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DLL3-Targeting T-Cell Engager Under Study in Neuroendocrine Prostate Cancer

By: Julia Fiederlein Cipriano, MS
Posted: Tuesday, April 9, 2024

The delta-like canonical Notch ligand 3 (DLL3)-targeting T-cell engager HPN328 appears to be well tolerated and clinically active in patients with relapsed or refractory metastatic neuroendocrine prostate cancer and other DLL3-expressing neuroendocrine neoplasms, according to Himisha Beltran, MD, of Dana-Farber Cancer Institute, Boston, and colleagues. These interim results from a phase I/II study were presented during the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium (Abstract 121).

Patients with neuroendocrine prostate cancer (n = 10), small cell bladder cancer (n = 2), and small cell lung cancer or other neuroendocrine neoplasms (n = 54) were treated with single-agent HPN328 in target doses ranging from 0.015 to 24 mg across 14 dose-escalation cohorts. The entire population had a median of two prior regimens.

Cytokine-release syndrome (52%), fatigue (35%), dysgeusia (33%), nausea (17%), vomiting (14%), diarrhea (14%), decreased appetite (12%), and pyrexia (11%) were the most frequently reported treatment-related adverse events. Nearly all cases of cytokine-release syndrome were documented after the initial priming dose and not subsequent infusions. The most commonly observed adverse events of grade 3 or higher were neutropenia, pneumonia, and anemia. Two patients experienced a dose-limiting toxicity of grade 3 cytokine-release syndrome at a priming dose of 2 mg, but subsequent target dose escalation up to 24 mg with a priming dose of 1 mg showed no further occurrences; the maximum tolerated dose at the target dose has not yet been reached.

Of the six patients with prostate cancer and at least one imaging study, three had an unconfirmed partial response. Both of those with small cell bladder cancer achieved a confirmed partial response. HPN328 demonstrated linear pharmacokinetics with dose-proportional increases in exposure; it showed a median half-life of 71 hours. The investigators observed transient increases in cytokines up to 24 hours after treatment, as well as T-cell activation.

Disclosure: For full disclosures of the study authors, visit

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