Table 3:

Benefit-Risk Assessment

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	Bladder cancer is the 6th leading cause of mortality from cancer in the US. In the United States in 2024, the incidence and mortality of bladder were 83,190 and 16,840, respectively. About 30% of patients with newly diagnosed bladder cancer have muscle invasive disease; 20-25% of patients with NMIBC will progress to MIBC as part of the natural history of their disease. Recurrences after RC are common, with up to 45% of patients developing metastatic disease within 3 years.	Patients with MIBC are at high risk of recurrence after RC and have a serious and life-threatening condition.
Current Treatment Options	The current standard-of-care treatment options for patients with stage II-IIIA MICB are: Neoadjuvant cisplatin-based combination chemotherapy followed by RC, or Bladder preservation with concurrent chemoradiotherapy and maximal TURBT In the adjuvant setting, patients can receive cisplatin-based chemotherapy if they have residual disease at the time of cystectomy (pT3-4 or N+) and did not receive neoadjuvant cisplatin-based chemotherapy. FDA approved nivolumab in 2021 as an adjuvant treatment for patients with high-risk bladder cancer (pT2-pT4a or ypN+ in patients with neoadjuvant or pT3-pT4a in patients without neoadjuvant) based on the results of CHECKMATE-274 trial and improved DFS.	There are no current FDA-approved peri-operative treatment options for patients with MIBC and, as of the current status of CHECKMATE-274, no adjuvant therapies that have demonstrated improved OS. Due to the high recurrence rate and mortality of patients with MIBC even after neoadjuvant and adjuvant treatments, effective and tolerable FDA-approved treatment options are needed.
Benefit	NIAGARA was a randomized, open-label trial evaluating durvalumab plus gemcitabine and cisplatin in the neoadjuvant setting followed by adjuvant durvalumab vs cisplatin plus gemcitabine in patients with stage II-IIIA MIBC. The trial met its dual primary endpoint. EFS per BICR in ITT population at IA-2 had a HR 0.68 (95% CI: 0.558 – 0.817, p < 0.0001). Median EFS was not reached in the GC-D arm compared with 46.1 months in the GC arm. The IA of OS (28.7% maturity) demonstrated a statistically significant improvement in OS with a HR of 0.75 (95% CI: 0.594 - 0.934, p = 0.0106). Median OS had not been reached for either treatment arm.	The observed EFS and OS improvements in the NIAGARA trial are statistically significant and clinically meaningful to patients with MIBC who are cisplatin-eligible and candidates for RC.
Risk and Risk Management	Durvalumab was well-tolerated in most study patients with an acceptable safety profile. No new adverse reactions were identified, and no changes were made to the labeled warnings and precautions for durvalumab. No REMS will be required for this application. The most common adverse reactions (≥ 20% of patients) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, diarrhea, pyrexia, and abdominal pain.	The risk-benefit profile of nivolumab is acceptable in the approved patient population

Source: FDA’s multi-disciplinary review (U.S. FDA. Clinical Review–BLA 761069, supplements 050; not public).

MIBC: Muscle invasive bladder cancer, NMIBC: Non-muscle invesive bladder cancer, RC: radical cystectomy, TURBT: Transurethral resection of bladder tumor, EFS: event free survival, OS: overal survival, IA: interim analysis, REMS: risk evaluation and mitigation strategy