Phase 3 Randomized Open‑Label Study of ZL‑1310 versus Investigator‑Chosen Topotecan in Relapsed Small Cell Lung Cancer

Primary objective: to compare the anti-tumor activity of ZL‑1310 with investigator’s choice therapy and to compare overall survival between the two arms in patients with relapsed Small Cell Lung Cancer. Secondary objectives:

• Compare efficacy of ZL‑1310 versus investigator’s choice therapy.
• Assess intracranial anti-tumor activity in participants with baseline brain metastases.
• Evaluate safety and tolerability of ZL‑1310 relative to the comparator.
• Assess health-related quality of life and patient‑reported outcomes.

The trial enrolled 246 participants diagnosed with Small Cell Lung Cancer (SCLC). Both male and female adults were eligible, covering a broad adult age spectrum as reflected by the study’s age‑range classifications. Eligible individuals required histologically confirmed disease, progression after first‑line platinum‑based chemotherapy (with or without an anti‑PD‑(L)1 agent), and measurable lesions per RECIST v1.1. Additional inclusion criteria comprised an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of at least three months, adequate organ and marrow function, and willingness to provide tumor tissue. Participants with treated, stable central nervous system metastases or untreated, asymptomatic CNS disease not requiring steroids or local therapy were allowed. No specific dietary, physical‑activity, or other lifestyle restrictions were stipulated beyond standard clinical trial requirements. The cohort included vulnerable subjects as defined by regulatory guidance.

The study is a randomized, open‑label, phase 3 trial comparing ZL‑1310, a DLL3 antibody‑drug conjugate, with investigator’s choice therapy (topotecan hydrochloride) in participants with relapsed Small Cell Lung Cancer. Screening (Visit 1) confirms eligibility, obtains tumor tissue, and records baseline disease per RECIST v1.1. Eligible subjects are randomized 1:1 to receive either ZL‑1310 (1.60 mg/kg IV infusion) or topotecan (IV 1.50 mg/m² or oral 2.30 mg/m²). Treatment cycles are given every 21 days; safety labs, imaging, and patient‑reported outcomes are assessed each cycle. Follow‑up visits occur every 6 weeks for tumor assessment, laboratory tests, and adverse‑event monitoring until disease progression, withdrawal, or study completion. The end‑of‑study visit is performed 30 days after the final dose to collect final safety and survival data. Participant involvement is expected to last up to 24 months, including screening, treatment, and follow‑up. Early termination may occur for unacceptable toxicity, disease progression per RECIST, withdrawal of consent, or loss to follow‑up. Primary endpoints are objective response rate assessed by blinded independent central review and overall survival; secondary endpoints include duration of response, progression‑free survival, CNS response, treatment‑emergent adverse events, and health‑related quality‑of‑life measures. Recruitment is planned from June 2026 to November 2028.

The investigational product, DLL3 antibody drug conjugate ZL‑1310, is supplied as an intravenous infusion solution. The prescribed dose is 1.60 mg/kg administered by infusion through a peripheral or central venous line. Infusion is performed in accordance with the protocol‑defined schedule for each treatment cycle, and drug accountability is maintained through infusion records and electronic dosing logs to ensure compliance.

Topotecan hydrochloride, used as the comparator therapy, is administered in two formulations. An oral formulation is dosed at 2.30 mg/m², while an intravenous formulation is dosed at 1.50 mg/m². Both routes are given according to the investigator’s choice schedule specified in the study protocol. Compliance with oral dosing is monitored by pill count and patient diary, and intravenous administration is documented in infusion records and drug accountability logs.

Efficacy assessment will be based on a hierarchy of predefined endpoints. The primary efficacy endpoints are the confirmed objective response rate (ORR) evaluated by Blinded Independent Central Review using the RECIST v1.1 criteria, and overall survival (OS). Secondary efficacy endpoints include duration of response (DoR) and progression‑free survival (PFS), each assessed by both central review and the investigator according to RECIST v1.1, confirmed ORR by the investigator, time to response (TTR) by both review methods, and CNS response and duration of CNS response evaluated by central review using the Response Assessment in Neuro‑Oncology for Brain Metastases (RANO‑BM) criteria.

Patient‑reported outcomes will be measured using the EQ‑5D‑5L instrument (including the EQ‑5D‑5L index and visual analog scale) and the European Organisation for Research and Treatment of Cancer quality‑of‑life questionnaires (EORTC‑QLQ‑C30 and EORTC‑QLQ‑LC13). Time to deterioration of lung‑cancer symptoms, health‑related quality of life, and physical functioning will be derived from these questionnaires. Safety‑related efficacy parameters encompass the incidence of treatment‑emergent adverse events graded per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), clinically significant laboratory changes, and other relevant clinical assessments.