PII-092 - YOU MUST CHOOSE, BUT CHOOSE WISELY – PHASE 2 DOSE SELECTION FOR INBRX-109, A TETRAVALENT DEATH RECEPTOR 5 (DR5) AGONIST ANTIBODY.

S. Bhagwat¹, C. Veldstra¹, B. Eckelman¹, K. Willis¹, C. Bais¹, V. Adrianov¹, K. Bayer¹, J. Jensen¹, K. Brown², F. Engler³, A. Zandvliet⁴, Y. Lin⁵, J. Kalabus¹; ¹Inhibrx, San Diego, CA, USA, ²Certara, London, England, United Kingdom, ³Certara, Buffalo, NY, USA, ⁴Certara, Amsterdam, The Netherlands, ⁵Certara, Melbourne, Australia.

Background: Activation of Death Receptor 5 (DR5) naturally eliminates damaged and/or neoplastic cells. INBRX-109 is a precision-engineered, tetravalent death receptor 5 (DR5) agonist antibody designed to overcome the limitations of earlier-generation agonists. In vitro and in vivo preclinical studies using a human cancer cell line showed evidence of a bell-shaped dose-response curve, thus indicating that the conventional MTD approach for dose selection was not optimal for INBRX-109.

Methods: A PK/PD model was developed using PK and tumor volume data pooled from COLO205 cell line derived xenograft mouse studies. In the combined PK/PD model, INBRX-109 concentration in the central compartment was used to drive an empirical tumor growth stimulation function.

Data from the ongoing Ph 1 clinical study were utilized to enable development of a pop PK model.

Results: To characterize INBRX-109 PK and the dynamic relationship between INBRX-109 drug exposure and the resulting anti-tumor effect, population PK and PK/PD models were developed with data from preclinical efficacy models. Studies of INBRX-109 in COLO205 xenograft mouse models showed a bell-shaped dose-response relationship. A 2-compartment PK model with linear elimination best fit the nonclinical PK data. Dynamic tumor volume was best fitted by a tumor growth model featuring logistic growth and first-order elimination of tumor. The final PK/PD model suggested an optimally efficacious range of INBRX-109 concentrations. Simulations of clinical exposure were performed to confirm appropriate RP2D selection.

Conclusion: A 2-compartment PK model with linear elimination best described the disposition of INBRX-109 in humans. Overall, the nonclinical and clinical data and PK/PD modeling supported the selection of the 3 mg/kg Q3W dosing regimen in Phase 2.