In a randomized dose-expansion cohort, izalontamab brengitecan (Iza-Bren) showed promising efficacy, achieving a 33% objective response rate (ORR) at the 2.5 mg/kg dose level in patients with non-small cell lung cancer (NSCLC).
These findings were presented on Monday, September 14, at the 2026 World Conference on Lung Cancer (WCLC) during the session titled Novel Antibodies and ADCs.
Novel Antibodies and ADCs
Phase 1 Global Study of Iza-Bren in Patients With Metastatic EGFR-mutated NSCLC: Results of the Randomized Dose Expansion Cohort
Registered WCLC 2026 attendees can watch Dr. Alexander Spira and other presenters characterize the efficacy and safety of novel bispecific antibodies and/or ADCs, with on-demand access to session recordings via the virtual platform. WATCH NOW
Iza-Bren is a first-in-class bispecific antibody-drug conjugate (ADC) comprised of an EGFR x HER3 bispecific antibody conjugated to a novel topoisomerase 1 inhibitor payload (Ed-04) via a stable, tetrapeptide-based cleavable linker.
Previous results indicated promising efficacy, with a 30% confirmed ORR (cORR) at the 2.5 mg/kg dose in heavily pretreated patients with EGFR-mutant NSCLC. In August 2025, Iza-Bren received Breakthrough Therapy Designation in EGFR-mutant NSCLC from the FDA.
The global phase I study enrolled patients with EGFR-mutated metastatic NSCLC whose disease had progressed after prior treatment with third-generation EGFR tyrosine kinase inhibitors. Additional key eligibility criteria included no more than two prior lines of systemic chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and measurable disease per RECIST v1.1. A total of 81 patients were randomly assigned to receive Iza-Bren at doses of 1.5, 2.0, and 2.5 mg/kg intravenously on days 1 and 8 every 3 weeks (D1D8 Q3W).
The primary endpoint was safety, which, in turn, was used to determine the recommended phase III dose.
Baseline characteristics were generally balanced across dose groups in this heavily pretreated population; 64% of patients had received prior platinum-based chemotherapy and 17% prior amivantamab treatment.
“In this randomized dose expansion cohort, Iza-Bren at 2.5 mg/kg demonstrated promising efficacy with a tolerable safety profile in a heavily pretreated patient population with EGFR-mutated NSCLC across all dose levels,” said Alexander Spira, MD, PhD, FACP, FASCO, Director of the Virginia Cancer Specialists Research Institute and Chief Scientific Officer of NEXT Oncology.
As of the data cutoff on June 5, 2026, the total ORR was 30.9%, the cORR was 27.2%, the median duration of response (mDoR) was 5.7 months, and the median progression-free survival (mPFS) was 5.5 months. All dose levels showed promising efficacy; the 2.5 mg/kg dose level showed a trend toward higher ORR (33.3%), mDoR (9.7 months), and mPFS (6.9 months).
At the 2.5 mg/kg dose, 74% of patients experienced at least some tumor shrinkage with durable responses, and several patients maintained tumor responses for a year or more.
Promising efficacy was also observed in patients with progressive disease on prior amivantamab treatment. The ORR in patients with prior amivantamab was 35.7% versus 29.9% in patients with no prior amivantamab, and the mPFS was 5.4 versus 5.5 months, respectively.
The most common grade 3 or higher treatment-emergent adverse events (TRAEs) were hematological and manageable with standard measures. Since primary granulocyte colony-stimulating factor (G-CSF) prophylaxis was mandatory, neutropenia rates were low; most cases were transient, reversible, and non-recurrent. The incidence of neutropenic fever (1.2%) and interstitial lung disease (ILD)/pneumonitis (3.7%) was low, with no treatment-related deaths or new safety signals observed.
“We believe the totality of the safety, efficacy, and PK data supports the 2.5 mg/kg D1D8 Q3W dose level as the recommended phase III dose in the ongoing global registrational study (IZABRIGHT-Lung01)for patients with EGFR-mutated NSCLC after progression on a third-generation EGFR inhibitor,” Dr. Spira said.
