Bavituximab Plus Pembrolizumab Elicits Responses in Untreated Advanced HCC

David Hsieh, MD

Bavituximab (PGN401) in combination with pembrolizumab (Keytruda) produced responses in patients with previously untreated advanced hepatocellular carcinoma (HCC), according to data from a phase 2 trial (NCT03519997) presented at the 2023 Gastrointestinal Cancers Symposium.¹

Additionally, biomarker data from the study showed patients identified as biomarker positive with the Xerna™ TME Panel experienced higher response rates compared with patients who were biomarker negative.

Twenty-eight patients received bavituximab plus pembrolizumab and were evaluable for response. The objective response rate (ORR) was 32.1%, including a complete response rate (CR) of 7.1%, a partial response (PR) rate of 25.0%. The stable disease (SD) rate was 17.9%, and the progressive disease (PD) rate was 50.0%.

Among all patients with biomarker data available (n = 19), the ORR was 31.6%, with CR, PR, SD, and PD rates of 5.3%, 26.3%, 15.8%, and 52.6%, respectively. Biomarker-positive patients (n = 8) experienced an ORR of 62.5% with a CR rate of 12.5% and a PR rate of 50%. The SD and PD rates were 12.5% and 25.0%, respectively. In biomarker-negative patients (n = 11), the ORR was 9.1%. No patients had a CR and 1 had a PR. The SD and PD rates were 18.2% and 72.7%, respectively.

“Our newly reported clinical data in frontline liver cancer show a near doubling of response rate in the subset of patients classified as biomarker-positive by the Xerna TME Panel. The high response rate seen in these patients is rarely achieved in this challenging disease,” David Hsieh, MD, assistant professor at University of Texas Southwestern Medical Center and lead investigator of the trial, stated in a news release.²

“Moreover, our patients are potentially more reflective of typical U.S.-based patients compared to those included in recent large, pivotal trials that enrolled the majority of their patients at sites outside of the US,” he added. “We are therefore excited by the prospect of using this panel to optimize the care of patients with liver cancer.”

Bavituximab is a first-in-class chimeric monoclonal antibody that complexes with B2-glycoprotein 1 to inhibit immunosuppressive phosphatidylserine signaling. Phosphatidylserine is a highly immunosuppressive molecule that is typically expressed on the inner leaflet of the plasma membrane of normal cells. Phosphatidylserine is externalized to the outer leaflet of the plasma membrane on cells lining tumor blood vessels, tumor cells, and exomes in the tumor microenvironment.

The single-arm, phase 2 trial examined the clinical activity of the combination of bavituximab and pembrolizumab in patients with previously untreated, locally advanced or metastatic advanced HCC that is not amenable to locoregional therapy.

Enrolled patients received 3 mg/kg of intravenous (IV) bavituximab once per week plus 200 mg of IV pembrolizumab once every 3 weeks.

ORR is the trial’s primary end point. Secondary end points included overall survival, 6-month progression-free survival, duration of response, and safety. Correlative biomarkers were an exploratory end point.

The median patient age was 64 years (range, 60-67). Additionally, 85.7% of patients were male, 50% were White, 50% were Black, and 92.9% were non-Hispanic.

Regarding safety, bavituximab plus pembrolizumab was well tolerated, and investigators recorded no new safety signals. The most common any-grade treatment-related adverse effects (TRAEs) included diarrhea (17.9%), rash (10.7%), increased aspartate aminotransferase (10.7%), fatigue (10.7%), pruritus (10.7%), chills (7.1%), decreased platelet count (7.1%), and increased alanine transaminase (7.1%).

The most common grade 3 or higher TRAEs comprised rash, increased AST, and diarrhea, which were observed in 1 patient each.

Investigators conducted biomarker analysis with pre-treatment biopsies analyzed for RNA expression using the Xerna TME Panel to determine the dominant angiogenic and immunogenic biology of a patient’s tumor microenvironment (TME). A retrospective analysis was conducted to determine if tumors deemed biomarker positive with immune active or immune suppressed TME subtypes were more likely to respond to the combination of bavituximab plus pembrolizumab compared with tumors deemed biomarker negative with angiogenic or immune desert TME subtypes.

“The Xerna TME Panel has demonstrated remarkable consistency in identifying patients who are more likely to benefit from targeted and immune therapies across several malignancies,” Hagop Youssoufian, MD, chief medical officer of OncXerna Therapeutics and adjunct professor of Medicine at Brown University, stated in a news release. “Although this was a proof-of-concept study, the responses noted in the biomarker-positive subgroup of patients in this lethal disease indicate substantial activity by comparison to the most active and contemporary combination therapies. This is the latest example of OncXerna’s longstanding commitment to utilize the Xerna TME Panel to bring the right medicines to the right patients.”

References

1. Hsieh D, Kainthla R, Zhu H, et al. Phase 2 trial of pembrolizumab (pembro) and bavituximab (bavi) in advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2023;41(suppl 4):584. doi:10.1200/JCO.2023.41.3_suppl.584
2. OncXerna Therapeutics announces final results and new Xerna™ TME Panel biomarker data from a phase 2 trial of bavituximab plus pembrolizumab in patients with previously untreated advanced hepatocellular carcinoma. News release. January 23, 2023. Accessed January 24, 2023. http://bit.ly/3XTtCR3