PK/PD analyses of circulating tumor DNA (ctDNA) in patients with metastatic colorectal cancer (mCRC) treated with telisotuzumab adizutecan (ABBV-400).

233 Background: Telisotuzumab adizutecan (ABBV-400) is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload adizutecan. The ongoing first in human phase 1 trial (Study M21-404; NCT05029882) shows that ABBV-400 has encouraging radiographic response and ctDNA molecular response (MR) as monotherapy in patients with advanced solid tumors, including mCRC. Herein, correlation between ABBV-400 exposures and % change in ctDNA from baseline and PK/PD analyses using MR are presented for mCRC patients. Impact of c-MET expression and MET amplification ( MET -amp) status on exposures was also evaluated. Methods: Analyses utilized preliminary data in mCRC patients (N=122) from study M21-404 where subjects were treated with ABBV-400 (1.6 – 6.0 mg/kg Q3W). Serial PK samples were collected in cycles 1 (C1) and 3 (C3) and sparse samples across other cycles. C1 exposure metrics (C max , C avg , and C trough ) for both ABBV-400 conjugate and unconjugated payload were obtained by non-compartmental PK analysis. Baseline and C3 day 1 plasma samples were collected and analyzed using the Guardant INFINITY assay for biomarker analysis. ctDNA (circulating tumor fraction [cTF]) was estimated based on 1) variant allele frequency of somatic mutations in a 74 gene panel and 2) methylation signals across targeted regions of the Guardant INFINITY methylation panel. MR was defined as a 50% decrease in cTF from baseline. PK/PD correlations with % change in cTF at C3 and MR at C3 were evaluated. c-Met protein expression was assessed by IHC (VENTANA MET SP44 RxDx Assay) and MET -amp status was based on available local testing results and retrospective ctDNA testing. Results: Higher exposures of ABBV-400 conjugate and payload (primarily C avg for both analytes and C max for conjugate) correlated with greater decrease in % change in cTF at C3 from baseline, as assessed by the 74 gene panel (N =66) or methylation panel (N=74). PK/PD analysis showed that higher exposure was strongly correlated with higher probability of MR (n=66-74, nominal p < 0.05). ABBV-400 conjugate and payload exposures were comparable across c-Met expression H-score (range 9 – 295), cut-offs (≥90% with 1+ intensity, ≥50% with 2+, ≥10% with 3+, ≥25% with 3+, and ≥50% with 3+), and MET -amp status. Conclusions: Exposure-response analyses have previously shown correlation between ABBV-400 conjugate exposures and probability of efficacy (objective response rate) as well as safety in mCRC subjects. The current PK/PD analyses demonstrate that higher ABBV-400 conjugate and payload exposures are also correlated with liquid biopsy data, i.e., ctDNA and MR based on ctDNA. c-MET expression and MET-amp did not have impact on ABBV-400 exposures. Clinical trial information: NCT05029882 .