First-line tiragolumab plus atezolizumab and chemotherapy in patients with previously untreated, locally advanced unresectable or metastatic oesophageal cancer (MORPHEUS-EC): a randomised, open-label, phase 1b/2 trial.	BACKGROUND: Chemotherapy, with or without immunotherapy, is a standard of care for first-line treatment of locally advanced or metastatic oesophageal cancer. However, outcomes remain poor. We aimed to evaluate the activity and safety of tiragolumab, an anti-TIGIT monoclonal antibody, plus atezolizumab, an anti-PD-L1 monoclonal antibody, and chemotherapy in treatment-naive locally advanced unresectable or metastatic oesophageal cancer. METHODS: MORPHEUS-EC is a phase 1b/2, randomised, open-label, umbrella study done at 20 sites in Taiwan, South Korea, Australia, Israel, the UK, and the USA. Eligible patients were aged 18 years or older, had treatment-naive, locally advanced unresectable or metastatic oesophageal cancer, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned using a permuted-block method to receive tiragolumab (600 mg intravenously every 21 days) plus atezolizumab (1200 mg intravenously every 21 days) and chemotherapy (cisplatin 80 mg/m(2) intravenously every 21 days plus intavenous fluorouracil 800 mg/m(2) per 24 h on days 1-5 of each 21 day cycle), or atezolizumab and chemotherapy, or chemotherapy alone. The primary endpoint was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 in patients who received at least one dose of each drug for their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03281369, and is ongoing. FINDINGS: Between June 5, 2020 and Nov 8, 2022, 152 patients were assigned to the tiragolumab plus atezolizumab and chemotherapy (n=63), atezolizumab and chemotherapy (n=65), or chemotherapy (n=24) groups (136 [89%] were male and 16 [11%] were female, 98 [64%] were Asian and 50 [33%] were White). Median survival follow-up was 10·9 months (IQR 7·1-17·3) in the tiragolumab plus atezolizumab and chemotherapy group, 11·4 months (IQR 7·9-14·7) in the atezolizumab and chemotherapy group, and 8·7 months (3·9-12·0) in the chemotherapy group. Investigator-assessed confirmed objective response rate was 67·7% (95% CI 54·7-79·1; 42 of 62 patients) in the tiragolumab plus atezolizumab and chemotherapy group, 53·8% (41·0-66·3; 35 of 65) in the atezolizumab and chemotherapy group, and 47·8% (26·8-69·4; 11 of 23 patients) in the chemotherapy group. 49 (79%) of 62, 52 (80%) of 65, and 17 (74%) of 23 patients had a grade 3-4 adverse event in each group respectively, and 36 (58%) of 62, 33 (51%) of 65, and 11 (48%) of 23 had a serious adverse event. The most common treatment-related adverse events were nausea (46 [74%] of 62, 47 [72%] of 65, and 18 [78%] of 23) and decreased appetite (29 [47%], 29 [45%], and 10 [43%]). No deaths were treatment related. INTERPRETATION: These results support the additional benefit of tiragolumab combined with atezolizumab and chemotherapy for patients with treatment-naive, locally advanced unresectable or metastatic oesophageal cancer. Further validation of tiragolumab plus atezolizumab and chemotherapy has been performed in the phase 3 SKYSCRAPER-08 trial (NCT04540211). FUNDING: F Hoffmann-La Roche-Genentech.	esophagus