TPS374 Background: The current standard of care for patients (pts) diagnosed with unresectable, locally advanced esophageal squamous-cell carcinoma (ESCC) is definitive platinum-based concurrent chemoradiotherapy (dCRT). However, ESCC has poor prognosis, with more than half of tumors reoccurring after dCRT (Smyth et al. Nat Rev Dis Primers 2017), highlighting the need for additional therapy options in this setting. Cancer immunotherapies have demonstrated activity in ESCC, and targeted inhibition of the PD-L1/PD-1 pathway may be further amplified using novel anti-TIGIT agents such as tiragolumab. In preclinical mouse models, concomitant blockade of PD-L1/PD-1 and TIGIT pathways demonstrated prolonged survival over the respective single-agents. In the phase II CITYSCAPE study (NCT03563716), tiragolumab plus atezolizumab (anti-PD-L1) resulted in a clinically meaningful improvement in PFS and higher ORR vs atezolizumab alone (31.3 vs 16.2%) in first-line pts with PD-L1+ (TPS ≥1%) metastatic NSCLC. SKYSCRAPER-07 (NCT04543617) will determine if tiragolumab plus atezolizumab combination therapy provides superior clinical benefit to atezolizumab monotherapy or placebo in pts with unresectable ESCC whose cancers have not progressed following dCRT. We hypothesize that combination therapy will prolong PFS and OS compared with placebo in this setting. Methods: Eligible pts (≥18 years) must have unresectable ESCC, without progressive disease (PD) after platinum-based dCRT (according to regional oncology guidelines for ESCC); ECOG PS 0–1; no prior treatment with any immune checkpoint inhibitor. Approximately 750 pts will be randomized 1:1:1 to either Arm A (tiragolumab 600mg + atezolizumab 1200mg IV Q3W), Arm B (atezolizumab 1200mg + placebo IV Q3W) or Arm C (double placebo IV Q3W). Treatment will continue for up to 17 cycles of 21 days, or until unacceptable toxicity or investigator-assessed radiographic PD (per RECIST v1.1). Stratification factors include geographic region (Asia vs rest of world), PD-L1 expression and staging prior to dCRT (II vs III vs IV). Co-primary efficacy endpoints are investigator-assessed PFS and OS; key secondary endpoints include independent review facility-assessed PFS and DoR. Safety, pharmacokinetic, biomarker and immunogenicity analyses will be performed. Recruitment is ongoing. Clinical trial information: NCT04543617.