MORPHEUS-EC: A phase Ib/II open-label, randomized study of first-line tiragolumab (tira) + atezolizumab (atezo) + chemotherapy (CT) in patients (pts) with esophageal cancer (EC).

324Background: TIGIT is a novel inhibitory immune checkpoint on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, e.g. PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. We report interim data from MORPHEUS-EC (NCT03281369) evaluating the combination of tira + atezo with CT in pts with untreated locally advanced unresectable or metastatic EC. Methods: Eligible pts (locally advanced unresectable, or metastatic EC with no prior systemic treatment; ECOG PS 0–1) were randomized to receive: cisplatin 80mg/m2 + 5-FU 800mg/m2/24 hours on Days 1–5 of each cycle (CT); atezo 1200mg + cisplatin + 5-FU (atezo + CT); or tira 600mg + atezo + cisplatin + 5-FU (tira + atezo + CT) in 21-day cycles. Primary endpoint: investigator (INV)-assessed objective response rate (ORR). Key secondary endpoints: INV-assessed progression-free survival (PFS), overall survival (OS), safety. Results: 152 pts were randomized to: CT (n=24; control); atezo + CT (n=65) or tira + atezo + CT (n=63). As of 14 Mar 2023, median follow-up was 8.7 months (mo) in the CT arm, 11.4 mo in the atezo + CT arm and 10.9 mo in the tira + atezo + CT arm. Pt characteristics were generally balanced between arms. ORR was 47.8% (CT) vs 53.8% (atezo + CT) vs 67.7% (tira + atezo + CT). Median PFS was 4.1 mo (CT) vs 6.8 mo (atezo + CT) vs 6.9 mo (tira + atezo + CT) (Table). ORR and PFS benefit was generally consistent across all pre-specified subgroups, including PD-L1 status. There was a numerical improvement in OS with tira + atezo + CT vs atezo + CT and CT alone (Table). Grade 3–5 adverse events (AEs) were 82.6% vs 83.1% vs 85.5% and treatment-related Grade 4/5 AEs were 4.3% vs 7.7% vs 14.5% for CT vs atezo + CT vs tira + atezo + CT. AEs leading to any tx discontinuation were 21.7%, 16.9% and 35.5%, respectively. Conclusions: Clinically meaningful improvements in INV-assessed ORR and PFS and a trend of improved OS were observed with tira + atezo + CT when compared with CT and atezo + CT. These results support the contribution of both tira and atezo in combination with CT. The safety profile was consistent with the known risks of the individual tx. Clinical trial information: NCT03281369.