PII-060 - PHARMACOKINETICS (PK) AND SOLUBLE MET (SMET) PHARMACODYNAMICS (PD) OF REGN5093, A MET X MET BISPECIFIC ANTIBODY, IN PATIENTS (PTS) WITH MET-ALTERED ADVANCED NON-SMALL CELL LUNG CANCER (ANSCLC)

S. Masinde¹, R. Krishna², A. Paccaly¹, S. Fraser¹, S. Irvin¹, M. Retter¹, H. Magnan¹, T. Navas¹, J. Davis¹; ¹Regeneron Pharmaceuticals, Inc., ²Certara USA, Inc..

Background: REGN5093 is a human bispecific antibody that binds to 2 distinct epitopes of MET, and is in clinical evaluation for MET-altered aNSCLC.

Methods: An open label, Phase 1/2, first-in-human study evaluating the safety, tolerability, PK, PD, and antitumor activity of REGN5093 as monotherapy in MET-altered aNSCLC is in progress (NCT04077099). A modified 3+3 design (4+3) was used for the dose-escalation phase, and a Simon 2-stage design was used for the expansion phase. IV REGN5093 doses Q3W included 500, 1000, and 2000 mg in MET-altered aNSCLC. Pts in the expansion phase received IV REGN5093 2000 mg Q3W. Total REGN5093 concentrations (conc) and total sMET conc were measured in neat human serum using validated assays (an ELISA [LLOQ, 0.0614 mg/L] and an electrochemiluminescence assay [LLOQ, 0.041 mg/L]). Immunogenicity (assessed by ADA response against REGN5093) was evaluated using a validated electrochemiluminescence bridging assay. Noncompartmental analyses were performed to determine PK parameters. Total sMET conc were used as a surrogate biomarker of target engagement in the study.

Results: PK and sMET analyses were performed in 81 pts; immunogenicity was evaluated in 44 pts. The concentration-time profiles of REGN5093 in serum after the first IV doses of 500–2000 mg Q3W were characterized by an initial distribution phase followed by monoexponential elimination; total REGN5093 exposure was dose proportional. Generally, REGN5093 conc in pts with NSCLC agreed with predictions based on preclinical data. In the dose-escalation phase, mean conc increased ~2‑fold following dosing Q3W. On a molar basis, mean total REGN5093 conc exceeded mean total sMET conc at all doses over time, and was >100-fold greater at REGN5093 2000 mg Q3W. In the expansion phase, at REGN5093 2000 mg Q3W, total sMET conc reached a plateau and were consistent across the cohorts. None of the 44 pts evaluated for immunogenicity had a positive ADA response against REGN5093.

Conclusion: At REGN5093 2000 mg Q3W, exposure of total REGN5093 increased dose proportionally and total sMET conc reached a plateau, suggesting that total antibody conc in serum had saturated clearance due to MET binding. These findings support the IV REGN5093 2000 mg Q3W regimen to be considered as a Phase 2 dose.