On April 16, 2021, the Food and Drug Administration approved nivolumab (Opdivo, Bristol-Myers Squibb Company) in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

Efficacy was evaluated in CHECKMATE-649 (NCT02872116), a randomized, multicenter, open-label trial that enrolled 1,581 patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. PD-L1 combined positive score (CPS) was determined centrally using the Agilent/Dako PD-L1 IHC 28-8 pharmDx test. Patients received nivolumab in combination with chemotherapy (n=789) or chemotherapy alone (n=792); study treatment was administered as follows:

• Nivolumab 240 mg with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks, or mFOLFOX6 every 2 weeks.
• Nivolumab 360 mg with CapeOX (capecitabine and oxaliplatin) every 3 weeks, or CapeOX every 3 weeks.

The main efficacy outcome measures, assessed in patients with PD-L1 CPS ≥5 (n=955), were progression-free survival (PFS) assessed by blinded independent central review and overall survival (OS). CHECKMATE-649 demonstrated a statistically significant improvement in PFS and OS for patients with PD-L1 CPS ≥5. Median OS was 14.4 months (95% CI: 13.1, 16.2) in the nivolumab plus chemotherapy arm vs. 11.1 months (95% CI: 10.0, 12.1) in the chemotherapy alone arm (HR 0.71; 95% CI: 0.61, 0.83; p<0.0001). Median PFS was 7.7 months (95% CI: 7.0, 9.2) in the nivolumab plus chemotherapy arm versus 6.0 months (95% CI: 5.6, 6.9) in the chemotherapy alone arm (HR 0.68; 95% CI: 0.58, 0.79; p<0.0001).

As an additional efficacy outcome measure, a statistically significant improvement in OS was also demonstrated for all randomized patients (n=1,581) irrespective of CPS, with a median OS of 13.8 months (95% CI: 12.6, 14.6) in the nivolumab plus chemotherapy arm vs. 11.6 months (95% CI: 10.9, 12.5) in the chemotherapy alone arm (HR 0.80; 95% CI: 0.71, 0.90; p=0.0002).

The most common adverse reactions (incidence ≥20%) observed in patients receiving nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.

The recommended nivolumab dosages are:

• 360 mg every 3 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks.
• 240 mg every 2 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks.

View full prescribing information for Opdivo.

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. The FDA approved this application approximately 5 weeks ahead of the FDA goal date.

This application was granted priority review and orphan drug designation. A description of FDA expedited programs is 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.

For information on the COVID-19 pandemic, see the following resources:

• FDA: Coronavirus Disease 2019 (COVID-19)
• NCI: Coronavirus: What People With Cancer Should Know
• CDC: Coronavirus (COVID-19)

Follow the Oncology Center of Excellence on Twitter @FDAOncology.