Pembrolizumab in Combination with Neoadjuvant Chemoradiotherapy for Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction

Mojun Zhu, Chunhua Chen, Nathan R. Foster, Christopher Hartley, Taofic Mounajjed, Marcela A. Salomao, Briant F. Fruth, Staci E. Beamer, Yohan Kim, Susan M. Harrington, Henry C. Pitot, Cristobal T. Sanhueza, Yening Feng, Joerg Herrmann, Robert R. McWilliams, Fabrice Lucien, Bing Q. Huang, Wen Wee Ma, Tanios S. Bekaii-Saab, Haidong DongDennis Wigle, Daniel H. Ahn, Chris L. Hallemeier, Shanda Blackmon, Harry H. Yoon

Research output: Contribution to journalArticlepeer-review


Purpose: This phase Ib/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 [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (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 ¼ 0.046]. 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 (EV) 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.

Original languageEnglish (US)
Pages (from-to)3021-3031
Number of pages11
JournalClinical Cancer Research
Issue number14
StatePublished - Jul 15 2022

ASJC Scopus subject areas

  • Medicine(all)


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