BXCL701 Plus Pembrolizumab is Safe and Generates Early Antitumor Activity in Advanced PDAC

The pancreatic cancer treatment paradigm has been “left behind” in the larger immunotherapy boom that has benefitted patients with many other tumor types, emphasizing the need for more therapeutic options, such as the novel combination of BXCL701 plus pembrolizumab (Keytruda) for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC), according to Benjamin A. Weinberg, MD, FACP.

“[BXCL701 plus pembrolizumab] represents an important chemotherapy-free potential type of treatment paradigm for patients with this disease, who often [endure a lot] from prior lines of chemotherapy,” Weinberg said during an interview with OncLive®. “We hope it offers an opportunity to make the immune system work against pancreatic cancer.”

In the interview, Weinberg discussed the rationale for evaluating BXCL701 plus pembrolizumab in patients with advanced PDAC, key efficacy and safety data, the combination’s potential future role in clinical practice, and next steps for research in this area.

Weinberg is an associate professor of Medicine in the Division of Hematology and Oncology at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC.

OncLive: What was the rationale for evaluating BXCL701 plus pembrolizumab in second-line advanced PDAC?

Weinberg: Pancreatic cancer is a difficult disease to manage, and we’re always looking for new, novel treatment options. Immunotherapy, which has revolutionized the management of many diseases, has left some behind, especially pancreatic cancer. Trying to turn some of these cold tumors into hot tumors that can respond to [treatments] like immune checkpoint inhibition is relevant. It’s not just great for us, it’s great for our patients to have another treatment option.

We conducted the phase 2 EXPEL PANC study [NCT05558982] study based on strong preclinical science from our scientific collaborators at Georgetown [with] Louis Weiner, MD, and his lab. Preclinically, they saw that in mouse models of human pancreatic cancer, inhibiting DPP4, DPP8, DPP9, and FAP, which is done using the novel oral drug BXCL701, synergized with anti–PD-1 inhibition. [Hitting these targets] requires T cells and NK cells. All these targets are overexpressed in human pancreatic cancer, and they also seem to downregulate intratumoral fibrosis, which has antifibrotic properties, to allow more T cells to infiltrate into the immune tumor microenvironment.

What were the key efficacy data from EXPEL PANC?

[EXPEL PANC investigated] BXCL701—an oral dipeptidyl peptidase and FAP inhibitor—plus pembrolizumab in patients with metastatic pancreatic adenocarcinoma who had already received 1 prior line of treatment. We presented the results at the 2025 ESMO Gastrointestinal Cancers Congress. We had a 17% overall response rate, including 3 patients who [achieved a partial response]. This is an ongoing study where we’re hoping to accumulate more clinical data and incorporate pre- and non-treatment tumor biopsies to show on the molecular level and in the tumor immune microenvironment that we are hitting the target [and identify what is] happening in responders vs nonresponders. Those data will be forthcoming.

We also presented results from 16 evaluable patients who had stable disease or better at the 18-week scan. The median progression-free survival [(PFS) at 18 weeks] is our primary end point. [This trial uses] a Simon 2-stage design, and we still need to enroll more patients to figure out whether we’re going to hit that first stage. However, the goal [of stage 1] is to have 7 out of 19 patients with either SD or better at the 18-week scan. We showed a median PFS of 2.3 months; the median overall survival has not yet been reached. We also showed that in [patients with] microsatellite-stable metastatic pancreatic cancer, we can shrink tumors in the lymph nodes, as well as in the liver, which has historically been resistant to targeting with immunotherapy.

What were the key safety data?

The safety signals were minimal with this combination. Most of the adverse effects (AEs) were as anticipated with pembrolizumab. We did see autoimmune arthralgias in approximately 2 patients who were on the trial for 6 months or longer, 1 of whom required corticosteroids. However, we’ve seen relatively few immune-related AEs. BXCL701 can cause hypotension, and therefore, we started at a lower dose for the first week. There were also a couple patients who did not escalate to the full dose per protocol, but no patients had significant clinical issues with hypotension and anemia, another known AE associated with BXCL701.

Although these data are still preliminary, what are some of their potential future clinical implications?

Pembrolizumab [and other] immune checkpoint inhibitors by themselves have not worked in metastatic pancreatic cancer. We hope that this [regimen can] modify the stroma to allow the inflammasome to develop and allow an influx of T cells and NK cells into the tumor immune microenvironment. [This may] show that we can achieve synergy [between] PD-1 inhibition [and BXCL701]. Then maybe [we can investigate this combination in] earlier-line settings, like in the maintenance first-line setting, and then potentially in combination with other novel drugs, especially KRAS inhibitors.

What are the expected next steps for this research?

We’re hoping to complete the accrual of the study, get to the Simon 2-stage [part of the design, and enroll more patients. If not, we hope to combine [BXCL701] with novel drug targets, such as the new generation of KRAS inhibitors. We’ve seen preclinical evidence showing that this paradigm synergizes well with dipeptidyl peptidase FAP and PD-1 inhibition. We’re hoping to look for these novel combinations to inform the next set of clinical trials.

Reference

1. Weinberg BA, Lekan A, Malchiodi ZX, et al. BXCL701 plus pembrolizumab in second-line advanced pancreatic ductal adenocarcinoma. Ann Oncol. 2025;36:S101-S102. doi:10.1016/j.annonc.2025.05.274