ASCO 2021: Phase 1b Study of AMG 757, a Half-Life Extended Bispecific T-Cell Engager Targeting DLL3, in De Novo or Treatment Emergent Neuroendocrine Prostate Cancer

(  There has been a proliferation in treatment options for patients with metastatic castration resistant prostate cancer (mCRPC) in the last 10 years. While the most commonly utilized approaches in prostate cancer are cytotoxic chemotherapy or target the androgen-axis (including abiraterone acetate and enzalutamide), subtypes of prostate cancer, including neuroendocrine prostate cancer, have a particularly poor prognosis and respond poorly to these therapies. Many patients with neuroendocrine prostate cancer have histologic transformation of their disease following standard treatment approaches, including novel hormonal treatments.

As a result, work has sought to identify novel targets. One such target is the inhibitory Notch ligand, Delta-like ligand 3 (DLL3), which is highly expressed on the surface of cancer cells. AMG 757 is an HLE BiTE immuno-oncology therapy which was designed to redirect cytotoxic T cells to tumor cells by binding DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In vitro studies demonstrated activity of AMG 757 showed in vitro activity in DLL3-expressing NETs, including NEPC.


In an on-going first-in-human study among patients with small cell lung cancer (NCT03319940), AMG 757 appears to be safe and effective, prompting interest in its use in neuroendocrine prostate cancer.  

In the Prostate, Testicular, Penile Poster session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Aggarwal presented the design of NCT04702737, an open-label, phase 1b study evaluating AMG 757 infusion in patients with metastatic de novo or treatment-emergent NEPC. This study comprises two phases: dose exploration and then dose expansion.


To be eligible for inclusions, patients must be adults (≥18 years old) with neuroendocrine prostate cancer whose disease progressed or recurred after at least one prior treatment including a platinum-based regimen for de novo NEPC or an androgen signaling inhibitor. In addition, patients must have measurable disease per modified RECIST 1.1 per Prostate Cancer Working Group 3 modifications, ECOG performance status ≤2, life expectancy of more than 3 months, adequate organ function, and no untreated/symptomatic brain metastases.


The primary objectives of this study are to evaluate the safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757. Secondary objectives are to evaluate antitumor activity (ie, objective response, duration of response, progression-free survival, overall response) and characterize pharmacokinetics. The starting dose for dose exploration will be based on the dose deemed safe and tolerable in the ongoing trial of AMG 757 in SCLC. The study is open to enrollment.

Presented by: Rahul R. Aggarwal, MD, Associate Professor, Medicine, Medical Oncologist within the Division of Hematology/Oncology at the University of California San Francisco

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

email news signup