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

Abstract

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 = 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.

Figure 1.

Rate of pCR in MC1541 overall and according to baseline expression of PD-L1 in the TME (CPS ≥ 10 vs. <10; A). PFS (B) and OS (C) by pCR status for patients in MC1541.

Figure 2.

PFS (A) and OS (B) in MC1541 patients according to baseline expression of PD-L1 in the TME (CPS ≥ 10 vs. <10) and in a PD-L1-unselected propensity-score-matched cohort.

Figure 3.

A, Transmission electron microscopy images of a single EV isolated at baseline from a patient treated on MC1541 with PD-L1 CPS = 2 and TPS = 0 in the TME. Right, A single EV expresses multiple PD-L1 molecules shown by immunogold as intense black dots on the membrane surface (arrowheads) and in surrounding peri-membrane glycocalyx matrix (arrows). Left, A single EV without staining for PD-L1. B, pCR rate after chemoradiation in MC1541 patients according to baseline PD-L1 expression (CPS < 10 and ≥10) and baseline level of PD-L1-expressing EVs.