Nivolumab plus chemotherapy or ipilimumab versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: 5-year follow-up results from CheckMate 648

BACKGROUND: Both nivolumab plus chemotherapy (P < 0.001) and nivolumab plus ipilimumab (P = 0.001) demonstrated significant overall survival (OS) benefit compared with chemotherapy for patients with previously untreated advanced esophageal squamous-cell carcinoma (ESCC) and programmed death-ligand 1 (PD-L1) ≥1%. We report OS and additional analyses at a minimum follow-up of 5 years. PATIENTS AND METHODS: The open-label, phase III CheckMate 648 trial (NCT03143153) enrolled patients with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomly assigned 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. The primary endpoints were OS and progression-free survival (PFS) by blinded independent central review (BICR) in patients with tumor cell PD-L1 expression ≥1%. Key secondary endpoints included OS and PFS by BICR in all randomly assigned patients. RESULTS: In total, 970 patients were randomly assigned. At the 5-year minimum follow-up, OS improvement continued to be observed with nivolumab plus chemotherapy versus chemotherapy [hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.48-0.79] and nivolumab plus ipilimumab versus chemotherapy (HR 0.62, 95% CI 0.48-0.80) in patients with tumor cell PD-L1 ≥1%. OS benefit was also observed in all randomly assigned patients (HR 0.77, 95% CI 0.65-0.92 for both nivolumab plus chemotherapy and nivolumab plus ipilimumab versus chemotherapy). PFS benefit was observed with nivolumab plus chemotherapy versus chemotherapy in the tumor cell PD-L1 ≥1% (HR 0.67, 95% CI 0.51-0.88) population but not with nivolumab plus ipilimumab versus chemotherapy (HR 1.03, 95% CI 0.78-1.35). Among all treated patients, grade 3-4 treatment-related adverse events were observed in 49% of patients in the nivolumab plus chemotherapy group, 33% in the nivolumab plus ipilimumab group, and 37% in the chemotherapy group. CONCLUSIONS: Nivolumab-containing treatment regimens continued to demonstrate clinically meaningful OS benefit versus chemotherapy at the 5-year follow-up, with no new safety signals. These data further support nivolumab in combination with chemotherapy or ipilimumab as first-line treatment for patients with advanced ESCC.