Randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.

4128 Background: Pancreatic cancer (PC) is a challenging target for immunotherapy due to suppressive immune-microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of tumor-infiltrating lymphocytes (TILs). We hypothesized that the combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC were randomized 2:1 to the investigational treatment (Arm A) of pembrolizumab 200mg IV every 3 weeks concurrently with CRT (capecitabine 825 mg/m2 orally twice daily and radiation 50.4 Gy in 28 fractions over 28 days) or CRT only (Arm B) prior to surgical resection. The primary endpoints were treatment safety and density of TILs with the objective to estimate differences in TILs density between the investigational and the control arms. Immune cell densities were assessed using multiplexed immunofluorescence on resected tumor specimens. Densities of CD8+TILs were measured in 2-10 representative regions containing residual cancer per case and then averaged to obtain overall densities. The study was amended after enrollment of 37 patients to allow FOLFIRINOX prior to CRT, given changes in standard of care. Results: 37 patients were enrolled (24 Arm A and 13 Arm B). Post-neoadjuvant therapy, 13 patients had unresectable disease (9 on A and 4 on B), and 24 patients underwent surgery and were evaluable for the TILs primary endpoint (17 arm A and 7 arm B). The mean difference (A-B) in CD8+ cell density was 36 cells/mm2 (95% CI -85 to 157, stdev 130) (p 0.48). Additional analysis did not show significant differences in CD8+Ki67+ (activated cytotoxic T-cells), CD4+, and CD4+FOXP3+ (regulatory T cells), M1- or M2-like polarized macrophages, or granulocytes. The median recurrence free survival (RFS) was 18.2 months on Arm A and 14.1 on Arm B (p 0.41) and Overall Survival was 27.8 months on Arm A and 24.3 on Arm B (p 0.68) with a median follow up of 2.2 years. The most common grade 3 treatment-related toxicities were lymphopenia reported in 29% on Arm A and 31% on Arm B followed by diarrhea in 8% on Arm A attributed to CRT. There was only 1 DLT of increased ALT attributed to the combination on Arm A that resolved after holding the treatment and receiving steroids. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizumab is safe. Preliminary analysis shows that the addition of pembrolizumab to CRT has minimal effects on several immune cell populations including CD8+TILs in the PC microenvironment. The study is currently enrolling 25 more patients who receive FOLFIRINOX prior to randomization to CRT+/- Pembrolizumab, which will help to dissect the immune modulatory effect of chemotherapy followed by CRT. Clinical trial information: NCT02305186.