BXCL701 plus pembrolizumab in second-line advanced pancreatic ductal adenocarcinoma: Final outcomes of the EXPEL PANC trial.

4201 Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to immune checkpoint inhibitors, in part due to a cold tumor immune microenvironment (TME). BXCL701 (‘701) is a small molecule inhibitor of dipeptidyl peptidases 4, 8, 9 and fibroblast activation protein. We have shown that combinations of ‘701 and anti-PD1 antibodies lead to tumor regression in murine PDAC models due to 1) activation of the inflammasome and expression of CXCL9 to attract and activate CXCR3+ lymphocytes, 2) tumor invasion of CD8+ T cells and other effector cells, 3) induction of adaptive immunity, and 4) reduced fibrosis in the PDAC TME. We sought to evaluate the efficacy of this combination in patients (pts) with previously-treated advanced PDAC. Methods: In this phase II clinical trial (NCT05558982), pts with second-line advanced PDAC received ‘701 at a 0.2 mg PO BID dose on days 1-7 and then 0.3 mg BID on days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID on days 1-14 every 21 days in all subsequent cycles, administered with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective was to determine the 18-week progression-free survival rate (PFS 18weeks ) in pts with advanced PDAC treated in the second-line setting. We estimated that the historical second-line PFS 18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and a power of 80%, if the true rate is 50%, we would need 19 pts in stage 1 and 20 pts in stage 2 (a total of 39 evaluable). Seven of 19 evaluable pts would need to be progression-free at 18 weeks to trigger stage 2. Results: Twenty-one pts were enrolled. Four out of 18 evaluable pts (22%) were alive and progression-free at 18 weeks. Three had partial responses (PR, 17%), and 4 had stable disease (SD, 22%), for a disease control rate of 39%. One responder had MSI-H PDAC, while the other 2 had MSS disease. Median follow-up was 4.5 months. Median PFS was 2.3 months (95% CI 1.6 – 5.3), and median overall survival was not reached (NR, 95% CI 4.5 – NR). Three pts (14%) had PFS exceeding 6 months (2 PR, 1 SD). No new safety signals have been identified. Baseline and on-treatment tumor biopsies will be analyzed to understand the mechanisms underlying therapeutic benefit and to examine the characteristics of responders vs. non-responders. Conclusions: ‘701 plus pembrolizumab in second-line advanced PDAC did not reach the preliminary efficacy endpoint to trigger the second stage. However, there were encouraging signs as this combination induced objective responses in 2 MSS pts, and PFS exceeded 6 months in 3 pts. Ongoing correlative studies should elucidate predictive markers of efficacy and resistance to this novel immunotherapy combination. Clinical trial information: NCT05558982 .