Abstract CT151: Comparative pharmacokinetics and tumor activation of fibroblast activation protein (FAP)-enabled pre|CISION® peptide drug conjugates

Abstract Background: pre|CISION® peptide drug conjugates comprise a peptide moiety bound to a payload by a linker that is specifically cleaved by FAP, a protease selectively overexpressed in the tumor microenvironment (TME) of many solid tumors. The pre|CISION® peptide moiety prevents cellular entry of the conjugate unless cleaved by FAP, enabling targeted delivery of released payload directly to tumors. Two payloads are described using this platform: AVA6000 (doxorubicin [dox]; pre-clinical and clinical) and AVA6103 (exatecan, pre-clinical). Methods: Pharmacokinetic (PK; plasma and intra-tumoral) parameters of the conjugate and released payload were investigated pre-clinically (for both AVA6000 and AVA6103) in tumor-bearing mice. Clinical validation was sought for AVA6000 given intravenously q2w or q3w in a first-in-human, 3+3 dose escalation Phase 1 trial exploring the safety, PK and preliminary efficacy. Results: Preclinical data with both AVA6000 and AVA6103 demonstrate substantial tumor-specific payload release, with high tumor-to-plasma ratios ranging from 10:1 to > 200:1 indicating selective release and uptake within the tumor. Preliminary analysis of PK data with AVA6103 in murine models demonstrated a differentiated PK profile versus AVA6000 with sustained payload release in the tumor (tumor:plasma of 10:1 longer than 24 hours) with no systemic exatecan exposure beyond 4 hours. In the Phase 1 trial of AVA6000, 63 patients received escalating doses of AVA6000 from 80mg/m2 (equivalent to 54 mg/m2 dox) to 385 mg/m2 (260 mg/m2 dox) with no MTD identified in the trial. Importantly, of the 63 patients dosed, 53 patients received molar equivalent doses of dox higher than the conventional 75 mg/m2 dose. PK proof of principle was demonstrated in patients treated with AVA6000, with elevated released tumor dox concentrations (median tumor:plasma 100:1 at 24 hours post first dose) and lower plasma Cmax of released dox (77.9-92.5% reduction). The AUC of released dox was lower (4.8-77%) across dose levels when compared with published data for conventional dox (75 mg/m2). In addition, released dox had a 40% lower volume of distribution and a >40% increase in plasma elimination half-life compared with conventional dox (75 mg/m2, historical data). Clinical toxicities were reduced relative to historical data and preliminary signals of efficacy were seen, including a disease control rate of 90% in patients with salivary gland cancers (n=10) treated at >250 mg/m2 doses. Conclusion: In the Phase 1 trial, AVA6000 exhibits promising tumor-targeting characteristics with encouraging clinical activity and reduced systemic toxicities validating the tumor-specific FAP cleavage mode of action. These AVA6000 data along with the preclinical PK data with AVA6103 have informed the predictive modeling to support the clinical development of AVA6103 by optimizing the delivery of the exatecan payload. Citation Format: Gezim Lahu, Udai Banerji, William C. Tap, Natalie Cook, Jeff T. Evans, Ruth Plummer, Alan Anthoney, Christopher Plummer, Rhona Dawson, Paul Loadman, Huw Jones, Nelson Kinnersley, Ruairidh Edwards, Curtis Rink, Ellen Watts, Gilad Gordon, Lee D. Cranmer, Chris Twelves. Comparative pharmacokinetics and tumor activation of fibroblast activation protein (FAP)-enabled pre|CISION® peptide drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT151.