The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial

David Hsiehchen (), Muhammad S. Beg, Radhika Kainthla, Jay Lohrey, Syed M. Kazmi, Leticia Khosama, Mary Claire Maxwell, Heather Kline, Courtney Katz, Asim Hassan, Naoto Kubota, Ellen Siglinsky, Anil K. Pillai, Hagop Youssoufian, Colleen Mockbee, Kerry Culm, Mark Uhlik, Laura Benjamin, Rolf A. Brekken, Chul Ahn, Amit G. Singal, Hao Zhu, Yujin Hoshida and Adam C. Yopp
Additional contact information
David Hsiehchen: University of Texas Southwestern Medical Center
Muhammad S. Beg: University of Texas Southwestern Medical Center
Radhika Kainthla: University of Texas Southwestern Medical Center
Jay Lohrey: University of Texas Southwestern Medical Center
Syed M. Kazmi: University of Texas Southwestern Medical Center
Leticia Khosama: University of Texas Southwestern Medical Center
Mary Claire Maxwell: University of Texas Southwestern Medical Center
Heather Kline: University of Texas Southwestern Medical Center
Courtney Katz: University of Texas Southwestern Medical Center
Asim Hassan: University of Texas Southwestern Medical Center
Naoto Kubota: University of Texas Southwestern Medical Center
Ellen Siglinsky: University of Texas Southwestern Medical Center
Anil K. Pillai: University of Texas Southwestern Medical Center
Hagop Youssoufian: OncXerna Therapeutics
Colleen Mockbee: OncXerna Therapeutics
Kerry Culm: OncXerna Therapeutics
Mark Uhlik: OncXerna Therapeutics
Laura Benjamin: OncXerna Therapeutics
Rolf A. Brekken: University of Texas Southwestern Medical Center
Chul Ahn: University of Texas Southwestern Medical Center
Amit G. Singal: University of Texas Southwestern Medical Center
Hao Zhu: University of Texas Southwestern Medical Center
Yujin Hoshida: University of Texas Southwestern Medical Center
Adam C. Yopp: University of Texas Southwestern Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3–11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.

Date: 2024
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DOI: 10.1038/s41467-024-46542-y

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