On May 27, 2022, the U.S. Food and Drug Administration (FDA) approved the following for the first-line treatment of patients with advanced or metastatic esophageal squamous cell carcinoma:
- Nivolumab (Opdivo) in combination with fluoropyrimidine- and platinum-based chemotherapy
- Nivolumab in combination with ipilimumab.
CheckMate 648
Efficacy was evaluated in CheckMate 648 (ClinicalTrials.gov identifier: NCT03143153), a randomized, active-controlled, open-label trial in 970 patients with previously untreated, unresectable, advanced recurrent or metastatic esophageal squamous cell carcinoma. Prior treatment with curative intent was allowed if it was completed more than 6 months before trial enrollment. The trial excluded patients with brain metastasis that was symptomatic, those with active autoimmune disease, those 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 assigned (1:1:1) to receive one of the following treatments:
- Nivolumab at 240 mg on days 1 and 15, fluorouracil at 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 at mg/m2 intravenously on day 1 (of a 4-week cycle)
- Nivolumab at 3 mg/kg every 2 weeks in combination with ipilimumab at 1 mg/kg every 6 weeks
- Fluorouracil at 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin at 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
The major efficacy outcome measures were overall survival and blinded independent central review–assessed progression-free survival.
Results
CheckMate 648 demonstrated statistically significant improvements in overall survival in all randomly assigned patients and in the subpopulation with tumor cell PD-L1 ≥ 1% for both nivolumab-containing regimens when individually compared to chemotherapy.
In the intention-to-treat (ITT) population (all patients randomly assigned), overall survival results revealed:
- The hazard ratio of the comparison nivolumab, fluorouracil, and cisplatin vs chemotherapy was 0.74 (95% confidence interval [CI] = 0.61–0.90, P = .0021)
- The hazard ratio of the comparison of nivolumab and ipilimumab vs chemotherapy was 0.78 (95% CI = 0.65–0.95, P = .0110).
In the ITT population, the median overall survival was 13.2 months (95% CI = 11.1–15.7 months) in the nivolumab, fluorouracil, and cisplatin arm; 12.8 months (95% CI = 11.3–15.5 months) in the nivolumab and ipilimumab arm; and 10.7 months (95% CI = 9.4–11.9 months) in the fluorouracil and cisplatin arm.
In the tumor cell PD-L1 ≥ 1% population, overall survival results revealed:
- The hazard ratio of the comparison nivolumab, fluorouracil, and cisplatin vs chemotherapy alone was 0.54 (95% CI = 0.41–0.71, P < .0001)
- The hazard ratio of the comparison of nivolumab and ipilimumab vs chemotherapy was 0.64 (95% CI = 0.49–0.84, P = .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 at 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, Health Canada, Israel’s Ministry of Health Pharmaceutical Administration, and Switzerland’s Swissmedic. The application reviews may be 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.
Nivolumab was granted Orphan Drug designation for esophageal cancer.
