Multicenter randomized controlled trial of neoadjuvant chemoradiotherapy alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic adenocarcinoma

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival (OS). We hypothesized that adding programmed cell death protein 1 (PD-1) blockade to chemoradiotherapy would be well tolerated and increase TILs among patients with localized PDAC.

Methods: Patients were randomized 2:1 to Arm A (receiving pembrolizumab plus chemoradiotherapy (capecitabine and external beam radiation)) or Arm B (receiving chemoradiotherapy alone) before anticipated pancreatectomy. Primary endpoints were (1) incidence and severity of adverse events during neoadjuvant therapy and (2) density of TILs in resected tumor specimens. TIL density was assessed using multiplexed immunofluorescence histologic examination.

Results: Thirty-seven patients were randomized to Arms A (n=24) and B (n=13). Grade ≥3 adverse events related to neoadjuvant treatment were experienced by 9 (38%) and 4 (31%) patients in Arms A and B, respectively, with one patient experiencing dose-limiting toxicity in Arm A. Seventeen (71%) and 7 (54%) patients in Arms A and B, respectively, underwent pancreatectomy. Median CD8⁺ T-cell densities in Arms A and B were 67.4 (IQR: 39.2-141.8) and 37.9 (IQR: 22.9-173.4) cells/mm², respectively. Arms showed no noticeable differences in density of CD8⁺Ki67⁺, CD4⁺, or CD4⁺FOXP3⁺ regulatory T cells; M1-like and M2-like macrophages; or granulocytes. Median OS durations were 27.8 (95% CI: 17.1 to NR) and 24.3 (95% CI: 12.6 to NR) months for Arms A and B, respectively.

Conclusions: Adding pembrolizumab to neoadjuvant chemoradiotherapy was safe. However, no convincing effect on CD8⁺ TILs was observed.

Keywords: Adjuvants, Immunologic; Clinical Trials as Topic; Combined Modality Therapy; Immune Checkpoint Inhibitors; Immunotherapy.

Figure 1

Schematic illustration of study design. Patients with histologically confirmed resectable or borderline resectable pancreatic ductal adenocarcinoma were enrolled and randomized in a 2:1 ratio to receive CRT plus pembrolizumab or CRT alone prior to anticipated pancreatectomy. During neoadjuvant therapy, peripheral blood mononuclear cells were collected for analysis by flow cytometry. At pancreatectomy, tissue was collected for analysis by immunofluorescence imaging. Patients were followed for 2 years while receiving adjuvant chemotherapy at the discretion of their treating oncologist. CRT, chemoradiotherapy.

Figure 2

Consolidated Standards of Reporting Trials diagram of patient groups. ¹ Evaluable for safety endpoint (n=37). ² Evaluable for immunologic endpoint (n=24). CRT, chemoradiotherapy

Figure 3

Survival analyses. Kaplan-Meier curves depicting (A) progression-free survival (PFS); (B) overall survival; and (C) recurrence-free survival of patients who underwent pancreatectomy. Arm A (CRT plus pembrolizumab) is depicted in blue while Arm B (CRT alone) is depicted in red. CRT, chemoradiotherapy.

Figure 4

Immune landscape in resected pancreatic ductal adenocarcinoma (PDAC), stratified by treatment setting. Examples of multiplex immunofluorescence images and corresponding phenoplots for T-cell subsets, myeloid cell subsets and macrophage polarization panel in neoadjuvant chemoradiation (CRT) plus pembrolizumab-treated and neoadjuvant CRT-treated PDACs (A). Boxplots showing the distribution of overall (combined intraepithelial and stromal areas) immune cell densities in 15 neoadjuvant CRT plus pembrolizumab-treated and 7 neoadjuvant CRT-treated PDACs (B). Scale bars represent 50 µm. DAPI, 2-(4-amidinophenyl)−1H-indole-6-carboxamidine.