On 6 March 2024, the US Food and Drug Administration (FDA) approved nivolumab (Opdivo, Bristol-Myers Squibb Company) in combination with cisplatin and gemcitabine for first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma (UC).
Efficacy was evaluated in CheckMate 901 (NCT03036098), a randomised, open-label study enroling 608 patients with previously untreated unresectable or metastatic UC. Patients were randomised (1:1) to receive either nivolumab in combination with cisplatin and gemcitabine up to 6 cycles followed by nivolumab alone for up to two years or cisplatin and gemcitabine up to 6 cycles. In both arms, patients discontinuing cisplatin were permitted to receive carboplatin. Randomisation was stratified by tumour PD-L1 expression and presence of liver metastasis.
The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS), assessed by blinded independent central review using RECIST v1.1.
Statistically significant benefits in both OS and PFS were demonstrated for nivolumab in combination with cisplatin and gemcitabine followed by nivolumab compared to cisplatin and gemcitabine alone. Median OS was 21.7 months (95% confidence interval [CI] 18.6, 26.4) for patients who received nivolumab in combination with cisplatin and gemcitabine and 18.9 months (95% CI 14.7, 22.4) for those who received cisplatin and gemcitabine alone (hazard ratio [HR] 0.78, 95% CI 0.63, 0.96; two-sided p-value = 0.0171). Median PFS was 7.9 months (95% CI 7.6, 9.5) and 7.6 months (95% CI 6.0, 7.8), respectively (HR 0.72, 95% CI 0.59, 0.88; two-sided p-value = 0.0012).
The most common adverse reactions (≥15%) in patients receiving nivolumab with platinum-doublet chemotherapy were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, peripheral neuropathy, urinary tract infection, diarrhoea, oedema, hypothyroidism, and pruritis.
The recommended nivolumab dose for this indication is:
- 360 mg every 3 weeks in combination with cisplatin and gemcitabine every 3 weeks for up to 6 cycles followed by
- 240 mg every 2 weeks or 480 mg every 4 weeks as a single agent until disease progression, unacceptable toxicity, or a maximum treatment of 2 years from first dose.
This review was conducted under Project Orbis, an initiative of the FDA’s Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Swissmedic. The application reviews are ongoing at the other regulatory agencies.
This review used the Real-Time Oncology Review pilot programme, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review.
Healthcare professionals should report all serious adverse events suspected to be associated with any medicine and device to FDA’s MedWatch Reporting System.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate.