Izalontamab brenitecan (BL-B01D1), an EGFR x HER3 bispecific antibody, demonstrated antitumor activity and a tolerable safety profile, especially at higher dose levels, in patients with previously treated EGFR-mutated metastatic non–small cell lung cancer (NSCLC). These data from a randomized dose-expansion cohort of a phase I study were presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC; Abstract OA10.01).
“These findings support continued development of iza-bren and provide the rationale for advancing the 2.5 mg/kg regimen into the global phase III IZABRIGHT-Lung01 trial for patients with previously treated EGFR-mutated NSCLC,” said Alexander Spira, MD, NEXT Oncology Virginia and Virginia Cancer Specialists.
Background and Study Methods
Izalontamab brenitecan is an EGFR x HER3 bispecific antibody conjugated to an Ed-04 topoisomerase 1 inhibitor payload via a stable tetrapeptide-based cleavable linker.
The global phase I study enrolled 80 patients with EGFR-mutated metastatic NSCLC who were randomly assigned to receive izalontamab brenitecan at 1.5 mg/kg, 2.0 mg/kg, or 2.5 mg/kg intravenously on days 1 and 8 of an every-3-week cycle. Patients were enrolled in the study irrespective of their EGFR or HER3 expression levels. Primary granulocyte colony-stimulating factor prophylaxis was also mandated in the study design.
The study aimed to find the recommended phase III dose based on safety, efficacy, and pharmacokinetics across the three studied dose levels.
Key Findings
Across all dose levels, the overall response rate was 28.8%, with a confirmed overall response rate of 23.8%; the disease control rate was 72.5%. The overall median duration of response was 5.7 months (95% confidence interval [CI] = 3.0 to not reached) and the median progression-free survival was 5.4 months (95% CI = 2.9–7.8).
At the 2.5 mg/kg dose, the overall response rate was 33.3%, consisting of nine partial responses, eight of which were confirmed (29.6%). Twelve patients also had stable disease, for a disease control rate of 77.8%. Five patients had progressive disease and one patient was not evaluable. The median duration of response was not reached and the median progression-free survival was 6.9 months (95% CI = 4.0 to not reached).
A trend was noted of increased efficacy with higher doses.
The rate of grade 3 or higher treatment-related adverse events was 47.5% overall. No treatment-related adverse events led to death and only one patient required dose discontinuation due to an event. The most frequent grade 3 or higher events were mostly hematologic, including anemia (21.3%), neutropenia (20%), and thrombocytopenia (5%), as well as non-hematologic events of nausea, fatigue, and hypokalemia (2.5% each). There was one case of neutropenia fever noted as well as two cases of pneumonitis, both at the lower dose levels.
In the 2.5-mg/kg dose group, the rate of grade 3 or higher anemia was 29.6%, 29.6% for neutropenia, and 7.4% for thrombocytopenia.
Going forward, the 2.5-mg/kg dose of izalontamab brenitecan on days 1 and 8 of a 3-week cycle will be investigated in the phase III IZABRIGHT-Lung01 trial in patients with EGFR-mutated NSCLC who have progressed on a third-generation EGFR inhibitor.
DISCLOSURES: For full disclosures of the study authors, visit abstractsonline.com.
