Randomized phase 3 study of tarlatamab, a DLL3-targeting bispecific T-cell engager (BiTE), compared to standard of care in patients with relapsed small cell lung cancer (DeLLphi-304).

Luis G. Paz-Ares Hospital Universitario 12 de Octubre, CNIO-H120 Lung Cancer Unit, Ciberonc and Universidad Complutense, Madrid, Spain info_outline Luis G. Paz-Ares, Enriqueta Felip, Myung-Ju Ahn, Fiona Helen Blackhall, Hossein Borghaei, Byoung Chul Cho, Melissa Lynne Johnson, Suresh S. Ramalingam, Martin Reck, Alicia Zhang, Chia-Hsin Ju, Mukul Minocha, Sujoy Mukherjee, Gaurav Suri, Danielle Jandial, D Gwyn Bebb

Authors Luis G. Paz-Ares Hospital Universitario 12 de Octubre, CNIO-H120 Lung Cancer Unit, Ciberonc and Universidad Complutense, Madrid, Spain info_outline Luis G. Paz-Ares, Enriqueta Felip, Myung-Ju Ahn, Fiona Helen Blackhall, Hossein Borghaei, Byoung Chul Cho, Melissa Lynne Johnson, Suresh S. Ramalingam, Martin Reck, Alicia Zhang, Chia-Hsin Ju, Mukul Minocha, Sujoy Mukherjee, Gaurav Suri, Danielle Jandial, D Gwyn Bebb Organizations Hospital Universitario 12 de Octubre, CNIO-H120 Lung Cancer Unit, Ciberonc and Universidad Complutense, Madrid, Spain, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of (South), The Christie NHS Foundation Trust, Division of Cancer Sciences, Manchester, United Kingdom, Fox Chase Cancer Center, Philadelphia, PA, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of (South), Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, Winship Cancer Institute, Emory University Hospital, Atlanta, GA, LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany, Amgen Inc., Thousand Oaks, CA, Amgen Limited, Uxbridge, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Amgen Background: Small cell lung cancer (SCLC) is an aggressive malignancy for which very few patients achieve long term disease control; response to most treatments is transient and second line treatment options are limited. Delta-like ligand 3 (DLL3) is a Notch ligand aberrantly expressed on the surface of up to 85% of SCLC cells and minimally expressed in normal tissues, making it an attractive therapeutic target. Tarlatamab is a bispecific T cell engager (BiTE) molecule designed to bind DLL3 on target cancer cells and CD3 on T cells, thereby driving T cell-dependent killing of tumor cells. Results from the first-in-human study in patients with relapsed/refractory SCLC (DeLLphi-300; NCT03319940) demonstrate tarlatamab efficacy in pretreated patients with confirmed responses in 23% of patients and median duration of response > 12 months. 1 Median overall survival (OS) was 13.2 months. Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 31% of patients and TRAEs resulted in discontinuation in 4% of patients. This promising efficacy/safety profile is being evaluated further in a phase 2, open-label study in patients with relapsed/refractory SCLC after ≥2 lines of prior treatment (DeLLphi-301; NCT05060016). Methods: NCT05740566 is a randomized, open-label, phase 3 study of tarlatamab compared with standard of care (SOC) in ~700 patients with relapsed SCLC after platinum-based first-line chemotherapy. 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). The primary objective is to compare the efficacy of tarlatamab with SOC on prolonging OS. Key secondary endpoints include comparison of progression free survival (PFS) based on investigator assessment per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and patient-reported outcomes (PRO) including disease-related symptoms, physical function, and global health status of quality of life. Key eligibility criteria include adults with histologically or cytologically confirmed relapsed SCLC who progressed following 1 platinum-based regimen. Patients must have measurable lesions as defined per RECIST 1.1 within the 21-day screening period and must have adequate organ function. Exclusions include untreated or symptomatic central nervous system metastases, history of immune checkpoint inhibitor use resulting in severe immune-mediated adverse event, and previous history of NSCLC. Enrollment is ongoing. References 1. Paz-Ares L, et al. J Clin Oncol . DOI:1200/JCO.22.02823. Clinical trial information: NCT05740566.

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