FDA Approves Adjuvant Nivolumab for Surgically Resected, High-Risk Bladder Cancer

The FDA has granted approval to nivolumab (Opdivo) as an adjuvant treatment for patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement or PD-L1 status, according to a press release issued by Bristol Myers Squibb.¹ 

Approval was granted based on the first positive phase 3 trial of an immunotherapy in the adjuvant setting of surgically-resected, high-risk MIUC, CheckMate-274 (NCT02632409), which investigated nivolumab versus placebo in randomized, double-blind, multicenter fashion. 

“This approval is a major milestone for patients who have undergone major surgery to remove the bladder or parts of the urinary tract and are in need of additional treatment approaches that can help reduce the risk of their UC returning,” said Matthew D. Galsky, MD, a CheckMate -274 primary investigator and professor of Medicine, director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, and associate director for Translational Research at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, in a press release. “Nivolumab provides a new FDA-approved treatment shown to reduce the risk of disease recurrence or death based on the safety and efficacy findings from CheckMate -274, and has the potential to become a new standard of care option in this setting.”

In the study, adjuvant nivolumab achieved a statistically significant and clinically meaningful improvement in disease-free survival compared with placebo in patients with MIUC treated in both the intention-to-treat (ITT) population as well as in the subgroup with a PD-L1 ≥ 1%, meeting its co primary and end point.^2,3

Patients in the study were randomized 1:1 after radical surgery to receive nivolumab 240 mg administered once every 2 weeks or placebo for up to 1 year of adjuvant treatment. Overall, 353 patients were treated with nivolumab and 356 received placebo. The secondary end point was non-urothelial tract recurrence-free survival (NUTRFS), disease-specific survival (DSS), and overall survival (OS). The exploratory end points of the study were distant-metastasis-free survival (DMFS), safety, and health-related quality-of-life.

Results from CheckMate-274 were most recently presented with the 2021 Genitourinary Cancers Symposium. In the ITT population, the median DFS was 21.0 months in those treated with nivolumab compared with 10.9 months among those given placebo (HR, 0.70; 98.31% CI, 0.54-0.89; P < .001) at a median follow-up of 20.8 months for the nivolumab arm versus 19.5 months in the placebo arm. 

A total of 140 patients in the study were positive for PD-L1 expression and in these patients, the median DFS not reached) in the immunotherapy arm versus 10.8 months in the placebo arm (HR, 0.53; 98.87% CI, 0.34-0.84; P < .001), showing a 47% reduction in the risk of disease recurrence or death with nivolumab.

The findings related to the secondary end points were also presented showing that in the ITT population, the median NUTRFS was 24.6 months in the nivolumab arm versus 13.7 months in the placebo group (HR, 0.72; 95% CI, 0.58-0.89). Among patients with PD-L1–positive tumors, the median NUTRFS in those treated with nivolumab was not reached compared with 10.9 months in the placebo arm (HR, 0.54; 95% CI, 0.38-0.77).

The median DMFS observed with adjuvant nivolumab in the ITT population was 35.0 months versus 29.0 months in the placebo arm (HR, 0.74; 95% CI, 0.58-0.93). In the PD-L1–positive group, the median DMFS was NR in those treated with nivolumab compared with 21.2 months in those who received placebo (HR, 0.60; 95% CI, 0.41-0.88).

Nivolumab display a safety profile in CheckMate-274 that was consistent with previous reports in other cancers, including in patients with metastatic UC. Overall, adverse events (AEs) were observed in 98.9% of patients in the nivolumab arm compared with 95.4% in the placebo arm. The AEs observed were grade 3 or higher for 42.7% of patients who were treated with nivolumab versus 36.8% of the placebo arm. 

Any-grade treatment-related AEs were observed in 77.5% of the nivolumab arm versus 55.5% in the placebo arm, and grade 3 or higher TRAEs occurred in 17.9% of patients versus 7.2% of patients, respectively. Moreover, any-grade TRAEs led to treatment discontinuation in 12.8% of the nivolumab-treated population versus 2.0% of the placebo arm, and grade 3 or higher TRAEs led to treatment discontinuation in 7.1% of the nivolumab arm compared with 1.4% of the placebo arm.

“At Bristol Myers Squibb, our leading research in immunotherapy has helped transform the way many cancers are treated, and we are continuing to bring these advancements to patients with earlier stages of disease, particularly in challenging cancers with significant unmet need,” said Adam Lenkowsky, senior vice president and general manager, US Cardiovascular, Immunology and Oncology, Bristol Myers Squibb, in a press release. “UC is the third type of cancer where Opdivo has been the first approved PD-1 inhibitor in the adjuvant setting. Now with this advancement, we can offer new hope to the conversations between healthcare providers and their UC patients where historically no approved treatment options have existed to help prevent disease recurrence post-surgery.”

_References

_{1. U.S. Food and Drug Administration approves Opdivo® (nivolumab) for the adjuvant treatment of patients with high-risk urothelial carcinoma. News release. August 20, 2021. Accessed August 20, 2021. https://bit.ly/3kahSaH}

_{2. Adjuvant treatment with Opdivo (nivolumab) demonstrates statistically significant and clinically meaningful improvement in disease-free survival in patients with muscle-invasive urothelial carcinoma in phase 3 CheckMate -274 trial. News release. February 8, 2021. Accessed July 21, 2021. https://bit.ly/3xVVSWJ} 

_{3. Bajorin DF, Wijes JA, Gschwend J. et al . Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021. 384(22):2102-2114. doi: 10.1056/NEJMoa2034442.}