A phase Ia/b first-in-human, open-label, multicenter study of BI 905711, a bispecific TRAILR2 agonist, in patients with advanced gastrointestinal cancers

115 Background: BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17. This cross-linking drives CDH17-dependent TRAILR2 oligomerization, leading to caspase activation and eventual apoptosis, inhibiting tumor growth in preclinical models of GI cancer. Methods: This Phase Ia/b study of BI 905711 in patients (pts) with advanced GI cancers (NCT04137289) aimed to determine the maximum tolerated dose (MTD) based on the proportion of pts with dose-limiting toxicities (DLT) and explore preliminary antitumor activity. In Phase Ia, pts received BI 905711 every 14 days. One pt with colorectal cancer (CRC) was enrolled at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts with CRC were enrolled at each subsequent level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Up to 4 pts with non-CRC GI cancers were included at the dose level below the CRC cohort. Dose escalation was guided by a Bayesian logistic regression model. Results: As of 01 August 2022, 48 pts (CRC: n = 26; non-CRC: n = 22, including 13 with pancreatic ductal adenocarcinoma [PDAC]) had received BI 905711 (dose range 0.02–4.8 mg/kg); pts had a median age of 61 years (range 27–78) and had received a median of 3 (range 1–11) prior lines of treatment. No DLTs were observed and the MTD was not reached. 41 pts had AEs (grade [G] 3–5: 14 pts; serious: 13 pts). 17 pts had treatment-related AEs (TRAEs); 4 TRAEs were G3: AST increased (2 pts), fatigue and ALT increased (1 pt each). 1 pt had serious TRAEs: G2 decreased appetite and G3 fatigue. 2 pts had G1/2 infusion-related reactions that resolved and did not prevent resumption of treatment. PD biomarker modulation on the level of plasma caspase-3/7 activity was most common at 0.6 mg/kg (4/7 pts) or 1.2 mg/kg (2/6 pts). 13 pts achieved stable disease (SD) and 8 pts were progression-free for ≥4 months (PFS4). In pts with CRC, 6 pts achieved SD and 3 had PFS4. Among non-CRC pts, 7 pts achieved SD (PDAC: n = 6) and 5 had PFS4 (PDAC: n = 4). Median duration of treatment was 30.5 days (range 15–246) overall and 71 days (range 15–211) in the 0.6 mg/kg group (n = 8, predicted therapeutic dose; of whom 3 pts had PFS4: CRC: n = 1/4 [all CDH17+]; non-CRC: n = 2/4). Conclusions: In heavily pretreated pts, BI 905711 was associated with a tolerable safety profile and early signs of disease control. BI 905711 will be further assessed in Phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly. Clinical trial information: NCT04137289 .