinoma and 21% had upper tract disease; in the control arm, these rates were 78.9% and 21.1%, respectively. About 40% of patients in both treatment arms had PD-L1–positive disease and just under half, or 43%, had prior neoadjuvant cisplatin-based chemotherapy.

Notably, no differences in DFS benefit with nivolumab were reported in a subgroup analysis of the ITT population, regardless of age, sex, or performance status.

The PD-1 inhibitor also improved the median non–urothelial tract recurrence-free survival (NUTRFS) and distant metastasis-free survival in the ITT population and the subgroup of patients with PD-L1 positivity. In the ITT population, the NUTRFS with adjuvant nivolumab was 24.6 months, while it was 13.7 months with placebo (HR, 0.72; 95% CI, 0.58-0.89). In the subgroup of patients with PD-L1–positive disease, the NUTRFS was not reached with the PD-1 inhibitor vs 10.9 months with placebo (HR, 0.54; 95% CI, 0.38-0.77).

Safety findings with nivolumab were consistent with prior data of the agent in patients with solid tumors. Results indicated that 17.9% of patients in the adjuvant nivolumab arm had treatment-related adverse effects (TRAEs) compared with 7.2% of those on the placebo arm.

Additionally, 12.8% and 2% of patients on the investigative and control arms, respectively, experienced any-grade TRAEs. Pruritis, fatigue, diarrhea, and rash, were among the most commonly experienced TRAEs in the adjuvant nivolumab arm.

In March 2021, the European Medicines Agency validated a type II variation application for nivolumab as an adjuvant treatment for patients with surgically resected, high-risk muscle-invasive urothelial carcinoma based on data from CheckMate-274.

Previously, in July 2014, nivolumab was the first PD-1 inhibitor to received regulatory approval anywhere in the world. The agent is now approved for use in over 65 countries. The immunotherapy agent was given the green light in October 2015 for use in combination with ipilimumab (Yervoy) in patients with metastatic melanoma and this indication has since been approved in over 50 countries.

References

1. US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Opdivo (nivolumab) as adjuvant treatment for patients with muscle-invasive urothelial carcinoma. News release. Bristol Myers Squibb. April 30, 2021. Accessed April 30, 2021. https://bit.ly/2R9Swic
2. Bajorin DF, Witjes JA, Gschwend J, Schenker M. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). J Clin Oncol. 2021;39(suppl 6):391. doi:10.1200/JCO.2021.39.6_suppl.391