The combination of BXCL701 and pembrolizumab has demonstrated early clinical activity in patients with second-line advanced pancreatic ductal adenocarcinoma (PDAC), according to preliminary results from the ongoing EXPEL PANC Phase II trial presented at the ESMO Gastrointestinal Cancers Congress 2025 in Barcelona.
Dr. Benjamin A. Weinberg from Georgetown University Medical Center reported that among 18 response-evaluable patients, the combination achieved a 17% overall response rate and 39% disease control rate, with all responses being partial. Notably, four patients (25%) remained progression-free at the 18-week primary endpoint assessment.
Addressing Immunotherapy Resistance in Pancreatic Cancer
PDAC remains one of the most challenging cancers to treat, characterized by high resistance to conventional therapies, particularly immune checkpoint inhibitors. The lack of efficacy of ICIs in PDAC is largely attributed to its immunologically "cold" tumor microenvironment, which is often marked by immune evasion mechanisms and a dense stromal barrier that limits the infiltration of immune cells, especially effector T cells.
BXCL701 is a small molecule inhibitor targeting dipeptidyl peptidases (DPPs) 4, 8, 9, and fibroblast activation protein (FAP), which play critical roles in promoting immune suppression, fibrosis, and tumor progression. Preclinical models have shown that BXCL701 can enhance the efficacy of immune checkpoint inhibitors by promoting immune activation, reducing fibrosis, and fostering tumor infiltration by cytotoxic T cells.
Trial Design and Treatment Regimen
The EXPEL PANC trial enrolled patients with histologically confirmed PDAC who had progressed on prior first-line chemotherapy. The treatment regimen involves BXCL701 administration at 0.2 mg twice daily for the first 7 days of the first cycle, followed by 0.3 mg twice daily from days 8 to 14. For all subsequent cycles, patients continue receiving BXCL701 at 0.3 mg twice daily on days 1-14 of each 21-day cycle. Pembrolizumab is administered intravenously at a fixed dose of 200 mg every 21 days.
The study employs a Simon's two-stage design with a primary endpoint of progression-free survival at 18 weeks, expecting to enroll 39 evaluable patients. The trial's design is based on historical data indicating that the expected PFS at 18 weeks in this population is 30% or less, aiming to detect an improvement to 50% or higher.
Clinical Outcomes and Durability
Among the 21 patients enrolled, with 16 evaluable for efficacy at 18 weeks, the median progression-free survival was 2.3 months (95% CI 1.58-5.29 months). The median overall survival has not yet been reached, suggesting that a significant proportion of patients remain alive at the time of analysis.
"Of note, we had 3 patients with durable stable disease [lasting 6 months or longer], and we showed [via a patient case] that in [patients with] microsatellite-stable metastatic pancreatic cancer, we can shrink tumors not just in the lymph nodes, but also in the liver, which has historically been resistant to targeting with immunotherapy," Dr. Weinberg noted.
Safety Profile
No new safety signals were identified in the trial. The adverse events observed were consistent with the known profiles of BXCL701 and pembrolizumab, with no unexpected toxicities reported. The regimen was well tolerated across the patient population.
Biomarker Investigation
Tumor biopsies are being analyzed to investigate potential biomarkers of response and resistance, as well as to understand the underlying mechanisms contributing to the observed therapeutic benefit. Baseline and on-treatment tumor biopsies are being collected to investigate biomarkers of therapeutic response and resistance, aiming to refine patient selection for future trials.
The study remains ongoing, with additional patients needed to determine whether the trial meets the prespecified efficacy threshold to advance beyond stage 1. The findings highlight the importance of targeting the tumor microenvironment and overcoming its immunosuppressive barriers to enhance the efficacy of immunotherapy in PDAC.
