June 2022: For the first-line therapy of individuals with advanced or metastatic esophageal squamous cell carcinoma (ESCC), the Food and Drug Administration has approved the following:
In combination with fluoropyrimidine- and platinum-based chemotherapy, nivolumab (Opdivo, Bristol-Myers Squibb Company) and a combination of nivolumab and ipilimumab (Yervoy, Bristol-Myers Squibb Company)
Efficacy was assessed in 970 patients with previously untreated unresectable advanced, recurrent, or metastatic ESCC in the CHECKMATE-648 (NCT03143153) randomised, active-controlled, open-label trial. Prior curative treatment was permitted if finished more than six months prior to study enrolment. Those with symptomatic brain metastases, active autoimmune illness, receiving systemic corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to evident tumour invasion to organs adjacent to the esophageal tumour were excluded from the study. Patients were assigned to one of the following treatments at random (1:1:1):
240 mg nivolumab intravenously on days 1 and 15, 800 mg/m2/day fluorouracil intravenously on days 1 through 5 (for 5 days), and 80 mg/m2 cisplatin intravenously on day 1 (of a 4-week cycle).
Nivolumab 3 mg/kg every two weeks, and ipilimumab 1 mg/kg every six weeks
On days 1 through 5 (for 5 days), fluorouracil 800 mg/m2/day intravenously, and cisplatin 80 mg/m2 intravenously (of a 4-week cycle).
Overall survival (OS) and progression-free survival as judged by a blinded independent central review (BICR) were the main efficacy outcome measures (PFS). When both nivolumab-containing regimens were separately compared to chemotherapy, CHECKMATE-648 revealed statistically significant increases in OS in all randomised participants and in the subpopulation with tumour cell (TC) PD-L1 1%.
OS results in the ITT group (all participants randomised) revealed:
Nivolumab, fluorouracil, and cisplatin had an HR of 0.74 (95 percent CI 0.61, 0.90; p=0.0021) when compared to chemotherapy.
When nivolumab and ipilimumab were compared to chemotherapy, the HR was 0.78 (95 percent CI 0.65, 0.95; p=0.0110).
In the ITT group, the median OS for the nivolumab, fluorouracil, and cisplatin arm was 13.2 months (95 percent CI: 11.1, 15.7), 12.8 months (95 percent CI: 11.3, 15.5) for the nivolumab and ipilimumab arm, and 10.7 months (95 percent CI: 9.4, 11.9) for the fluorouracil and cisplatin arm.
The OS results in the TC PD-L1 1% population revealed:
Nivolumab, fluorouracil, and cisplatin had an HR of 0.54 (95 percent confidence interval: 0.41, 0.71; p0.0001) when compared to treatment alone.
When nivolumab and ipilimumab were compared to chemotherapy, the HR was 0.64 (95 percent CI: 0.49, 0.84; p=0.0010).
Nausea, decreased appetite, lethargy, constipation, stomatitis, diarrhoea, and vomiting were the most prevalent adverse events (20%) in patients treated with nivolumab with fluoropyrimidine- and platinum-containing treatment in CHECKMATE-648. Rashes, lethargy, pyrexia, nausea, diarrhoea, and constipation were the most prevalent adverse events (20%) in individuals treated with nivolumab plus ipilimumab in CHECKMATE-648.
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.