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Pharmacokinetic parameters for BI 905711 as monotherapy (NCT04137289)a.

Summary of the most frequently reported adverse events by CTCAE preferred term for BI 905711 as monotherapy (>10% of patients) or combination therapy (≥25% of patients).

Representativeness of study participants with advanced CRC.

Baseline demographics and disease characteristics.

Pharmacokinetic parameters (AUC0–336 and Cmax) after infusion of BI 905711 (0.02–4.8 mg/kg) during cycles 1 and 3 of (A) monotherapy study (NCT04137289) and (B) combination study (NCT05087992). Ia, study phase Ia; Ib, study phase Ib; Q2W, every 2 weeks. For numbers of evaluable patients in cycles 1 and 3, refer to Table 4.

Effect of BI 905711 monotherapy on plasma caspase 3/7 activity in patients with advanced GI cancers (n = 104)a. N/A, not applicable; Q1W, every 1 week; Q2W, every 2 weeks. aThe figures show caspase 3/7 activity levels in cycles 1 and 3 for the BI 905711 monotherapy study (NCT04137289). Baseline correction was done to the predose of cycle 1. The blue lines represent patients who showed a ≥2-fold increase in caspase 3/7 activity in either one or both cycles, whereas the orange lines represent patients who did not show a ≥2-fold increase in caspase 3/7 activity. A filled square indicates that the patient successfully achieved PFS of at least 4 months, whereas the open circle indicates a shorter PFS. A lack of symbol indicates missing PFS data.

Purpose:BI 905711, a TRAILR2/cadherin-17 (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 the 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 to 1.2 mg/kg plus biweekly folinic acid (leucovorin), 5-fluorouracil, and irinotecan (FOLFIRI) and bevacizumab. Phase Ib assessed selected doses and regimens given biweekly or weekly (3 weeks on and 1 week off). Safety, efficacy, and pharmacokinetics/pharmacodynamics were evaluated.Results:In NCT04137289, 110 patients [median age 61 years; 80% with colorectal cancer; median of three prior therapies (range, 1–6)] received monotherapy. No dose-limiting toxicities (DLT) occurred, MTD was not reached, RP2D was not determined, and 48.2% of patients had treatment-related adverse events (TRAE), most commonly nausea (16.4%). In 104 response-evaluable patients, 22.1% achieved stable disease (SD). In NCT05087992, 12 patients with colorectal cancer (median age 54.5 years) 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% 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.Significance:Translating preclinical activity of TRAILR2 agonists into the clinic has been hampered by severe hepatotoxicity. BI 905711, a bispecific antibody against TRAILR2 and CDH17, was developed to enhance efficacy and reduce hepatotoxicity. Two phase 1 studies (NCT04137289 and NCT05087992) demonstrated tolerability and minimal hepatotoxicity, dose-proportional pharmacokinetics, and increased markers of target engagement. Antitumor activity was limited. These data show that BI 905711 has reduced TRAIL-related hepatotoxicity in the clinic.

Individual pharmacokinetic parameters of cycle 3 based on ADA status in combination study.

Full eligibility criteria for BI 905711 as A) monotherapy (NCT04137289) or B) combination therapy (NCT05087992).