FDA Approves Nivolumab in Combination With Chemotherapy and in Combination With Ipilimumab for First-Line Esophageal Squamous Cell Carcinoma Indications

Efficacy was evaluated in a randomized, active-controlled, open-label trial (CHECKMATE-648; NCT03143153) of 970 patients with previously untreated unresectable advanced, recurrent, or metastatic ESCC. Prior treatment with curative intent was allowed if patients completed it more than six months before enrolling in the trial. The trial excluded patients with symptomatic brain metastasis, with active autoimmune disease, receiving systemic corticosteroids or immunosuppressants, or at high risk for bleeding or fistula because of 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 per day via IV infusion on days 1–5 (for five days), and cisplatin 80 mg/m² via IV infusion on day 1 of a four-week cycle
• Nivolumab 3 mg/kg every two weeks in combination with ipilimumab 1 mg/kg every six weeks
• Fluorouracil 800 mg/m² per day via IV infusion on days 1–5 (for five days) and cisplatin 80 mg/m² via IV infusion on day 1 of a four-week cycle

The major efficacy outcome measures were overall survival (OS) and blinded independent central review (BICR)-assessed progression-free survival (PFS). The trial 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 intention-to-treat (ITT) population, OS results revealed:

• HR of the comparison nivolumab, fluorouracil, and cisplatin versus chemotherapy was 0.74 (95% CI = 0.61, 0.90; p = 0.0021).
• HR of the comparison of nivolumab and ipilimumab versus 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:

• HR for the comparison nivolumab, fluorouracil, and cisplatin versus chemotherapy alone was 0.54 (95% CI = 0.41, 0.71; p < 0.0001).
• HR of the comparison of nivolumab and ipilimumab versus chemotherapy was 0.64 (95% CI = 0.49, 0.84; p = 0.0010).

The most common adverse reactions occurring in 20% or more of 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 reported in 20% or more of 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 two weeks or 480 mg every four weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy; or 3 mg/kg every two weeks or 360 mg every three weeks with ipilimumab 1 mg/kg every six weeks.

View the full prescribing information for nivolumab (https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125554s106lbl.pdf).

The review was conducted under Project Orbis (https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis), an initiative of FDA’s Oncology Center of Excellence. 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, Health Canada, Israel’s Ministry of Health Pharmaceutical Administration, and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies.

The review 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 data submission prior to the filing of the entire clinical application, and the Assessment Aid (https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid), a voluntary submission from the applicant to facilitate FDA’s assessment.

Nivolumab was granted orphan drug designation for esophageal cancer.

Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine and 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 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).