An investigational DLL3-targeting antibody-drug conjugate (ADC), ZL-1310, has shown promising results in patients with previously treated extensive-stage small cell lung cancer (ES-SCLC). Data from a phase 1a/1b study (NCT06179069) presented at the EORTC-NCI-AACR (ENA) Symposium 2024 indicate a significant objective response rate and a manageable safety profile, offering a potential new treatment avenue for this challenging cancer.
Objective Responses and Durability
The study revealed an objective response rate (ORR) of 74% (95% CI, 48.8%-90.9%) among 19 evaluable patients. Anti-tumor activity was observed across all dose levels of ZL-1310, and responses were seen in patients with DLL3 H-scores ranging from 5 to 260. Notably, no responses occurred in tumors lacking DLL3 expression, highlighting the importance of DLL3 as a target. After a median follow-up of 2.4 months, the median duration of response (DOR) was not estimable at the time of analysis, with 13 of 14 responding patients still receiving treatment, and one patient continuing treatment for over 6.5 months.
Efficacy in Brain Metastases
ZL-1310 also demonstrated efficacy in patients with brain metastases, a particularly difficult-to-treat subgroup. Among 6 evaluable patients with brain metastases at baseline, all achieved a partial response (PR) following treatment with ZL-1310. One patient who had progressed on prior DLL3-targeted bispecific therapy also experienced a PR at the time of first tumor assessment.
Safety and Tolerability
The safety profile of ZL-1310 was generally favorable. In the safety population of 25 evaluable patients, the ADC was well-tolerated at all dose levels, with most treatment-emergent adverse effects (TEAEs) being grade 1/2. One dose-limiting toxicity—grade 4 transient neutropenia or thrombocytopenia—was reported at the 2.4 mg/kg dose. Overall, 20% (n = 5/25) of patients experienced grade 3 or higher treatment-related AEs (TRAEs), with neutropenia being the most common (12%: n = 3/25). Serious TRAEs and dose reductions occurred in 8% (n = 2/25) and 12% (n = 3/25) of patients, respectively. Importantly, no TEAEs led to treatment discontinuation.
Mechanism of Action and Clinical Significance
ZL-1310 is designed as a humanized anti-DLL3 monoclonal antibody linked to a topoisomerase 1 inhibitor. This design aims to leverage the tumor microenvironment to reduce off-target payload toxicity, a limitation often associated with first-generation ADCs. The ongoing phase 1 study includes a monotherapy dose-escalation portion, where 25 patients received ZL-1310 at doses of 0.8 mg/kg, 1.6 mg/kg, 2.0 mg/kg, or 2.4 mg/kg. The primary endpoints of the trial are dose-limiting toxicities, TEAEs, and SAEs, while secondary endpoints include ORR, DOR, progression-free survival, disease control rate, overall survival, and pharmacokinetics.
Expert Commentary
Alexander Spira MD, PhD, FACP, FASCO, co-director of Virginia Cancer Specialists Research Institute, commented on the findings: "The preliminary results from the ongoing phase 1 trial of ZL-1310 suggest that this next-generation ADC therapy has the potential to deliver anti-tumor responses in the majority of patients with ES-SCLC, with good tolerability. This is particularly encouraging given the urgent need for improved treatment options for these patients. These promising data support continued evaluation of ZL-1310 as a monotherapy in the dose-expansion phase of the ongoing phase 1 clinical trial and in combination."
Future Directions
Rafael G. Amado, MD, president and head of Global Research and Development at Zai Lab, the developer of ZL-1310, stated, "Based on the encouraging preliminary findings from our phase 1 trial, we look forward to continuing development of ZL-1310 and advancing this promising asset across lines of therapy as part of our global oncology pipeline."
