tarlatamab (AMG 757)

P1, N=41, Active, not recruiting, Amgen | Phase classification: P1b --> P1 | Trial primary completion date: Mar 2023 --> Aug 2025

P3, N=400, Recruiting, Amgen | Not yet recruiting --> Recruiting

P2, N=222, Active, not recruiting, Amgen | Trial completion date: Feb 2025 --> Oct 2025 | Trial primary completion date: Feb 2024 --> Oct 2024

P3, N=490, Recruiting, Amgen | N=700 --> 490 | Trial primary completion date: Sep 2025 --> Aug 2027

P3, N=400, Not yet recruiting, Amgen | Trial primary completion date: Jul 2028 --> Oct 2029

Tarlatamab is a novel promising therapeutic antibody currently under investigation for its potential use in previously treated SCLC patients. This mini-review will explore the current state of second-line treatment options for SCLC, their clinical efficacy, and future directions.

P3, N=550, Not yet recruiting, Amgen

P3, N=400, Not yet recruiting, Amgen | Trial primary completion date: Oct 2026 --> Jul 2028

P3, N=700, Recruiting, Amgen | Trial primary completion date: Nov 2024 --> Sep 2025

P1, N=392, Recruiting, Amgen | Trial completion date: Apr 2025 --> Oct 2025

P1, N=340, Recruiting, Amgen | Phase classification: P1b --> P1

P3, N=400, Not yet recruiting, Amgen

P1, N=392, Recruiting, Amgen | Trial completion date: Oct 2025 --> Apr 2025

P1b, N=340, Recruiting, Amgen | Trial completion date: Nov 2025 --> Jan 2027 | Trial primary completion date: Nov 2024 --> Dec 2025

P1b, N=23, Active, not recruiting, Amgen | Trial completion date: Jan 2026 --> Jan 2025

P1, N=392, Recruiting, Amgen | Trial completion date: Mar 2025 --> Oct 2025

While treatment with platinum and etoposide chemotherapy and a programmed death-ligand 1 (PD-L1) inhibitor has modest benefit for a subset of patients, most patients develop resistance and relapse. The increased cytotoxic activity observed with the combination of tarlatamab and chemotherapy and/or anti-PD-L1 treatment suggests that tarlatamab may be used together with standard of care therapy to increase response rate or durability. These data support the continued clinical evaluation of tarlatamab in patients with SCLC, including in combination with chemo-immune therapy in the first-line setting.

The Phase III clinical trials of Rova-T, a drug targeting DLL3, have not yielded the expected results. However, other drugs that target DLL3, such as AMG119, AMG757 and DLL3-targeted NIR-PIT, bring new ideas for SCLC treatment. Overall, DLL3 remains a valuable target for SCLC.

NE = not estimable Conclusions Tarlatamab demonstrated impressive antitumor activity with durable responses and promising survival. Tarlatamab showed a favorable benefit-risk profile with no new safety signals, supporting the use of tarlatamab in pts with previously treated SCLC.

P1b, N=23, Active, not recruiting, Amgen | Trial completion date: Aug 2025 --> Jan 2026

No abstract available

First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.

No abstract available

P3, N=700, Recruiting, Amgen | Not yet recruiting --> Recruiting

P1b, N=41, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=100 --> 41 | Trial completion date: Apr 2027 --> May 2025 | Trial primary completion date: Apr 2026 --> Mar 2023

P1b, N=340, Recruiting, Amgen | Trial completion date: May 2025 --> Nov 2025 | Trial primary completion date: May 2024 --> Nov 2024

P2, N=222, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2023 --> Jan 2024

No abstract available

P1b, N=100, Recruiting, Amgen | N=60 --> 100 | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Oct 2023 --> Apr 2026

Patients will be randomized 1:1 to receive tarlatamab or SOC therapy (lurbinectedin or topotecan in US, Canada, Australia, Singapore, Korea; amrubicin in Japan; topotecan in all countries except Japan), stratified by prior anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) exposure, chemotherapy-free interval, presence of brain metastases, and SOC (topotecan/amrubicin vs lurbinectedin). DOI:1200/JCO.22.02823. Clinical trial information: NCT05740566.

