Adding the phosphatidylserine-targeting antibody bavituximab to the immunotherapy agent pembrolizumab may improve response rates without compromising safety in patients with hepatocellular carcinoma, according to a recent study published by Hsieh et al in Nature Communications. The findings demonstrate the potential benefits of augmenting immunotherapy for hepatocellular carcinoma and other types of cancers.
Background
Hepatocellular carcinoma is the most common type of hepatic cancer and the fourth leading cause of cancer-related mortality across the world. In 2007, the U.S. Food and Drug Administration approved the targeted therapy drug sorafenib, which was then the only existing treatment for unresectable hepatocellular carcinoma. Although the drug is capable of slowing the growth of tumor-feeding blood vessels, it only extends survival by a few months.
Immunotherapies have since emerged as the most effective treatment options for patients with hepatocellular carcinoma. Nonetheless, only a fraction of patients responds to these drugs when delivered alone. For instance, about 16% of patients with hepatocellular carcinoma respond to treatment with pembrolizumab alone. Additionally, combining multiple immunotherapies may increase the likelihood of severe and potentially lethal side effects.
Previous research has shown that phosphatidylserine—a fatty phospholipid sometimes present on the surface of cancer cells—appeared to interact with immune cells to prevent them from attacking tumors. Bavituximab works to neutralize phosphatidylserine but showed no effect on tumor response, progression, or survival when administered alone across multiple cancer types or when combined with sorafenib in hepatocellular carcinoma; however, bavituximab was never tested in combination with immunotherapy agents.
Study Methods and Results
In the recent phase II clinical trial, researchers assigned 28 patients with unresectable hepatocellular carcinoma to undergo imaging at baseline. The patients subsequently received bavituximab plus pembrolizumab and underwent periodic imaging to determine whether their tumors shrank, stopped growing, or continued to grow and spread.
After an average follow-up of 28.5 months, the researchers found that 32% (n = 9) of the patients responded to the combination therapy—two of whom had a complete response with no evidence of disease on imaging at the end of the trial. The combined therapy halted cancer progression in an additional 32% (n = 9) of the patients. Among those who responded to the drugs, their tumors continued to shrink for a median of 13.3 months, and four of the patients were still responding to the combination therapy by the end of the trial.
After comparing the results with prior trials, the researchers noted that adding bavituximab did not appear to increase side effects over those taking pembrolizumab alone—representing the potential safety of the combination therapy.
Conclusions
“This study shows the promise of improving the success of cancer immunotherapies by targeting other immunomodulating proteins simultaneously,” emphasized lead study author David Hsieh, MD, Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Experimental Therapeutics Research Program at the Harold C. Simmons Comprehensive Cancer Center at the UT Southwestern Medical Center.
These findings indicated that adding phosphatidylserine-targeting agents to immunotherapy regimens could increase the rate of response among patients with hepatocellular carcinoma and potentially other cancer types in which this protein might affect anticancer immunity.
Disclosure: The research in this trial was supported by Merck, grants from the National Cancer Institute (NCI), the European Commission, the Cancer Prevention and Research Institute of Texas, and the NCI’s Cancer Center Support Grant. For full disclosures of the study authors, visit nature.com.
