A FIRST-in-human trial has demonstrated encouraging clinical activity and manageable safety for the DLL3-targeted antibody-drug conjugate SHR-4849 in patients with relapsed small cell lung cancer (SCLC).
The Phase I dose-escalation and expansion study enrolled 54 patients with relapsed disease across five dose levels ranging from 0.8 to 4.2 mg/kg. Among 42 evaluable patients, the objective response rate reached 59.5%, with a disease control rate of 90.5%. Responses deepened in patients followed for at least 12 weeks, with objective responses seen in 69.2 percent of this subgroup. At the 2.4 mg/kg expansion dose, the response rate rose to 77.8%, suggesting meaningful anti-tumor activity at clinically feasible dosing levels.
SHR-4849 is composed of a humanized anti-DLL3 IgG1 monoclonal antibody linked to a DNA topoisomerase I inhibitor via a cleavable linker. DLL3 is highly expressed in SCLC, a malignancy with limited treatment options and poor outcomes, making it an attractive therapeutic target.
Treatment-related adverse events were generally manageable, with the most common being decreased white blood cell count, anemia, neutropenia, and nausea. No treatment-related events resulted in dose discontinuation or death, and no dose-limiting toxicities were observed below 4.2 mg/kg. Plasma exposure to the free toxin remained low across all dose levels, supporting the safety profile.
The trial continues with dose expansion to determine the recommended Phase II dose. Investigators emphasized the potential of SHR-4849 to provide a new therapeutic option for patients with DLL3-expressing relapsed SCLC, warranting further clinical development.
“These encouraging early data support further investigation of SHR-4849 as a potential treatment for patients with DLL3-positive relapsed SCLC,” said principal investigator Linlin Wang of the Affiliated Cancer Hospital of Shandong First Medical University.
Reference: International Association for the Study of Lung Cancer (IASLC). First-in-Human Trial Shows Promising Results for DLL3-Targeted Antibody-Drug Conjugate SHR-4849 in Relapsed Small Cell Lung Cancer. September 7, 2025. Available at: https://www.iaslc.org/iaslc-news/press-release/first-human-trial-shows-promising-results-dll3-targeted-antibody-drug. Last accessed: September 9, 2025. [Press release].
