Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic small cell lung cancer (SCLC).

3002 Background: iza-bren is a first-in-class ADC comprised of an EGFR x HER3 bispecific antibody conjugated to a novel topo-I inhibitor payload (Ed-04) via a stable tetrapeptide-based cleavable linker. Unlike existing ADCs targeting general tumor antigens, iza-bren uniquely targets the EGFR and HER3 pathways, which are implicated in the aggressive biology of SCLC. It has shown promising clinical activity and a manageable safety profile in patients (pts) with advanced or metastatic solid tumors. Results for safety/efficacy from this phase I study in SCLC pts are presented. Methods: Pts with locally advanced or metastatic SCLC who had progressed on prior systemic therapies were enrolled and treated at 2.0, 2.5 mg/kg D1D8 Q3W, or 4.5, 5.0 mg/kg D1 Q3W. Tumor scans were done every 6 weeks. Efficacy was evaluated in the overall cohort and specific subgroups, with a particular focus on pts with limited prior treatment exposure. Results: As of Dec 5, 2024, a total of 58 SCLC pts were enrolled. All pts who received at least one dose of iza-bren are included in the analysis. The median follow-up was 16.4 mo, ORR was 55.2%, confirmed ORR was 44.8%, median PFS was 4.0 mo, and median OS was 12.0 mo. Among the 52 pts at 2.5 mg/kg, 20 pts received only 1 prior line of PD(L)-1 and PBC combination treatment. In this subgroup, ORR was 80.0%, confirmed ORR was 75.0%, median DOR was 5.6 mo, median PFS was 6.9 mo, and median OS was 15.1 mo. The most frequent hematologic TRAEs (all grades) were anemia (84.5%), leukopenia (74.1%), thrombocytopenia (72.4%), and neutropenia (70.7%); the most frequent non-hematologic TRAEs were asthenia (41.4%), hypoalbuminemia (39.7%), stomatitis (34.5%), nausea (31.0%), and vomiting (31.0%). Grade 3 and above TRAEs which were predominantly hematologic in nature, were able to be effectively managed with standard supportive measure including dose reductions, as demonstrated by the TRAE leading to discontinuation rate of 12.1%. Two infection-related deaths (1 respiratory failure, 1 gastrointestinal infection) associated with iza-bren were reported. No ILD was observed. No new safety signals were identified. Conclusions: In SCLC pts, iza-bren has demonstrated an encouraging efficacy with a manageable safety profile. Notably, the high confirmed response rate of 75% in pts with limited prior treatment underscores its potential as a novel therapeutic option for SCLC, a disease with limited therapeutic advancements over decades. The phase III study of iza-bren in SCLC pts who received 1 prior line of PD(L)-1 and PBC combination treatment is ongoing (NCT06500026). Clinical trial information: NCT05194982 .