Iza-Bren (also known as izalontamab brengitecan; BL-B01D1) is an investigational bispecific antibody–drug conjugate (ADC) engineered to target both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), two critical drivers of tumor growth and therapeutic resistance in epithelial malignancies. Resistance to EGFR-targeted therapies, particularly tyrosine kinase inhibitors (TKIs), remains a major challenge in cancers such as non–small cell lung cancer (NSCLC) and nasopharyngeal carcinoma, where adaptive HER3 signaling sustains downstream oncogenic pathways (Hynes & MacDonald, 2009; Sithanandam & Anderson, 2008).
By combining dual receptor targeting with intracellular delivery of a potent cytotoxic payload, Iza-Bren is designed to overcome pathway redundancy and tumor heterogeneity that limit the durability of single-target therapies (Beck et al., 2017).
Molecular Structure And Mechanism Of Action
Iza-Bren is a bispecific EGFR×HER3 antibody–drug conjugate linked to a topoisomerase I inhibitor payload (Ed-04) via a cleavable linker. Upon binding EGFR and/or HER3 on the tumor cell surface, the ADC is internalized through receptor-mediated endocytosis. Lysosomal cleavage of the linker releases the payload into the cytoplasm, where it induces DNA damage and tumor cell death (Ducry & Stump, 2010).
Dual targeting enhances tumor selectivity and internalization while suppressing compensatory HER3-mediated PI3K/AKT signaling, a well-established mechanism of resistance to EGFR inhibition (Baselga & Swain, 2009).
Regulatory Milestone: FDA Breakthrough Therapy Designation
In August 2025, the U.S. Food and Drug Administration granted Breakthrough Therapy Designation to Iza-Bren for patients with locally advanced or metastatic EGFR-mutated NSCLC whose disease progressed after EGFR TKI therapy and platinum-based chemotherapy. This designation reflects preliminary clinical evidence suggesting substantial improvement over existing therapies and enables expedited regulatory interaction (FDA, 2025).
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Phase I And Early Clinical Development
Early-phase global studies evaluated Iza-Bren in patients with advanced solid tumors expressing EGFR and/or HER3. In the BL-B01D1-LUNG-101 Phase I trial, Iza-Bren demonstrated robust antitumor activity in heavily pretreated patients, achieving a confirmed objective response rate of approximately 55% at the 2.5 mg/kg dose, with a median progression-free survival of 5.4 months. Responses were observed in both EGFR-mutated and EGFR wild-type NSCLC, and no interstitial lung disease was reported in this cohort (SystImmune & Bristol Myers Squibb, 2025). These data supported continued dose expansion and registrational development.
Phase III Registrational Evidence In Nasopharyngeal Carcinoma
At the ESMO 2025 Congress, results from the BL-B01D1-303 Phase III trial were presented in recurrent or metastatic nasopharyngeal carcinoma (NPC). Iza-Bren significantly improved outcomes compared with physician’s choice chemotherapy, achieving a BICR-assessed objective response rate of 54.6% versus 27.0%, a median progression-free survival of 8.38 months versus 4.34 months (hazard ratio 0.44), and a median duration of response of 8.5 months versus 4.8 months. Overall survival data were immature at the time of reporting, but benefits were consistent across subgroups (SystImmune press release, 2025; ESMO Congress data, 2025).
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Activity In EGFR-Mutated NSCLC
In EGFR-mutated NSCLC, Iza-Bren has demonstrated particularly strong signals. In a Phase II monotherapy study in post-TKI patients who were chemotherapy-naïve, Iza-Bren achieved a median progression-free survival of 12.5 months and an objective response rate of approximately 56%, representing one of the longest PFS outcomes reported in this setting to date (ILCN report, 2025).
Even more striking results were observed in combination studies. In a Phase II cohort evaluating Iza-Bren plus osimertinib as frontline therapy for EGFR-mutated NSCLC, investigators reported a 100% objective response rate and a 12-month PFS rate of approximately 92%, with median PFS not yet reached at the time of analysis (IASLC press briefing, 2025).
Safety Profile Across Clinical Studies
Across trials, Iza-Bren has shown a manageable safety profile, with hematologic adverse events such as neutropenia and anemia being the most commonly reported toxicities. These events were generally manageable with dose modifications and supportive care. Importantly, interstitial lung disease—a concern with several EGFR-directed agents—has not emerged as a dominant safety signal to date (SystImmune & Bristol Myers Squibb, 2025). Mandatory neutropenia prophylaxis and close monitoring have been incorporated into later-phase trials to further mitigate risk.
Broader Development Program And Ongoing Trials
Iza-Bren is currently being evaluated across multiple tumor types and treatment settings, including:
- First-line metastatic triple-negative breast cancer
- Second-line metastatic EGFR-mutated NSCLC
- Second-line metastatic urothelial carcinoma
These studies aim to define optimal patient selection, sequencing, and combination strategies while validating survival benefit (SystImmune development update, 2025).
Clinical Positioning And Future Outlook
By integrating dual EGFR×HER3 targeting with potent cytotoxic delivery, Iza-Bren represents a mechanistically distinct strategy within the EGFR treatment landscape. Its activity in TKI-resistant disease, strong combination data with osimertinib, and confirmed Phase III benefit in NPC position it as a potential new standard in selected settings pending regulatory approval.
Future research will focus on biomarker-driven patient selection, durability of benefit, and long-term safety, particularly as Iza-Bren moves into earlier lines of therapy.
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Written by Armen Gevorgyan, MD