O-3 Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648

Abstract

NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis, including factors associated with the timing of the onset of treatment effect. Patients with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in patients with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized patients. Duration of response (DOR) per BICR and PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) per investigator were exploratory endpoints. Among all patients randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo at 13-month minimum follow-up. ORR (95% CI) was 47% (42–53) with NIVO + chemo, 28% (23–33) with NIVO + IPI, and 27% (22–32) with chemo. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 months; 39%, 48%, and 23%, respectively). Piecewise HRs of overall survival between treatment arms and factors associated with delayed onset of effect of NIVO + IPI relative to chemo-based regimens will be presented. The majority of treatment-related adverse events with potential immunologic etiology (select TRAEs) were grade 1 or 2, and grade 3/4 events occurred in ≤ 6% of patients with NIVO + chemo and NIVO + IPI. Select TRAEs of any grade occurred within a median of 5 to 31 weeks with NIVO + chemo and 4 to 12 weeks with NIVO + IPI across organ categories. Nonendocrine select TRAEs resolved in most patients in the NIVO + chemo (57% to 91%) and NIVO + IPI (63% to 95%) groups across organ categories with the use of established management algorithms (median time to resolution, 2 to 17 weeks and 3 to 12 weeks, respectively). NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of patients with prolonged DOR vs chemo, along with acceptable safety profiles. These results provide further support for each regimen as a new potential first-line standard therapy in advanced ESCC.