FDA Approves Nivolumab in Combination with Cisplatin and Gemcitabine for Unresectable or Metastatic Urothelial Carcinoma

March 7, 2024

The following is a message from the Director of the FDA Oncology Center of Excellence, Dr. Richard Pazdur:

On March 6, 2024, the Food and Drug Administration 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).

Full prescribing information for Opdivo will be posted here.

Efficacy was evaluated in CHECKMATE-901 (NCT03036098), a randomized, open-label trial enrolling 608 patients with previously untreated unresectable or metastatic UC. Patients were randomized (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). On both arms, patients discontinuing cisplatin were permitted to receive carboplatin. Randomization was stratified by tumor 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% 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, diarrhea, edema, 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 Oncology Center of Excellence. 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 (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies. 

This review used the Real-Time Oncology Review (RTOR) pilot program, 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. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

Follow the Oncology Center of Excellence on X (formerly Twitter) @FDAOncology