Phase 1, FIH study of cabotamig, a TCE CDH17 X CD3, in CDH17-expressing GI malignancies.

3603 Background: Cadherin-17 (CDH17) is a specific cancer target; aberrant expression is up to >95% in GI tumors (stomach, pancreas, bile duct, rectum, small bowel and colon). Cabotamig (ARB202) is a humanized, IgG4, T-cell engaging antibody (TCE) that binds to CDH17 and CD3 T-cells forming synapse to aid activation. This study evaluated the safety, pharmacokinetics (PK), biomarkers, and anti-tumor activity of cabotamig in patients (pts) with CDH17+ gastrointestinal (GI) cancers. Methods: Pts ≥18 years with locally advanced or metastatic CDH17+ GI cancers refractory to therapies, measurable disease and ECOG 0/1 were enrolled. MABEL calculations per FDA TCE guidance were used (0.0003 mg/ml to 1.0 mg/ml by ½ log increments). For safety given multi log difference in CDH17 density, an initial dose of 1/10 was given 3 days before the remaining 9/10. In the 4th cohort, patients with stable disease were given additional doses (7/10 cohort 4-6). Cohort was split into colorectal cancers (CRC) and non-CRC groups given the differences in CDH17 levels and symptoms. After the 7th cohort dosing proceeded to dose optimization. Data cutoff 02142025. Results: Pts (CRC 15/22 total) received cabotamig at 1/10 dose (0.00003-0.032 mg/kg) followed by 9/10 dose (0.0003 to 0.32 mg/kg) across 7 cohorts with the max. of 37.8(3.8/34) mg. The max. tolerated dose was not reached. Dose responsive cytokine release syndrome (CRS) symptoms were evident with more symptoms between the 1/10 and 9/10 dose and with increasing intensity with escalation. Treatment related AEs (CRS 17, fever 16, nausea 7, diarrhea 5, vomiting 5 fatigue 3 chills 2) were reported with 1 st set or 2 nd infusions and occurred in all patients without pre-corticosteroids in the 4 th cohort and intensified even with premed up to the 7 th cohort. PK data indicated dose proportionality and faster-than-typical IgG4 clearance. Anti-tumor biomarker activity, primarily CEA, but when present included other CA markers, showed a dose response (increase then a decrease to levels below baseline, consistent with target cell lysis) with a peak response between the 5 th and 6 th cohorts. Conclusions: This first-in-human (FIH) study (NCT05411133) targeting CDH17 in GI cancer pts showed a tolerable safety profile for cabotamig up to 0.32mg/kg. Step-up dosing appeared to mitigate dose responsive on-target tumor CRS and the lack of persistent GI toxicities indicated minimal on-target normal GI mucosal effects. Dose responsive biomarker anti-tumor activity of cabotamig was observed. Clinical trial information: NCT05411133 .