Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study. Journal of Clinical Oncology

LBA4001Background: NIVO demonstrated superior overall survival (OS) vs chemo in previously treated patients (pts) with ESCC (ATTRACTION-3). We report OS and progression-free survival (PFS) from CheckMate 648, the first global phase III study to evaluate both an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC. Methods: Adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Pts were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo alone. Primary endpoints for both comparisons were OS and PFS per blinded independent central review (BICR) in pts with tumor cell PD-L1 ≥ 1%. Hierarchically tested secondary endpoints included OS and PFS in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, and chemo arms (49% with tumor cell PD-L1 ≥ 1%). With 13 months (mo) minimum follow-up, NIVO + chemo and NIVO + IPI led to statistically significant improvement in OS vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Statistically significant PFS benefit was also observed for NIVO + chemo vs chemo (HR 0.65 [98.5% CI 0.46?0.92]; P = 0.0023) in pts with tumor cell PD-L1 ≥ 1%. PFS in NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% did not meet the prespecified boundary for significance. The objective response rate (per BICR) was 53% (NIVO + chemo), 35% (NIVO + IPI), and 20% (chemo) in pts with tumor cell PD-L1 ≥ 1% and in all randomized pts was 47%, 28%, and 27%, respectively; longer median (95% CI) duration of response was observed vs chemo for pts with tumor cell PD-L1 ≥ 1%: 8.4 (6.9?12.4), 11.8 (7.1?27.4), and 5.7 (4.4?8.7) mo and for all randomized pts: 8.2 (6.9?9.7), 11.1 (8.3?14.0), and 7.1 (5.7?8.2) mo, respectively. No new safety signals were identified (Table). Conclusions: NIVO plus chemo and NIVO plus IPI both demonstrated superior OS vs chemo, along with durable objective responses and acceptable safety, in pts with advanced ESCC, and each represents a potential new 1L treatment option. Clinical trial information: NCT03143153.OS (tumor cell PD-L1 ≥ 1%)NIVO + chemoN = 158NIVO + IPIN = 158ChemoN = 157Median OS, mo (95% CI)15.4 (11.9?19.5)13.7 (11.2?17.0)9.1 (7.7?10.0)HR vs chemo (CI; P value)0.54 (99.5% CI 0.37?0.80;P < 0.0001)0.64 (98.6% CI 0.46?0.90;P = 0.001)?OS (all randomized pts)N = 321N = 325N = 324Median OS, mo (95% CI)13.2 (11.1?15.7)12.8 (11.3?15.5)10.7 (9.4?11.9)HR vs chemo (CI; P value)0.74 (99.1% CI 0.58?0.96;P = 0.0021)0.78 (98.2% CI 0.62?0.98;P = 0.011)?Safety: treatment-related events ?(all treated pts), n (%)N = 310N = 322N = 304Any grade/grade 3?4297 (96)/147 (47)256 (80)/102 (32)275 (90)/108 (36)Leading to discontinuationa106 (34)57 (18)59 (19)Deaths5 (2)5 (2)4 (1)aDue to any component of the regimen.