725MO Phase I Trial of the DLL3/CD3 IgG-like T Cell Engager BI 764532 in Patients (pts) with DLL3-positive (+) Tumours: Focus on Neuroendocrine Carcinomas

DLL3 is highly expressed on small-cell lung cancer (SCLC) tumours and neuroendocrine carcinomas (NECs). BI 764532 is a DLL3/CD3 IgG-like T cell engager with potent preclinical activity. NCT04429087 is an ongoing phase I dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, extrapulmonary (ep) NEC or large cell neuroendocrine lung carcinoma. Here we focus on pts with epNEC. BI 764532 was given intravenously in 4 regimens: Regimen A (RA; fixed dose q3w); RB1 (fixed dose qw); RB2 (step-in doses, then fixed dose); RB3 (step-in, followed by target dose). Treatment (Tx) continued until progressive disease, unacceptable toxicity, other withdrawal criteria or maximum Tx duration (36 months). Main objective: maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532. Other objectives: safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy based on investigator review (RECIST v1.1). As of 26 July 2023, 129 pts received ≥1 dose (≥ 0.03 μg/kg) of BI 764532 (RA: n=24; RB1: n=10; RB2: n=79; RB3: n=16). Male: 59%; median age: 60 (range 32–81); ECOG PS 0/1: 28/71%; prior PD1/PD-L1 Tx: 49%; ≥2 prior lines of Tx: 70%. Dose limiting toxicities: 1 pt on RA (Grade [G]3 confusion) and 6 pts on RB2 (G5 immune effector cell-associated neurotoxicity syndrome [ICANS]; G4 cytokine release syndrome [CRS]; G3 CRS; G3 ICANS; G3 nervous system disorder and G2 infusion-related reaction). MTD has not been reached; dose escalation is ongoing. 53 pts with epNEC have been treated (ongoing in 14). TRAEs (any/G≥3): 92/17%. The most common TRAEs (any/G≥3) were: CRS (72/4%); pyrexia (26/0%); dysgeusia (19/0%) and fatigue (17/0%); there were no Tx discontinuations due to TRAEs. In the efficacy population, there were 46 pts with epNEC (gastrointestinal: n=23; genitourinary: n=16; unknown origin: n=7). ORR/DCR was 22/41%. In pts who received clinically active doses of BI 764532 (n=36), ORR/DCR was 28/47%. BI 764532 showed clinically manageable tolerability; MTD has not been reached. Promising efficacy was observed in pts with epNEC. The study is ongoing.