The following is a message from the Director of the FDA Oncology Center of Excellence, Dr. Richard Pazdur:
On May 27, 2022, the Food and Drug Administration approved the following for the first-line treatment of patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC):
- nivolumab (Opdivo, Bristol-Myers Squibb Company) in combination with fluoropyrimidine- and platinum-based chemotherapy, and
- nivolumab in combination with ipilimumab (Yervoy, Bristol-Myers Squibb Company).
Efficacy was evaluated in CHECKMATE-648 (NCT03143153), a randomized, active-controlled, open-label trial in 970 patients with previously untreated unresectable advanced, recurrent or metastatic ESCC. Prior treatment with curative intent was allowed if completed more than six months before trial enrolment. The trial excluded patients with brain metastasis that were symptomatic, active autoimmune disease, receiving systemic corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to apparent invasion of tumor to organs adjacent to the esophageal tumor. Patients were randomly allocated (1:1:1) to receive one of the following treatments:
- nivolumab 240 mg on days 1 and 15, fluorouracil 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
- nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks.
- fluorouracil 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
The major efficacy outcome measures were overall survival (OS) and blinded independent central review (BICR)-assessed progression-free survival (PFS). CHECKMATE-648 demonstrated statistically significant improvements in OS in all randomized patients and in the subpopulation with tumor cell (TC) PD-L1 ≥1% for both nivolumab-containing regimens when individually compared to chemotherapy.
In the ITT population (all patients randomized) OS results revealed:
- The HR of the comparison nivolumab, fluorouracil, and cisplatin vs. chemotherapy was 0.74 (95% CI 0.61, 0.90; p=0.0021).
- The HR of the comparison of nivolumab and ipilimumab vs. chemotherapy was 0.78 (95% CI 0.65, 0.95; p=0.0110).
In the ITT population, the median OS was 13.2 months (95% CI: 11.1, 15.7) in the nivolumab, fluorouracil, and cisplatin arm, 12.8 months (95% CI: 11.3, 15.5) in the nivolumab and ipilimumab arm, and 10.7 months (95% CI: 9.4, 11.9) in the fluorouracil and cisplatin arm.
In the TC PD-L1 ≥1% population OS results revealed:
- The HR for the comparison nivolumab, fluorouracil, and cisplatin vs. chemotherapy alone was 0.54 (95% CI: 0.41, 0.71; p<0.0001).
- The HR of the comparison of nivolumab and ipilimumab vs. chemotherapy was 0.64 (95% CI: 0.49, 0.84; p=0.0010).
The most common adverse reactions (≥20%) occurring in patients treated with nivolumab and fluoropyrimidine- and platinum-containing chemotherapy in CHECKMATE-648 were nausea, decreased appetite, fatigue, constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions (≥20%) occurring in patients treated with nivolumab and ipilimumab in CHECKMATE-648 were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.
The recommended nivolumab dose is:
- 240 mg every 2 weeks or 480 mg every 4 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy, or
- 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks.
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), Health Canada, and Switzerland’s Swissmedic. The application reviews may be 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.
Nivolumab was granted orphan drug designation for esophageal cancer.
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 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)
Please visit the FDA Hematology/Oncology (Cancer) Approvals & Safety Notifications webpage for a list of current and past approvals.