Exposure-response analyses from a randomized dose optimization study of telisotuzumab adizutecan (Temab-A) in combination with bevacizumab in patients with metastatic colorectal cancer (mCRC).

132 Background: Telisotuzumab adizutecan (Temab-A) is an antibody-drug conjugate (ADC) consisting of a c-Met targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload adizutecan. A randomized dose optimization study of Temab-A in combination with bevacizumab (BEV) in patients with mCRC has been conducted in Part 7 of the ongoing phase 1 trial (NCT05029882). Herein, results from the Temab-A exposure-response (ER) analyses for efficacy and safety to determine the optimal dose for this combination are presented. Methods: The ongoing phase 1 trial included a safety lead-in (Part 7a; 1.6 and 2.4 mg/kg every 3 weeks [Q3W] Temab-A+BEV) followed by a randomized dose optimization study evaluating two dose levels of Temab-A (Part 7b; 2.0 and 2.4 mg/kg Q3W) in combination with BEV and a third randomized arm evaluating standard of care (SOC); trifluridine/tipiracil+BEV; N=20) in patients with mCRC. Analyses utilized preliminary data from 63 subjects treated with Temab-A+BEV across the three dose levels from Parts 7a and b. Serial pharmacokinetic (PK) samples were collected and population PK modeling (using NONMEM) utilized to estimate post hoc exposure metrics for ER analyses. Objective response rate (ORR) was defined per RECIST v1.1. Grade 3+ adverse events (AEs) evaluated were neutropenia, anemia, and treatment-emergent AEs (TEAEs). ER correlations for efficacy and safety were evaluated using exposure-quartile plots and logistic regression. Relative dose intensity (RDI) analyses were performed. Results: PK following coadministration with BEV was consistent with monotherapy. ER analyses for efficacy showed Temab-A conjugate Cavg was correlated with ORR; indicating higher conjugate exposures resulted in an increased probability of ORR (p=0.014). ER evaluations for safety showed higher payload (and ADC) exposures correlated with safety events occurrence (Grade 3+ TEAEs; p < 0.04). The median RDI was 90-100%, with both dose levels of 2.0 and 2.4 mg/kg Q3W. The ER model-predictions showed 2.4 mg/kg Q3W Temab-A in combination with BEV is predicted to result in higher ORR than both 2.0 mg/kg and SOC, and higher Grade 3+ TEAEs than 2.0 mg/kg but similar safety profile compared to SOC. Results were similar with evaluations based on the randomized dose optimization (RDO) part 7b alone. Conclusions: Consistent strong ER relationships were demonstrated for Temab-A+BEV from an RDO study. These findings were similar to those from Temab-A monotherapy, which supported 2.4 mg/kg Q3W dosing in a cMet unselected mCRC population to provide good balance between efficacy and safety. Clinical trial information: NCT05029882 .