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The European Medicines Agency has validated its type II variation application for nivolumab as an adjuvant treatment for patients with surgically resected, high-risk muscle-invasive urothelial carcinoma.
The European Medicines Agency has validated its type II variation application for nivolumab (Opdivo) as an adjuvant treatment for patients with surgically resected, high-risk muscle-invasive urothelial carcinoma (MIUC), according to an announcement from Bristol Myers Squibb.1
The application is based on data from the phase 3 CheckMate-274 trial (NCT02632409), which showed that when nivolumab was given after surgery, patients with MIUC experienced an improvement in disease-free survival (DFS).2
Specifically, the median DFS achieved with adjuvant nivolumab in the intent-to-treat (ITT) population was 21.0 months vs 10.9 months with placebo (HR, 0.70; 98.31% CI, 0.54-0.89; P <.001). The immunotherapy also improved DFS in the subset of patients with PD-L1 positivity. The median DFS with adjuvant nivolumab had not yet been reached vs 10.8 months with placebo (HR, 0.53; 98.87% CI, 0.34-0.84; P <.001).
“Even patients who appear disease free after radical surgery for MIUC are at a high risk for recurrence, with around half of patients having their cancer return,” Dana Walker, MD, MSCE, vice president, development program lead, genitourinary cancers, at Bristol Myers Squibb, stated in the press release. “In the CheckMate-274 trial, [nivolumab] significantly reduced the risk of cancer recurrence or death, showing its potential to help address the need for safe and effective treatment options for this patient population.”
In the double-blind CheckMate-274 trial, investigators examined the efficacy and safety of adjuvant nivolumab compared with placebo in patients with high-risk MIUC following radical surgery. A total of 709 patients were randomized in a 1:1 fashion to receive either nivolumab at 240 mg once every 2 weeks (n = 353) or placebo (n = 356) for up to 1 year of adjuvant treatment.
To be eligible for enrollment, patients had to undergo radical surgery within 120 days with or without neoadjuvant cisplatin or they had to be ineligible for or have declined cisplatin-based chemotherapy; they also needed to be disease free per imaging.
The primary end point of the trial was DFS in the ITT population, as well as in those with a PD-L1 expression of 1% or higher. The median follow-up was 20.9 months for the immunotherapy and 19.5 months for placebo. Moreover, 53.3% of those in the investigative arm discontinued treatment vs 56.3% of those in the control arm. The most common reason for discontinuation was recurrent disease.
Among those who received adjuvant nivolumab, 79% had the tumor of origin be urinary bladder carcinoma, while 21% had upper tract disease. Among those given placebo, 78.9% had the tumor of origin be urinary bladder, while 21.1% had upper tract disease. Approximately 40% of patients in both arms had PD-L1 positivity and 43% previously received cisplatin-based neoadjuvant chemotherapy.
Additional results from a subgroup analysis of the ITT population indicated no differences with regard to age, sex, region, or performance status with regard to DFS benefit achieved with adjuvant nivolumab.
Nivolumab was also found to improve the median non–urothelial tract recurrence-free survival (NUTRFS) and distant metastasis-free survival in both the ITT and PD-L1–positive patient populations. Specifically, the NUTRFS in the ITT population was 24.6 months with adjuvant nivolumab vs 13.7 months with placebo (HR, 0.72; 95% CI, 0.58-0.89). The NUTRFS in the PD-L1–positive subgroup was not reached vs 10.9 months in the investigative and control arms, respectively (HR, 0.54; 95% CI, 0.38-0.77).
Regarding safety, data reported with nivolumab proved to be consistent with previously reported data with the agent in patients with solid tumors. Treatment-related adverse effects (TRAEs) that were grade 3 or higher in severity were reported in 17.9% of those in the nivolumab arm vs 7.2% of those in the placebo arm.
Any-grade TRAEs that resulted in treatment discontinuation were reported in 12.8% and 2% of patients in the investigative and control arms, respectively. The most frequently reported TRAEs in those who received adjuvant nivolumab included pruritis, fatigue, diarrhea, and rash.
“We look forward to working with the EMA toward the goal of bringing the first adjuvant immunotherapy option to patients with MIUC in the European Union,” added Walker in the release.
In July 2015, nivolumab was the first PD-1 inhibitor to receive regulatory approval anywhere in the world. The agent is approved in over 65 countries, including the United States, the European Union, Japan, and China. In October 2015, nivolumab was approved for use in combination with ipilimumab (Yervoy) for the treatment of patients with metastatic melanoma; it is approved in over 50 countries for this indication.