No abstract available

Targeting SCLC cell surfaceome with cellular therapies have shown promising efficacy and tolerability in DLL3-targeting CAR T (AMG119) and Bispecific T-cell engager (tarlatamab)...Moreover, given that novel therapeutics are often tested in the relapsed setting, we tested target expressions in SCLC cell lines after treatment with cisplatin and etoposide (standard frontline chemotherapy for SCLC) to see if target levels change. This study demonstrated efficacy of CAR Ts targeting several cell surfaceome targets enriched in certain subtypes of SCLC. The data supports further investigation of a subtype-specific personalized treatment of SCLC using CAR T therapies against surfaceome targets.

In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.

Delta-like canonical Notch ligand 3 is a protein frequently overexpressed in SCLC and is therefore being explored as a potentially promising therapeutic target in high-grade neuroendocrine lung cancer. In this article, we critically review the activity and efficacy of old DLL3 inhibitors antibody-drug conjugate (ADC) and their failures through new compounds and their possible applications in clinical practice, with a focus on new molecular classification of SCLC.

SSP/SG compare themselves favorably to those of other options available in relapse. A phase II test is being recruited in the CBPC 3L+ (NCT05060016).

These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE® immunotherapy has significant anti-tumor activity in this aggressive prostate cancer subtype.

CRS occurred in 56 pts (53%) with maximum gr1 in 41 pts and gr3 in 1 (1.0%), and 8 pts received tocilizumab for CRS. CRS is not unexpected based on tarlatamab's mechanism of action, is associated with rises in some cytokines yet remains generally low-grade, reversible, and confined to C1. Further characterization of tarlatamab's safety is ongoing.

One BiTE® molecule in development, AMG 757, is directed against delta-like ligand 3 (DLL3), which is expressed in small cell lung cancer tumor cells...During the course of development of this bioassay, characterization of the SHP-77-Luc line showed an increase in the luminescence assay signal and Maximum-to-Minimum (Max-to-Min) ratio of the dose response curve as the passage number of the cells increased. Our research revealed an increase in not only luciferase expression but also an increase in the cell surface and intracellular expression levels of DLL3 over time in culture, which ultimately resulted in the increased assay signal window.

The primary objective is to evaluate the safety, tolerability, and determine the recommended phase 2 dose and/or maximum tolerated dose of tarlatamab in combination with PD-L1 inhibition with or without chemotherapy. Secondary endpoints are objective response rate, duration of response, disease control, progression-free survival, overall survival, and pharmacokinetics.

Tarlatamab has an expected and manageable safety profile and delivers promising efficacy with excellent response durability amongst confirmed responders in this heavily pretreated SCLC population. The PFS/OS compares well to other therapies currently available for relapsed SCLC. A phase 2 study of tarlatamab in 3L+ SCLC (NCT05060016) is enrolling based on these results.

Secondary objectives are to evaluate antitumor activity by additional measures (duration of response, progression-free survival, disease control rate and duration, overall survival), safety and tolerability, immunogenicity, and pharmacokinetics. Sites in North America, Asia and Europe are participating in the trial with subjects already enrolled and enrollment ongoing.

Because of its high expression in neuroendocrine tumors compared to normal tissue, delta-like ligand 3 (DLL3) has emerged as a new therapeutic target in this setting.1,2 Targeting DLL3 with the half-life extended bispecific T cell engager (HLE BiTE®) immune therapy, tarlatamab, in a phase 1 clinical trial has demonstrated promising anti-tumor activity in small cell lung cancer (SCLC) patients.3 In order to more precisely guide patient selection and clinical trial design, a better understanding and quantification of DLL3 expression is required...Our work confirms that most high-grade neuroendocrine tumors express DLL3 across histology types and TNM stage. Our results suggest that a large subset of patients with high-grade lung neuroendocrine tumors may be a target population of interest for DLL3-targeted therapies.