Imdelltra (tarlatamab-dlle)

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

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=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

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

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.

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.

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

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

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.

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