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

Matthew H G Katz; Gina R Petroni; Todd Bauer; Matthew J Reilley; Brian M Wolpin; Chee-Chee Stucky; Tanios S Bekaii-Saab; Rawad Elias; Nipun Merchant; Andressa Dias Costa; Patrick Lenehan; Victoire Cardot-Ruffino; Scott Rodig; Kathleen Pfaff; Stephanie K Dougan; Jonathan Andrew Nowak; Gauri R Varadhachary; Craig L Slingluff; Osama Rahma

doi:10.1136/jitc-2023-007586

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

J Immunother Cancer. 2023 Dec 1;11(12):e007586. doi: 10.1136/jitc-2023-007586.

Authors

Matthew H G Katz¹, Gina R Petroni², Todd Bauer³, Matthew J Reilley⁴, Brian M Wolpin^{5

6}, Chee-Chee Stucky⁷, Tanios S Bekaii-Saab⁸, Rawad Elias⁹, Nipun Merchant¹⁰, Andressa Dias Costa¹¹, Patrick Lenehan^{12

13}, Victoire Cardot-Ruffino^{12

13}, Scott Rodig^{12

13}, Kathleen Pfaff^{14

15}, Stephanie K Dougan^{12

13}, Jonathan Andrew Nowak^{12

13}, Gauri R Varadhachary¹⁶, Craig L Slingluff³, Osama Rahma¹¹

Affiliations

¹ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA [email protected].
² Division of Translational Research and Applied Statistics, Department of Public Health Sciences, University of Virginia Health System, Charlottesville, Virginia, USA.
³ Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.
⁴ Division of Hematology and Oncology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁶ Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
⁷ Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA.
⁸ Division of Hematology and Medical Oncology, Department of Internal Medicine, Mayo Clin, Phoenix, Arizona, USA.
⁹ Hartford HealthCare Cancer Institute, Plainville, Connecticut, USA.
¹⁰ Department of Surgery, University of Miami, Coral Gables, Florida, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
¹² Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹³ Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.
¹⁴ Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹⁵ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁶ Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

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.

Publication types

Randomized Controlled Trial
Multicenter Study
Research Support, N.I.H., Extramural

MeSH terms

Adenocarcinoma* / drug therapy
Carcinoma, Pancreatic Ductal* / drug therapy
Humans
Neoadjuvant Therapy
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / metabolism
Tumor Microenvironment

Substances

pembrolizumab

Abstract

Publication types

MeSH terms

Substances

Grants and funding