The addition of the checkpoint inhibitor pembrolizumab to neoadjuvant chemoradiation has failed to overcome the immunosuppressive microenvironment of pancreatic cancer, according to data presented by Osama E. Rahma, MD, and colleagues at the Society for Immunotherapy of Cancer (SITC) 2021 Annual Meeting (Abstract 960).
Although the combination of chemoradiation plus pembrolizumab was found to be safe in the neoadjuvant setting, results of a small phase II study showed no expansion or activation of tumor-infiltrating lymphocytes (TILs) in patients with resectable or borderline resectable pancreatic cancer.
“Preliminary analysis shows that the addition of pembrolizumab to chemoradiation has minimal effects on intratumoral densities of TILs and other immune cell populations,” said lead study author Dr. Rahma, Clinical Director of the Center for Cancer Therapeutic Innovation at Dana-Farber Cancer Institute and Global Clinical Head for GI Oncology and GI Strategy at AstraZeneca.
Osama E. Rahma, MD
As Dr. Rahma explained, pancreatic cancer remains a challenging target for immunotherapy due to a variety of immune-suppressive mechanisms that inhibit antitumor immunity. However, the use of neoadjuvant chemoradiation has been shown to increase the presence of TILs in other tumor sites and in preclinical studies of pancreatic cancer. Thus, Dr. Rahma and colleagues hypothesized that the combination of chemoradiation and pembrolizumab could further expand and activate TILs.
Study Methodology
For this study, Dr. Rahma and colleagues randomly assigned patients at six clinical sites who had resectable or borderline resectable pancreatic cancer to receive either intravenous pembrolizumab at 200 mg every 3 weeks concurrently with chemoradiation (capecitabine at 825 mg/m2 orally twice daily and radiation at 50.4 Gy in 28 fractions over 28 days) or chemoradiation alone prior to surgical resection.
The primary endpoints were safety and difference in TIL density between study arms assessed using multiplexed immunofluorescence on resected tumor specimens. Investigators also performed single-cell RNA sequencing to quantify gene expression in T cells from tumors and peripheral blood and to track expanded T-cell clonotypes in these compartments. The study was amended after enrollment of 37 patients to allow FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil) prior to chemoradiation, given changes in standard of care.
A total of 37 patients were enrolled into the study (24 in the investigational arm and 13 in the control arm). After neoadjuvant therapy, 13 patients had unresectable disease, and 24 patients underwent surgery and were evaluable for the TIL primary endpoint.
Results
According to Dr. Rahma, the mean difference in CD8-positive T-cell density between study arms was 36 cells/mm2, which was not statistically significant (P = .48). Additional analysis did not show significant differences in activated cytotoxic T cells, regulatory T cells, M1- or M2-like polarized macrophages, or granulocytes. However, single-cell RNA sequencing revealed clonal expansion and expression of co-inhibitory markers among TIL subsets, said Dr. Rahma.
The median recurrence-free survival was 18.2 months for patients receiving combination pembrolizumab and chemoradiation vs 14.1 months for patients receiving chemoradiation alone (P = .41). With a median follow up of 2.2 years, overall survival was 27.8 months in the combination arm vs 24.3 in the control arm (P = .68).
The most common grade 3 treatment-related toxicities were lymphopenia (reported in 29% of patients in the investigational arm and 31% of patients in the control arm), followed by diarrhea.
“These data showed minimal effects on intratumoral densities of TILs,” said Dr. Rahama. “However, future research involving single-cell transcriptome analyses could enable in-depth characterization of the functional responses of T cells to pembrolizumab in the setting of chemoradiation.”
Disclosure: This study was funded by Merck. Dr. Rahma reported no conflicts of interest.
