BI 905711, a TRAILR2/CDH17 Bispecific Antibody, Alone or with Chemotherapy for Patients with Advanced Gastrointestinal Cancers: Phase I Study Findings

PURPOSE: BI 905711, a TRAILR2/CDH17 bispecific antibody, demonstrated preclinical apoptotic pathway activation and antitumor activity. Two phase Ia/Ib studies tested BI 905711 monotherapy (NCT04137289) or combination therapy (NCT05087992) in advanced, refractory gastrointestinal (GI) cancers. PATIENTS AND METHODS: Both studies aimed to determine maximum tolerated dose (MTD) (phase Ia) and recommended phase II dose (RP2D)/recommended dose for expansion (RDE) (phase Ib). In phase Ia, patients received BI 905711 monotherapy (0.02-4.8 mg/kg), or 0.6-1.2 mg/kg plus biweekly FOLFIRI and bevacizumab. Phase Ib assessed selected doses and regimens given biweekly or weekly (three weeks on, one week off). Safety, efficacy, and pharmacokinetics/pharmacodynamics were evaluated. RESULTS: In NCT04137289, 110 patients [median age 61; 80% with colorectal cancer (CRC); median 3 prior therapies (range 1-6)] received monotherapy. No DLTs occurred, MTD was not reached, RP2D was not determined, and 48.2% of patients had treatment-related AEs (TRAEs); most commonly nausea (16.4%). In 104 response-evaluable patients, 22.1% achieved stable disease (SD). In NCT05087992, 12 patients with CRC [median age 54.5) received combination treatment. Two patients reported DLTs, MTD was not reached, and the selected RDE was 0.6 mg/kg plus biweekly FOLFIRI and bevacizumab. Most patients (91.7%) had TRAEs, including decreased appetite (33.3%), alanine transaminase increased, aspartate transaminase increased, and diarrhea (25.0% each). Eleven patients (91.7%) achieved SD. Pharmacokinetic/pharmacodynamic data indicated linear dose-exposure and ≥2-fold activation of plasma caspase 3/7. CONCLUSIONS: In heavily pretreated patients with GI tumors, BI 905711 monotherapy or with FOLFIRI plus bevacizumab displayed a manageable safety profile and limited clinical activity.