PI-093 - A COMPREHENSIVE MIDD APPROACH TO ASSESS THE SAFETY AND EFFICACY OF TARGETED-THORIUM-CONJUGATES IN PATIENTS FOR EARLY DECISION MAKING.

M. Block¹, C. Wang², Y. Zhang², U. Kuhnert³, S. Hammer³, S. Johanssen³, C. Zieschang³, V. Jardine⁴, P. Kraemer⁵, H. Hennekes³, P. Morcos⁵; ¹Bayer AG, Leverkusen, Germany, ²Bayer AG, Wuppertal, Germany, ³Bayer AG, Berlin, Germany, ⁴Bayer UK, Reading, United Kingdom, ⁵Bayer, Whippany, NJ, USA.

Background: Pelgifatamab-corixetan, a PSMA Targeted-Thorium-Conjugate (TTC) specifically delivers alpha-particle radiation to prostate cancer tumors expressing PSMA by linking thorium-227 to the PSMA targeting monoclonal antibody. Different radiopharmaceuticals show myelosuppressive effects. The evaluation of expected frequencies for myelosuppression and the expectation for efficacy is key to get to early informed decisions. Here, we show a comprehensive modeling framework to assess the expected therapeutic window for pelgifatamab-corixetan.

Methods: Preclinical and clinical data were used to inform a model for myelosuppression, PSA response and tumor growth in patients. The model accounts for differences in radiation yield among cell cycle phases and captures specific properties of the addressed clinical population. The relation of PSA values to tumor growth were included. Model predictions were compared to observations from the Phase I study. A popPK/PD approach only informed by clinical data was applied to confirm the assessments.

Results: The model-based assessments predict a myelosuppression pattern, that resembles clinical observations on neutropenia and thrombocytopenia at all dose levels ranging from 0.25 to 6.6 MBq. The efficacy model was used to assess the related expected PSA responses. Different alternative scenarios were simulated to assess expectations based on the model.

Conclusion: The modeling framework presented has been qualified by preclinical and clinical data and is able to represent the clinical observations very well and to assess the expected PSA response for PSMA-TTC. The representation of the processes enables the assessment of preclinical and clinical data by the same platform. The platform approach can be used to assess other targeted radiotherapies in a similar way.