PI-073 - INTEGRATED MODEL-BASED ANALYSIS UTILIZING CO-EXPRESSED CHECKPOINT INHIBITOR DATA TO INFORM THE RECOMMENDED DOSE FOR EXPANSION (RDE) OF ANTI-TIGIT MAB M6223.

I. Kareva¹, P. Hu¹, W. Gao¹, E. Richter², K. Tadjalli Mehr², T. Kitzing², A. Victor², K. Venkatakrishnan¹, A. Zutshi¹, V. Pierre¹; ¹EMD Serono, Billerica, MA, USA, ²Merck KGaA, Darmstadt, Germany.

Background: M6223 is a humanized IgG1 mAb that inhibits TIGIT receptors on immune cells and restores immune competency in the tumor microenvironment (TME). This work aims to leverage emerging clinical PK/PD data to inform posology by optimizing TIGIT receptor target occupancy (TO) in the TME.

Methods: Serum PK and antidrug antibody data in 30 patients treated in study NCT04457778 with M6223 (10–2400 mg) IV every 2 weeks (Q2W; n=20), and M6223 + bintrafusp alfa (bifunctional TGF-β trap/anti–PD-L1) 1200 mg IV Q2W (n=10) were analyzed via population PK (popPK) methods. Estimated PK parameters and binding data were incorporated in a translational PK/PD model to describe the systemic and intratumoral M6223 disposition and ligand binding dynamics. Due to the dearth of TIGIT target engagement data and given the co-expression of TIGIT and PD-1 receptors on immune cells, we leveraged published anti–PD-1 tumor TO data for model calibration and development by assuming similar target expression. Further calibration was conducted by analyzing available data on other anti-TIGIT mAbs.

Results: M6223 mean clearance was 16 mL/h (44% CV). Our translational model described PK and blood TO data for M6223 and publicly available digitized data from clinically evaluated anti-TIGIT mAbs. Our analysis suggested that the typical recommended phase 2 dose for anti-TIGIT mAbs corresponds to >90% TIGIT TO in the TME. While sustained blood TIGIT TO >95% was observed at M6223 ≥900 mg Q2W, simulations predicted 1600 mg Q2W to provide >95% TME TO for clearance ranging from 12–35 mL/h. Integrated with multi-cycle tolerability and safety data, an RDE of 1600 mg Q2W was selected.

Conclusion: This example of M6223 illustrates the value of leveraging emerging clinical PK/PD and publicly available data to inform dosing strategy in early oncology drug development.