FDA Approves Nivolumab in Combination With Chemotherapy for Metastatic Gastric Cancer and Esophageal Adenocarcinoma

Efficacy was evaluated in a randomized, multicenter, open-label trial (CHECKMATE-649; NCT02872116) of 1,581 patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. Patients received either nivolumab in combination with chemotherapy (n = 789) or chemotherapy alone (n = 792). Study treatment was administered in two different comparison regimens:

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

Programmed death-ligand 1 (PD-L1) combined positive score (CPS) was determined centrally using the Agilent/Dako PD-L1 IHC 28-8 pharmDx test. The main efficacy outcome measures, assessed in 955 patients with PD-L1 CPS of 5 or higher, were progression-free survival (PFS) assessed by blinded independent central review and overall survival (OS). The trial demonstrated a statistically significant improvement in PFS and OS for patients with PD-L1 CPS of 5 or higher. Median OS was 14.4 months (95% CI = 13.1, 16.2) in the nivolumab-plus-chemotherapy arm versus 11.1 months (95% CI = 10.0, 12.1) in the chemotherapy-alone arm (hazard ratio = 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 six months (95% CI = 5.6, 6.9) in the chemotherapy-alone arm (hazard ratio = 0.68; 95% CI = 0.58, 0.79; p < 0.0001).

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

The most common adverse reactions (≥ 20%) were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.

The recommended nivolumab doses are 360 mg every three weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every three weeks or 240 mg every two weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every two weeks.

View the full prescribing information for nivolumab (https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s091lbl.pdf).

FDA conducted the review under Project Orbis (https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis), an initiative of its Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with the Australian Therapeutic Goods Administration, Brazilian Health Regulatory Agency, Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.

FDA used the Real Time Oncology Review (https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review-pilot-program) pilot program, which streamlined the manufacturer’s data submission prior to filing of the entire clinical application, and Assessment Aid (https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid), a voluntary submission from the applicant to facilitate FDA’s assessment. FDA approved the application approximately five weeks ahead of its goal date.

The 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 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics). 

Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine or device to FDA’s MedWatch Reporting System (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm) or by calling 800-FDA-1088. 

For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate (https://www.fda.gov/about-fda/oncology-center-excellence/project-facilitate) at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov (mailto:OncProjectFacilitate@fda.hhs.gov).