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Purpose: This phase 1b/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma. Patients and methods: Patients with GEJ adenocarcinoma (cT1-3NanyM0)received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response (pCR [ypT0N0]). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma. Results: We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met (7/31 [22.6%] achieved pCR). Patients with high (ie, combined positive score [CPS] {greater than or equal to}10) baseline expression of PD-L1 in the TME had a significantly higher pCR rate than those with low expression (50.0% [4/8] vs 13.6% [3/22]; P=.046). Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS <10, unprespecified analysis explored whether extracellular vesicles (EVs) could identify further responders: an elevated plasma level of PD-L1-expressing EVs was significantly associated with higher pCR. Conclusions:Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.