O-4 GEMSTONE-304: A phase 3 study of sugemalimab plus chemotherapy versus chemotherapy as first-line treatment of patients with unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC)

10.4) with NUC-1031+cis vs 12.6 months (11.0-15.1)with GemCis; HR 1.79.ORR by Blinded Independent Central Review (BICR) was 18.7% for NUC-1031+cis vs 12.4% for GemCis (odds ratio:1.59;99%CI:0.86-2.94;p¼0.049).PFS (BICR) was 4.9 months with NUC-1031+cis vs 6.4 months with GemCis (HR:1.45;95% CI:1.18-1.7;p < 0.001).The Grade 3 or higher TEAE profile was similar across the two arms, with exception of: liver-related events [increased ALT (17.8% vs 3.4%) and AST (9.1% vs 2.4%), both higher in NUC-1031+cis], hepatobiliary disorders [cholangitis (3.4% vs 1.6%) and biliary obstruction (1.8% vs 0.3%), both higher in NUC-1031+cis]; and haematological [anaemia (9.4% vs 18.0%) and neutropenia (14.1% vs 24.1%), both higher in GemCis].Treatment exposure was lower in NUC-1031+cis, which can be explained by a higher discontinuation rate due to TEAEs (30% vs 16%).More patients discontinued during the first 30-days of treatment with NUC-1031+cis (22% vs 10%), mainly due to Grade 3 ALT/AST increases, which were reversible, leading to a late protocol amendment allowing rechallenge of NUC-1031 at dose minus 1.Conclusions: At the dose and schedule utilised for NUC-1031 in this study, the primary endpoint was not met with a longer OS with GemCis, despite a higher ORR with NUC-1031+cis.NUC-1031+cis was associated with more liver-related TEAEs, leading to early discontinuation.While these early liver events were more frequent in NUC-1031+cis, they were observed in both arms and are likely a combination of druginduced liver toxicity, disease progression, and underlying liver dysfunction in this patient population.Clinical trial identification: NCT04163900.