Abstract

Immunotherapy has yet to demonstrate durable efficacy in pancreatic ductal adenocarcinoma (PDAC) despite the fact that pancreatic cancer cells have higher levels of immune checkpoint expression than other cancer cell types in which immunotherapy efficacy has been well established. We observed effective cytotoxicity with the combination therapy of pembrolizumab (an anti-PD-1 monoclonal antibody, mAb) and cabozantinib (an anti-MET small molecule) in vivo. This served as the basis for an investigator-initiated phase II clinical trial (NCT05052723). The trial was open to patients with treatment-refractory metastatic PDAC with a single-arm treatment protocol of pembrolizumab and cabozantinib. Here, we report the case of a patient with metastatic PDAC who had received two prior lines of systemic therapy and was enrolled in our trial after presenting with pulmonary metastasis. She had a durable response to cabozantinib and pembrolizumab and remained on the trial for 25 months before demonstrating radiographic signs of disease progression. Notably, her initial pathology revealed poorly differentiated adenocarcinoma with features of undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), which is an established rare variant of PDAC. Subsequent biopsies at metastatic sites revealed adenocarcinoma consistent with a pancreatic primary tumor. We hypothesize that the immune features of UCOGC, including increased PD-1 and PD-L1 expression and tumor-infiltrating lymphocytes, may have contributed to the effectiveness of this combination immunotherapy regimen in this patient’s response.

Document Type

Article

Publication Date

2026

Notes/Citation Information

© 2026 Reagan, McDonald, Kang, Saghaeiannejad Esfahani, Wright, Bailey, Ellis, Collette, Patel, Murillo, Stokley, Cavnar, Pandalai, Barry-Hundeyin, Moss and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Digital Object Identifier (DOI)

https://doi.org/10.3389/fonc.2026.1675133

Funding Information

The author(s) declared that financial support was received for this work and/or its publication. This work was partially funded by Exelixis and pembrolizumab was provided for the study by Merck. AR and HM were supported by NIH training grant T32CA160003.

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