DLL3-Targeted Antibody-Drug Conjugate Reignites Hope for Relapsed SCLC

Asad Rauf, MD University of Miami Miller School of Medicine | Chinmay Jani, MD University of Miami Health System | Aman Chauhan, MD University of Miami

Key Points

• DLL3 is emerging as a promising target in small-cell lung cancer (SCLC).

• SHR-4849, a DLL3-targeted antibody-drug conjugate, showed encouraging efficacy and safety in a phase 1 dose-escalation and expansion study.

• Grade 3 or higher adverse events occurred in 37% of patients.

• The objective response rate (ORR) was noted in 59.5% of evaluable patients.

Antibody-drug conjugates (ADCs) have rapidly transformed cancer care by enabling the targeted delivery of potent cytotoxic therapy. With FDA approvals in non-small cell lung cancer (NSCLC) and pan-tumor indications, ADCs have emerged as a powerful therapeutic class—combining molecular precision with chemotherapy strength. Agents like trastuzumab deruxtecan (targeting HER2) and datopotamab deruxtecan (targeting TROP2) have set new benchmarks in NSCLC, while ongoing innovation continues to expand the reach of ADCs across tumor types.

Until now, SCLC has largely remained outside this revolution. However, a recent first-in-human phase 1 trial presented at the 2025 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer (WCLC) showcased encouraging results for SHR-4849, a novel DLL3 (Delta-like ligand 3)-targeted ADC designed for relapsed SCLC.

On Target: DLL3 Brings New Hope for SCLC

For decades, the standard treatment for SCLC consisted of chemotherapy with platinum-based regimens. Later, immune checkpoint inhibitors were added, having demonstrated benefit in both limited- and extensive-stage SCLC. Despite these advances, the overall prognosis for patients with SCLC remains poor, and the need for additional treatment options persists. In this context, DLL3 has emerged as one of the most promising therapeutic targets. 

DLL3 belongs to a group of 5 ligands for receptors in the Notch signaling pathway, which plays an important role in regulating several cellular processes, including differentiation, proliferation, and apoptosis. DLL3 is highly expressed on the surface of neuroendocrine tumor cells and SCLC cells, with a high level of expression in 70% to 90% of tumors. Overexpression of DLL3 results in reduced surface expression of Notch receptors, which in turn results in increased proliferation of neuroendocrine cells, including SCLC.^1-3 Conversely, DLL3 is minimally expressed on normal tissue, making it an attractive target for therapy.^1,3

The story of DLL3-directed therapy has evolved through multiple drug classes, including bispecific T-cell engagers (BiTEs) and ADC platforms. Tarlatamab, a DLL3-directed BiTE, has already redefined the treatment paradigm by demonstrating meaningful and durable responses in previously treated SCLC. Its success has reignited interest in DLL3-targeted strategies and validated DLL3 as a clinically actionable biomarker.⁴

Rovalpituzumab tesirine (Rova-T) is a humanized anti-DLL3 ADC, which incorporates a pyrrolobenzodiazepine payload. Despite efficacy signals in early phase clinical trials, phase 3 trials of Rova-T failed to show improvement over the current standard of care. Despite this setback, DLL3-targeting ADCs continue to be an area of active research given their promising therapeutic characteristics.^5,6

First-In-Human Data Using SHR-4849

SHR-4849 is a novel ADC composed of a humanized IgG1 monoclonal antibody targeting DLL3, conjugated to a DNA topoisomerase I inhibitor via a cleavable linker. Linlin Wang, MD, PhD, and colleagues from Shandong First Medical University, Tai’an, China, reported the phase 1 study findings at WCLC 2025.⁷

The study enrolled 52 patients with relapsed/refractory SCLC and 2 patients with relapsed/refractory neuroendocrine carcinoma, who had been treated with at least 2 prior lines of therapy. They were treated across 5 dose levels in a dose-escalating manner (0.8 mg/kg, 2.4 mg/kg, 3.0 mg/kg, 3.5 mg/kg, 4.2 mg/kg). The treatment was administered intravenously every 3 weeks.

During dose escalation, treatment-related adverse events (TRAEs) of any grade occurred in nearly all patients (96%), with 37% experiencing grade 3 or higher TRAEs. The primary TRAEs included leukopenia, anemia, and neutropenia. Leukopenia and neutropenia were the most common grade 3 or higher adverse events, occurring in 26% of patients. No deaths or discontinuation of therapy were related to TRAEs, and there were no dose-limiting toxicities below the 4.2 mg/kg dose.

SHR-4849 also demonstrated encouraging antitumor activity. In the 42 evaluable patients with SCLC at the time of publication, the objective response rate (ORR) was 59.5% (n=25)—all of which had partial response.

Continued data maturity is expected, as 26 patients had less than 12 weeks of follow-up, with a higher ORR (69.2%) noted in patients with 12 or more weeks of follow-up. In patients who received the expanded dose of 2.4 mg/kg and had at least 12 weeks of follow-up, the ORR was 77.8% (n=7/9). 

Clinical Implications

Continued follow-up and data maturity from the phase 1 trial are expected and may strengthen the already encouraging early response data. Dose expansion efforts are also underway to determine the optimal dosing for phase 2 studies. While these early results do not yet change the treatment landscape, they highlight the growing potential of leveraging DLL3 as a therapeutic avenue in the near future. 

References 

1. Ding J, Yeong C. Advances in DLL3-targeted therapies for small cell lung cancer: challenges, opportunities, and future directions. Front Oncol. 2024; 14. doi:10.3389/fonc.2024.1504139
2. Owen DH, Giffin MJ, Bailis JM, et al. DLL3: an emerging target in small cell lung cancer. J Hematol Oncol. 2019;12(1):61. doi:10.1186/s13045-019-0745-2
3. Bylsma LC, Pundole X, Ju C-H, et al. Systematic literature review of the prevalence and prognostic value of delta-like ligand 3 protein expression in small cell lung cancer. Target Oncol. 2023;18(6):821-835. doi:10.1007/s11523-023-01008-x
4. Ahn M-J, Cho BC, Felip E et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med. 2023;389:2063-2075. doi:10.1056/NEJMoa2307980
5. Blackhall F, Jao K, Greillier L, et al. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC: results from the phase 3 TAHOE study. J Thorac Oncol. 2021;16(9):1547-1558. doi:10.1016/j.jtho.2021.02.009
6. ohnson ML, Zvirbule Z, Laktionov K, et al. Rovalpituzumab tesirine as a maintenance therapy after first-line platinum-based chemotherapy in patients with extensive-stage-SCLC: results from the phase 3 MERU study. J Thorac Oncol. 2021;16(9):1570-1581. doi:10.1016/j.jtho.2021.03.012
7. Wang L, Cheng Y, Meng X, et al. A first-in-human phase 1 study of SHR-4849 (IDE849), a DLL3-directed antibody-drug conjugate, in relapsed SCLC. Presented at the 2025 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer; Sept. 6-9, 2025; Barcelona, Spain. Abstract OA06.01.