Dr Spira on the Data Supporting the Phase 3 Development of Iza-Bren in EGFR-Mutant NSCLC

"By targeting something downstream of EGFR, [you’re] hopefully able to overcome resistance patterns."

Alexander I. Spira, MD, PhD, FACP, FASCO, co-director of the Virginia Cancer Specialists Research Institute and director of its Thoracic and Phase I Program, and chief scientific officer of NEXT Oncology, discussed dose-optimization data from a global phase 1 trial (NCT05983432) evaluating the EGFR x HER3 bispecific antibody-drug conjugate (ADC) izalontamab brengitecan (iza-bren) in patients with EGFR-mutated non–small cell lung cancer (NSCLC).

According to Spira, iza-bren pairs a topoisomerase-1 inhibitor payload with dual targeting of EGFR and its downstream partner HER3, an approach intended to overcome resistance that develops on EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib (Tagrisso). Even when bypass signaling emerges, he explained, the EGFR-directed arm of the ADC can still bind the receptor and induce cell death because EGFR remains expressed on the tumor cell surface.

The global, multicenter phase 1b dose-expansion cohort, conducted at both community and academic sites, enrolled a population Spira called representative of the broader EGFR-mutated NSCLC population, most of whom had progressed on a third-generation EGFR TKI and were predominantly nonsmokers. Response rates were similar across the 3 dose levels tested, up to 2.5 mg/kg, but progression-free survival (PFS) and duration of response trended modestly higher at the top dose, Spira said; at the 2.5-mg/kg dose, dosed on days 1 and 8 of each cycle, the confirmed objective response rate was 29.6% (95% CI, 13.8%-50.2%) and median PFS was 6.9 months (95% CI, 4.0-not reached), according to data presented at the 2026 World Conference on Lung Cancer.

Safety was manageable across dose levels, Spira noted, with a slight increase in anemia at 2.5 mg/kg that investigators plan to continue monitoring. Because all patients received mandatory primary growth factor support based on phase 1 experience with neutropenia, the toxicity of greatest concern with topoisomerase-1–based ADCs, the study did not show a significant increase in febrile neutropenia, neutropenia, or grade 5 events, Spira said.

With that risk-benefit profile in hand, Spira said 2.5 mg/kg was selected as the recommended phase 3 dose, and reported that the follow-up study, IZABRIGHT-Lung01 (NCT07100080), a global, randomized phase 3 trial of iza-bren vs platinum-based chemotherapy in this same patient population, is now open. The trial’s goal, he said, is to determine whether iza-bren can become a standard of care over chemotherapy alone.