P1, N=55, Recruiting, Boehringer Ingelheim | Trial completion date: Dec 2025 --> Aug 2026 | Trial primary completion date: Nov 2025 --> Jul 2026

P1, N=41, Completed, Amgen | Active, not recruiting --> Completed | Trial completion date: Aug 2025 --> Jul 2024 | Trial primary completion date: Aug 2025 --> Jul 2024

P1, N=23, Completed, Amgen | Active, not recruiting --> Completed | Trial completion date: Jan 2025 --> Sep 2024

P1, N=100, Recruiting, Amgen | Not yet recruiting --> Recruiting

P1, N=23, Active, not recruiting, Amgen | Phase classification: P1b --> P1

P2, N=120, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

Before the approval of Tarlatamab-dlle, only a few drugs, such as Atezolizumab and Durvalumab, received FDA approval for treating extensive-stage SCLC. It might be possible that Tarlatamab-dlle received accelerated FDA approval for extensive-stage SCLC, leaving some questions unanswered at this stage. This manuscript is focused on clinical, pre-clinical, and other pharmacological aspects of Tarlatamab-dlle for extensive-stage SCLC.

P2, N=30, Recruiting, Amgen | Not yet recruiting --> Recruiting

P1, N=282, Recruiting, Boehringer Ingelheim | Trial primary completion date: Sep 2024 --> Sep 2025

P1, N=54, Recruiting, Boehringer Ingelheim | Trial completion date: Dec 2025 --> Apr 2026

P1, N=30, Not yet recruiting, Suzhou Zelgen Biopharmaceuticals Co.,Ltd

P1, N=184, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=340 --> 184 | Trial completion date: Jun 2029 --> Aug 2028 | Trial primary completion date: Jun 2029 --> Aug 2028

P1, N=100, Not yet recruiting, Amgen

P2, N=222, Active, not recruiting, Amgen | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

These results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting.

P1/2, N=232, Recruiting, Harpoon Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | N=162 --> 232 | Trial primary completion date: Jul 2025 --> Jan 2026

P3, N=509, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting

P1, N=340, Recruiting, Amgen | Trial completion date: Jan 2027 --> Jun 2029 | Trial primary completion date: Jan 2027 --> Jun 2029

P2, N=120, Recruiting, Boehringer Ingelheim | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Sep 2024 --> Sep 2025

P1, N=269, Active, not recruiting, Amgen | N=392 --> 269

Tarlatamab is under regulatory review in Brazil, Canada, Israel and the UK, and clinical studies are underway in multiple countries. This article summarizes the milestones in the development of tarlatamab leading to this first approval for ES-SCLC with disease progression on or after platinum-based chemotherapy.

P1/2, N=42, Recruiting, Boehringer Ingelheim | N=30 --> 42 | Trial completion date: Feb 2025 --> Jun 2025 | Trial primary completion date: Feb 2025 --> Jun 2025

P2, N=30, Not yet recruiting, Amgen

P1, N=392, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting

Specific tumor biomarkers, such as delta-like ligand 3 (DLL3) and schlafen11 (SLFN11), may enable the selection of more efficacious, novel immunomodulating targeted treatments like bispecific T-cell engaging monoclonal antibodies (tarlatamab) and chemotherapy with PARP inhibitors...CTCs have been studied for their prognostic ability in SCLC; however, their value in guiding treatment decisions is yet to be elucidated. This review explores novel and promising targeted therapies in SCLC, summarizes current knowledge of CTCs in SCLC, and discusses how CTCs can be utilized for precision medicine.

DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies.

Rovalpituzumab tesirine (Rova-T) was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. The safety profile of FZ-AD005 was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of SCLC patients.

Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.

"Tarlatamab, targeting DLL3 and CD3, showed a 40% response rate in previously treated patients... In 248 early-stage SCLC, positivity for DLL3 was 58% with IHC and 87% with mRNA ISH. A trend for improved survival in patients with no DLL3 expression was observed. Future studies on DLL3 might improve SCLC treatment SCLC."

P3, N=550, Recruiting, Amgen | Not yet recruiting --> Recruiting

P1/2, N=61, Recruiting, Phanes Therapeutics | Phase classification: P1 --> P1/2

P1/2, N=78, Not yet recruiting, Suzhou Zelgen Biopharmaceuticals Co.,Ltd

P1/2, N=162, Recruiting, Harpoon Therapeutics | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Jul 2025

In addition to genomic alterations, we show a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide insights into patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with implications for the clinical development of cell surface targeting agents in CRPC.

Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development...Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review...DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

P1, N=340, Recruiting, Amgen | Trial primary completion date: Dec 2025 --> Jan 2027

Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3 expressing malignancies.

Findings from this phase 1 study of tarlatamab in pts with NEPC demonstrated manageable safety with encouraging anti-tumor activity in DLL3 expressing NEPC. Further investigation is ongoing.

No abstract available

No abstract available

We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.

We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared to a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.