698P Interim results from a phase I/II study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T cell engager in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NEN)

HPN328 is a delta-like canonical Notch ligand 3 (DLL3)-targeting T-cell engager (TCE). HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. Pts with relapsed/refractory, metastatic SCLC and other NEN associated with DLL3 expression are eligible. Primary objectives are safety, determination of the maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. HPN328 is administered IV once weekly with a priming dose preceding the target dose in higher dose cohorts. Adverse events (AEs) are graded (G) by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). As of 18Apr23, 44 pts received HPN328 doses of 0.015-24 mg across 11 cohorts (SCLC [n=29;66%]; NE prostate cancer [NEPC, n=6;14%]; other NEN [n=9;20%]). Median number of prior regimens was 2 (1-5); 59% previously received a PD-1/PD-L1 blocker. Treatment is ongoing in 20 pts. Treatment-related AEs in >10% of pts included CRS (46%), fatigue (23%), dysgeusia (21%), nausea (18%), pyrexia and vomiting (16% each), and anemia (11%). The 27 CRS events were G1 (n=14); G2 (n=11); G3 (n=2). G3 CRS was a dose-limiting toxicity (DLT) in 2 pts at a priming dose of 2 mg; dose escalation continues with a reduced priming dose to 1 mg. Three pts (2 SCLC, 1 NEN) have had confirmed partial response and an additional pt with SCLC had an initial report of complete response following the data cut-off date. Three pts remained on therapy for >1 year. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. HPN328 is well tolerated and clinically active. MTD determination and dose escalation are ongoing. Future planned cohorts include every other week dosing and HPN328 + atezolizumab. Updated safety and efficacy results including pts recently enrolled in backfill cohorts will be presented.