ZL-1310, a DLL3 ADC, in patients with extensive stage small cell lung cancer: Ph1 trial update.

Abstract

3041 Background: Treatment options are limited for patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) that progress after platinum-based chemotherapy (chemo). ZL-1310, a DLL3-targeted antibody drug conjugate (ADC) with a topoisomerase 1 inhibitor payload and cleavable linker, demonstrated promising preliminary results in pts with relapsed/refractory (r/r) ES-SCLC (Spira et al, ENA 2024). Here, we report updated data with additional pts and follow-up (NCT06179069). Methods: This is a two-part Phase I study of ZL-1310 administered intravenously every 3 weeks to pts with r/r SCLC who have progressed after at least one platinum-based chemo regimen. Part 1A is a monotherapy dose escalation; Part 2 is a randomized dose optimization/expansion. Study endpoints include safety parameters, objective response rate (ORR) per RECIST v1.1, duration of response (DOR), disease control rate (DCR) and pharmacokinetics (PK). Exploratory tumor biomarkers, including DLL3 expression (expressed as H-score), are examined. Results: As of 28 Jan 2025, 28 pts were enrolled in the dose escalation Part 1A and received ZL-1310 at dose levels ranging from 0.8 mg/kg to 2.8 mg/kg. The median time on study is 5.1 months (range 2.4-10.1+). Median age was 66 years (range 36-79); 43% were female; 75% had an ECOG performance status of 1; 93% progressed after prior anti-PD-L1 therapy; 39% had prior lung irradiation, and 36% had baseline brain metastases. Any-grade treatment-related adverse events (TRAEs) occurred in 89% of pts (Grade≥3 TRAEs, 39%). One pt (2.4 mg/kg) had dose limiting toxicities of neutropenia and thrombocytopenia; 5 pts underwent drug reduction and 5 had drug discontinued due to TRAE. Grade≥3 TRAEs occurring in more than 1 patient include anemia (6 pts), neutropenia (5), thrombocytopenia (3), WBC decreased (2), and interstitial lung disease (2). Objective responses were observed in 19 of 28 pts (68%), including one pt pending response confirmation, and a DCR of 93%. Responses were observed across all dose levels and all levels of DLL3 expression (H-score range: 0-260), including one pt with prior tarlatamab treatment. Pts with baseline brain metastases had an 80% response rate and 100% DCR. Fourteen of 19 (74%) responders remain on study. PK data from 25 pts showed dose-proportional increase of systemic ADC and payload exposure, with relatively low exposure of the payload and no significant accumulation. Conclusions: ZL-1310 demonstrated a tolerable safety profile and promising antitumor activity in r/r ES-SCLC, including pts with brain metastases, pt with prior tarlatamab, and in the setting of low DLL3 expression. Updated data, including patients in the randomized Part 2 dose optimization, will be presented. Clinical trial information: NCT06179069 .