NATIONAL HARBOR, Md. — An investigational bispecific T-cell engager appeared safe and demonstrated some clinical activity among patients with HER2-positive solid tumors, according to phase 1 dose-escalation study data presented at Society for Immunotherapy of Cancer Annual Meeting.
The results showed a disease control rate of 58% with no serious treatment-related adverse events.
PRS-343 (Pieris Pharmaceuticals) is a bivalent, bispecific fusion protein targeting CD137 (4-1BB) and HER2 on T cells and other immune cells. The bispecific molecule comprises an agonistic CD137-targeting Anticalin — commercially developed artificial proteins that can bind to antigens — genetically linked to a HER2-targeting antibody.
“By localizing 4-1BB activation to the tumor microenvironment, we thought we could avoid some of the systemic toxicities associated with naked 4-1BB antibodies,” Geoffrey Y. Ku, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center and one of the study co-authors, told the audience at STIC 2019.
“If the density of the HER2 protein is high enough, then it facilitates cross-linkage with 41-BB, which is an immune agonist that is present in activated T cells,” Ku said. He further explained that cross-linkage helps to improve T-cell exhaustion that is critical for T-cell expansion.
Patients in this dose-escalation study received 0.0005 to 8 mg/kg IV doses of PRS-343 once every 3 weeks. Patients who received the 8 mg/kg dose were treated once every 2 weeks.
Study objectives included determination of the maximum tolerated dose and overall safety profile.
Secondary objectives included disease control rate, ORR, pharmacodynamic biomarker response and pharmacokinetic profile. Researchers evaluated pharmacodynamic response — as determined by CD8-positive T cells on immunohistochemistry — using tumor biopsies taken before and after treatment with PRS-343.
The study included 53 patients (median age, 61 years: range 29-92; 62% women; 82% white; 59% with more than three previous lines of therapy) with gastric/esophagogastric junction cancer (n = 19), breast cancer (n = 14), gynecologic cancer (n = 6), colorectal cancer (n = 5), biliary tract cancer (n = 4), urothelial cancer (n = 2), melanoma (n = 1), pancreatic cancer (n = 1) and salivary duct cancer (n = 1).
Researchers determined the low end of the active dose range to be 2.5 mg/kg, based on pharmacokinetic analyses and observed kinetics of the CD8-positive T-cell expansion after treatment with PRS-343.
Nineteen patients treated at active dose levels before data cutoff on Sept. 6 were able to undergo evaluation for response to therapy. The analysis showed a disease control rate of 58%, with 11% of patients having a confirmed partial response per RECIST 1.1 criteria.
At the active doses, investigators noted a significant post-treatment expansion of CD8-positive T cells, particularly in the tumor nests. This was consistent with PRS-343’s mechanism of action, according to the investigators. Expansion of CD8-postive T cells after therapy appeared greater among patients who had a confirmed partial response or prolonged stable disease.
There were no grade 3 or grade 4 treatment-related adverse events. The most frequently reported treatment-related adverse events included fatigue (9%), chills (6%) and diarrhea (5%). None of the adverse events qualified as a dose-limiting toxicity. – by Drew Amorosi
Piha-Paul S, et al. Abstract O82. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-10, 2019; National Harbor, Md.
Disclosures : HemOnc Today could not confirm the researchers’ relevant financial disclosures at the time of reporting.