Abstract CT506: Exposure-response analysis of batiraxcept and application to recommended phase 2 dose in platinum-resistant ovarian and clear cell renal cancers
Authors: Mcintyre Gail , Rangwala Reshma , Dodds Michael G. , Barriere Olivier 
Published: June 2022

Abstract
Purpose: Batiraxcept is a novel Fc fusion protein that inhibits the growth arrest-specific (GAS)/AXL signaling pathway by binding the sole activating GAS6 ligand, which reduces AXL signaled invasion and migration of highly metastatic cells in vitro and inhibits metastatic disease in nonclinical models of aggressive human cancers. We used dose-exposure (D-E) and exposure-response (E-R) modeling and simulation to identify a recommended Phase 2 dose (RP2D). The D-E modeling is expected to apply to any cancer and batiraxcept combination, while the E-R modeling may be disease specific.
Patients and Methods: A population pharmacokinetic (PK)/pharmacodynamic (PD) model was applied to exposure data from healthy volunteers (n=24, Phase (P) 1 study, single ascending dose cohort [NCT03401528]) and platinum-resistant ovarian cancer (PROC) patients (n=42, P1b study [NCT03639246]) treated with either batiraxcept+paclitaxel or batiraxcept+pegylated liposomal doxorubicin to capture the D-E relationship of batiraxcept. A Cox Proportional Hazards Model was applied to progression-free survival (PFS) observed from the PROC patients, to capture the E-R relationship of batiraxcept. The models were used to study PFS in prospective studies of 5, 10, 15, and 20 mg/kg administered iv once every 2 weeks at the 10th, 50th (median), and 90th percentile of expected exposure metrics. In a separate P1b study in 2L+clear cell renal cell carcinoma (ccRCC), 23 patients were dosed with 15mg/kg or 20mg/kg batiraxcept in combination with standard of care cabozantinib [NCT04300140]. PK, PD, and clinical response data from both doses tested in ccRCC were compared to the modeling predictions generated from the PROC study.
Results: The PROC E-R analysis predicted that a dose of 15mg/kg would provide exposure levels associated with longer PFS, and a 20mg/kg dose did not add additional benefit. Fifteen mg/kg was identified as the RP2D from the PROC P1b study and is the batiraxcept dose being evaluated in combination with standard of care weekly paclitaxel in the ongoing PROC P3 study [NCT04729608]. PK and PD data from the ccRCC P1b study compare favorably with simulations from the PROC D-E model. Consistent with simulations from the PROC E-R analysis, the 20mg/kg dose did not provide additional benefit above that seen with the 15mg/kg dose in the ccRCC P1b study, indicating these doses are at the plateau of drug effect.
Conclusion: Consistent with emerging U.S. Food and Drug Administration guidance around a more thoughtful approach to dose selection in cancer (“Project Optimus”), E-R analysis supported the identification of batiraxcept 15mg/kg as the RP2D in the PROC P1b study. Furthermore, PK/PD and preliminary activity of batiraxcept 15mg/kg+cabozantinib are consistent with these data and support the batiraxcept RP2D of 15mg/kg across different tumor types and combinations with batiraxcept.
Citation Format: Gail Mcintyre, Reshma Rangwala, Michael G. Dodds, Olivier Barriere. Exposure-response analysis of batiraxcept and application to recommended phase 2 dose in platinum-resistant ovarian and clear cell renal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT506.