ESMO GI 2025 Highlights: BXCL701 + Pembrolizumab in Second-Line Advanced PDAC

The EXPEL PANC Phase II trial (NCT05558982), presented by Dr. Benjamin A. Weinberg from Georgetown University Medical Center at the ESMO Gastrointestinal (GI) Cancers Congress 2025 in Barcelona, investigates the combination of BXCL701 and pembrolizumab in patients with second-line advanced pancreatic ductal adenocarcinoma (PDAC). This study aims to evaluate the efficacy and safety of this combination therapy in a population historically resistant to immunotherapy.

Background

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and challenging cancers to treat, characterized by high resistance to conventional therapies, particularly immune checkpoint inhibitors (ICIs). The lack of efficacy of ICIs in PDAC is largely attributed to its immunologically “cold” tumor microenvironment (TME), which is often marked by immune evasion mechanisms and a dense stromal barrier that limits the infiltration of immune cells, especially effector T cells. Recent studies have focused on overcoming these barriers to make PDAC more amenable to immunotherapy.

One promising approach involves the inhibition of various factors that contribute to the TME’s immunosuppressive nature. 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, such as anti-PD1 antibodies, by promoting immune activation, reducing fibrosis, and fostering tumor infiltration by cytotoxic T cells. These findings have led to the initiation of the ongoing Phase II clinical trial, EXPEL PANC (NCT05558982), to evaluate the combination of BXCL701 and pembrolizumab, a PD-1 inhibitor, in patients with second-line advanced PDAC.

Methods

This Phase II trial (EXPEL PANC) is designed to assess the safety and efficacy of BXCL701 combined with pembrolizumab in second-line treatment of advanced PDAC. The study is conducted in an open-label manner and includes patients with histologically confirmed PDAC who have progressed on prior first-line chemotherapy. The treatment regimen involves BXCL701 administration at a dose of 0.2 mg twice daily (BID) for the first 7 days of the first cycle, followed by 0.3 mg BID from days 8 to 14. For all subsequent cycles, patients continue receiving BXCL701 at 0.3 mg BID on days 1-14 of each 21-day cycle. Pembrolizumab is administered intravenously at a fixed dose of 200 mg every 21 days, beginning on day 1 of each cycle.

The primary endpoint of the trial is progression-free survival at 18 weeks (PFS18weeks), which is a critical measure of early efficacy in this difficult-to-treat cancer population. Secondary endpoints include overall survival (OS), objective response rate (ORR), and disease control rate (DCR). A Simon’s two-stage design was employed, with the expectation that 39 evaluable patients will be required for the study. The trial’s design is based on historical data indicating that the expected PFS18weeks in this population is 30% or less, and the trial aims to detect an improvement in PFS18weeks to 50% or higher.

Results

A total of 21 patients were enrolled in the study, with 16 patients evaluable for efficacy at the 18-week mark. Of these, four patients (25%) were progression-free at 18 weeks, suggesting a potential benefit of the combination therapy.

Response Rates

• Three patients (17%) achieved partial responses (PR).
• Four patients (22%) had stable disease (SD).
• The overall disease control rate (DCR) was 39%.
• Median Progression-Free Survival (PFS): The median PFS for evaluable patients was 2.3 months (95% CI 1.58–5.29 months).

• Median Overall Survival (OS):The median OS has not yet been reached, suggesting that a significant proportion of patients remain alive at the time of the analysis.
• Safety: No new safety signals were identified. The adverse events observed were consistent with the known profiles of BXCL701 and pembrolizumab, with no unexpected toxicities reported.
• Biopsy Analysis: 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.

Preliminary results from this ongoing trial suggest that the combination of BXCL701 and pembrolizumab may show efficacy in treating second-line advanced PDAC, a typically immunotherapy-resistant population. Further analysis is required to confirm these findings and identify key biomarkers.

Key Takeaways

The preliminary results of the EXPEL PANC trial indicate that the combination of BXCL701 and pembrolizumab may provide a promising therapeutic strategy for second-line treatment of advanced PDAC, a cancer known for its poor prognosis and resistance to immunotherapy. The observed disease control rate and the partial responses seen in some patients are encouraging, especially given the historically low response rates to immune checkpoint inhibitors in this disease.

Further analysis of the ongoing trial data, including tumor biopsy results, will be critical in understanding the mechanisms of response and resistance to this combination regimen. The findings also highlight the importance of targeting the TME and overcoming its immunosuppressive barriers to enhance the efficacy of immunotherapy in PDAC.

As the study progresses, additional data on overall survival and long-term outcomes will be crucial for determining whether BXCL701 combined with pembrolizumab can offer meaningful clinical benefit to patients with advanced PDAC.

You can read the full abstract here