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.
Commentary by Robert J. Ignoffo
The anti–PD-1 monoclonal antibody nivolumab has been shown to result in a significantly longer OS than chemotherapy alone in the treatment of advanced esophageal SCC.1 It is currently approved by the FDA for the treatment of recurrent or metastatic esophageal SCC after chemotherapy, irrespective of PD-L1 expression. This phase 3 study assessed the combination of nivolumab with chemotherapy or with another immunotherapy versus chemotherapy (fluorouracil and cisplatin) alone in advanced esophageal SCC.
In the CheckMate-648 trial, first-line treatment with nivolumab plus chemotherapy and nivolumab plus ipilimumab resulted in significantly longer OS than chemotherapy alone in patients with advanced esophageal SCC, with no new safety signals identified. The median OS with nivolumab plus chemotherapy in the overall patient population and in those with tumor-cell PD-L1 expression of ≥1% exceeded 1 year, with patients surviving 2 to 6.3 months longer with the nivolumab-containing regimen than with chemotherapy alone. At 1 year, survival was between 10% and 21% higher in patients who received a nivolumab-containing regimen than those who received chemotherapy alone.
The objective responses were also higher in the nivolumab plus chemotherapy and nivolumab plus ipilimumab groups than the chemotherapy-alone group, regardless of PD-L1 expression. Complete responses were 2- to 4-fold higher in the 2 nivolumab-containing groups as well. Adverse events were highest with nivolumab plus chemotherapy and lowest with nivolumab plus ipilimumab.
Other PD-1 inhibitors are also active in this disease. Pembrolizumab plus chemotherapy has produced a longer median OS than chemotherapy alone in this patient population; these findings show the benefit of adding a PD-1 inhibitor to chemotherapy.2 The National Comprehensive Cancer Network (NCCN) guidelines currently list nivolumab and pembrolizumab for second-line treatment of advanced esophageal SCC. The CheckMate-648 trial provides positive data for nivolumab plus chemotherapy or for nivolumab plus ipilimumab for this patient population and should therefore be considered by the NCCN for the first-line setting.
- Kato K, Chul Cho B, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTIONS-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:1506-1517.
- Sun J-M, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398:759-771.