BACKGROUND: Esophageal cancer is a leading cause of cancer-related mortality worldwide, with squamous-cell carcinoma (SCC) accounting for a majority of the cases. First-line chemotherapy is the standard of care for advanced esophageal SCC, but survival outcomes are poor. First-line combination immunotherapy with the PD-1 inhibitor nivolumab plus the CTLA-4 inhibitor ipilimumab led to longer overall survival (OS) than chemotherapy or nivolumab monotherapy in solid tumors.
METHODS: The CheckMate-648 study was a global, randomized, open-label, phase 3 study of 970 treatment-naïve patients with unresectable, advanced, recurrent, or metastatic esophageal SCC. Patients were randomized (1:1:1) to nivolumab (240 mg every 2 weeks) plus chemotherapy (consisting of 4 weeks of fluorouracil 800 mg/m2 on days 1-5 and cisplatin 80 mg/m2 on day 1); to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks); or to chemotherapy alone. Patients could receive nivolumab or nivolumab plus ipilimumab for a maximum of 2 years. The primary end points were OS and progression-free survival (PFS).
RESULTS: After a minimum follow-up of 13 months, the median OS was 15.4 months with nivolumab plus chemotherapy versus 9.1 months with chemotherapy alone (hazard ratio [HR], 0.54; P <.001) in patients with PD-L1 expression of ≥1%, as well as in the overall population, with a median OS of 13.2 months versus 10.7 months, respectively (HR, 0.74; P = .002). Similarly, the OS was significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with PD-L1 expression of ≥1% (median OS, 13.7 vs 9.1 months, respectively; HR, 0.64; P = .001), as well as in the overall population (12.7 vs 10.7 months; HR, 0.78; P = .01). Among patients with PD-L1 expression of ≥1%, the PFS was 6.9 months with nivolumab plus chemotherapy versus 4.4 months (HR, 0.6; P = .002) with chemotherapy alone, but not with the immunotherapy combination of nivolumab plus ipilimumab compared with chemotherapy alone. The safety profiles of these agents were consistent with their known profiles at similar doses. The rates of grade 3 or 4 treatment-related adverse events were 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. The researchers noted that first-line treatment of patients with advanced esophageal SCC with nivolumab plus chemotherapy or with nivolumab plus ipilimumab had a significant OS benefit and durable responses compared with chemotherapy alone.
Source: Doki Y, Ajani JA, Kato K, et al; for the CheckMate 648 trial investigators. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386:449-462.