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

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On March 6, the U.S. Food and Drug Administration (FDA) approved the PD-1 inhibitor nivolumab (Opdivo) in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma.

CheckMate 901

Efficacy was evaluated in CheckMate 901 ( identifier NCT03036098), a randomized, open-label trial enrolling 608 previously untreated patients with unresectable or metastatic urothelial carcinoma. Patients were randomly assigned 1:1 to receive either nivolumab in combination with cisplatin and gemcitabine (for up to 6 cycles) followed by nivolumab alone for up to 2 years or cisplatin and gemcitabine (up to 6 cycles). On both arms, patients discontinuing cisplatin were permitted to receive carboplatin. Random assignment was stratified by tumor PD-L1 expression and presence of liver metastasis.

The major efficacy outcome measures were overall survival and progression-free survival, assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1.

Statistically significant benefits in both overall survival and progression-free survival were demonstrated for nivolumab in combination with cisplatin and gemcitabine followed by nivolumab compared to cisplatin and gemcitabine alone. Median overall survival was 21.7 months (95% CI = 18.6–26.4 months) for patients who received nivolumab in combination with cisplatin and gemcitabine and 18.9 months (95% CI = 14.7–22.4 months) for those who received cisplatin and gemcitabine alone (hazard ratio [HR] = 0.78, 95% CI = 0.63–0.96, two-sided P = .0171). Median progression-free survival was 7.9 months (95% CI = 7.6–9.5 months) and 7.6 months (95% CI = 6.0–7.8 months), respectively (HR = 0.72, 95% CI = 0.59–0.88, two-sided P = .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 six 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 that provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review 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 also granted Priority Review.