Small-cell lung cancer (SCLC), accounting for 13–15% of lung cancer cases, is known for its aggressive nature and poor prognosis, with a 5-year survival rate of only 3% for metastatic disease. The resistance to standard chemotherapy and the limited improvement in overall survival (OS) with immune checkpoint inhibitors (ICIs) highlight the urgent need for more effective treatments. DLL3, an inhibitory ligand that suppresses Notch signaling, has emerged as a significant therapeutic target due to its high expression in up to 85% of SCLC cases across various stages and treatment statuses.
Rovalpituzumab tesirine (Rova-T), the first-in-class DLL3-targeted antibody-drug conjugate (ADC), showed promise in early trials with an objective response rate (ORR) of 18% overall and 38% in patients with high DLL3 expression. However, subsequent phase III trials did not demonstrate superiority over standard treatments, leading to discontinuation of further clinical investigations due to adverse events and limited efficacy.
Tarlatamab (AMG757), a DLL3-targeted bispecific T-cell engager (BiTE), has shown encouraging results in phase I and II studies, with ORRs of 23.4% and 40%, respectively, and manageable safety profiles. The ongoing phase III trials aim to further evaluate its efficacy in different treatment settings, including as a second-line therapy and in combination with ICIs.
Other emerging therapies targeting DLL3 include ZL-1310, an ADC currently under clinical investigation, and BI764532, a BiTE with promising early results. Additionally, chimeric antigen receptor (CAR) T-cell therapies, such as AMG119, and radiopharmaceutical therapies are being explored for their potential to target DLL3-expressing SCLC cells effectively.
Despite the progress, the role of DLL3 expression as a predictive biomarker remains uncertain, with mixed results across studies. Further research is needed to identify reliable biomarkers and to explore the potential of combining different DLL3-targeted therapies to enhance treatment outcomes for SCLC patients.
