Background: HPN328 is a delta like canonical Notch ligand 3 (DLL3)-targeting T-cell engager (TCE) derived from the TriTAC platform, designed to minimize off-target toxicities. HPN328 contains 3 binding domains, engineered to redirect T cells to kill DLL3-expressing cancer cells: anti-DLL3 for target engagement, anti-CD3 for T-cell engagement, and anti-albumin for half-life extension. Methods: This ongoing Ph1/2a study is evaluating HPN328 in patients (pts) with metastatic small cell lung cancer (SCLC) and other neuroendocrine (NE) cancers associated with DLL3 expression. Eligible pts must have disease that is relapsed/refractory to standard systemic therapy. Primary endpoints are safety, tolerability, and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-tumor activity (RECIST 1.1). HPN328 is administered IV, once weekly. AEs are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Results: As of Feb 3^rd, 2022, 16 pts were enrolled in 8 dose-escalation cohorts at doses from 0.015mg to 12.0mg (SCLC n = 10 (62.5%); NE prostate cancer (NEPC) n = 2 (12.5%); other NE neoplasms (NEN) n = 4 (25%)). Median pt age was 61 (43-73) yrs. Pts received a median of 3 (1-5) prior treatments; 75% received a PD-1 blocker. At baseline, 6 pts (37.5%) had treated brain metastases and 8 (50%) had liver metastases. Median treatment duration was 10.6 (3.3-31.3 plus) weeks. Treatment is ongoing in 7 pts (44%; median 16.5 weeks). CRS was reported in 5 pts (31%); events were grade 1 or 2, occurred within 24 hrs of the 1^st or 2^nd dose and did not recur with rechallenge. No ≥ Grade-3 CRS occurred. No dose-limiting toxicities were observed, and no AEs led to discontinuation. HPN328 exhibited linear PK, with dose-proportional increases in exposure and a median half-life of 71 hrs. Small, transient increases in select cytokines and chemokines were observed up to 24 hrs post dose. T-cell activation and margination were observed, consistent with target engagement. DLL3 expression was confirmed on IHC analysis of most baseline biopsies. 15 pts were efficacy evaluable. 6 of 15 (40%) had decrease in sum of target lesion diameters (4 SCLC, 1 NEPC, 1 NEN). 3 of 9 (33%) SCLC pts across all doses had > 30% decrease (weeks on treatment: 17.2, 16.9 [ongoing], and 25.1 [ongoing, confirmed PR]). At doses ≥1.215mg, 2 of 4 (50%) SCLC pts had > 30% decrease and 1 had > 20% decrease. 4 pts (25%) had stable disease: 2 SCLC, 1 NEPC, 1 NEN (Thymic atypical carcinoid). Conclusions: HPN328 is a novel half-life extended DLL3-targeting TCE that is well tolerated and clinically active. AEs have been transient, manageable, and consistent with class. No ≥ Grade-3 CRS occurred. Tumor shrinkage has been observed, including 1 confirmed PR. Dose escalation is ongoing; updated data will be presented. Clinical trial information: NCT04471727.