Dual Targeting: Iza-bren Shows Promising Early Results Across Solid Tumors

Samantha El Warrak, MBBS University of Miami Miller School of Medicine | Chinmay Jani, MD University of Miami Health System

November 17, 2025

Malignant tumor in the lung with cancerous growth and tumor cells, medical illustration of lung cancer pathology for oncology and cancer research.
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Bispecific antibody-drug conjugates (ADCs) that target both EGFR and HER3 and are linked to the novel topoisomerase I inhibitor payload Ed-04 represent a significant advancement in targeted cancer therapy, offering greater efficacy and selectivity than monospecific ADCs.

Izalontamab brengitecan (iza-bren/BL-B01D1), a novel ADC, was presented at the 2025 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer (WCLC). It’s the first-in-class bispecific ADC designed to bind both EGFR and HER3 receptors, which are frequently overexpressed in various solid tumors and implicated in tumorigenesis and therapeutic resistance. 

The conjugate comprises an anti-EGFR IgG1 antibody fused to anti-HER3 single-chain fragments through a glycine-serine linker, carrying the Ed-04 payload—a camptothecin-derived topoisomerase I inhibitor—at a high drug-to-antibody ratio. Upon binding to either EGFR or HER3 on tumor cells, iza-bren is internalized and releases Ed-04 in lysosomes, leading to DNA damage and tumor cell death.1

Iza-Bren’s Emerging Therapeutic Role

Preclinical studies demonstrated that iza-bren outperformed monospecific ADCs targeting EGFR or HER3 alone, showing robust antitumor activity across multiple cancer models.1 In phase 1 and 1b clinical trials, iza-bren showed promising efficacy in heavily pretreated patients with metastatic esophageal squamous cell carcinoma (ESCC) non-small cell lung cancer (NSCLC) and urothelial carcinoma, with objective response rates (ORR) ranging from 29% to 44% and disease control rates up to 88% at recommended doses (2.2-2.5 mg/kg every 3 weeks).2-5 Notably, patients with EGFR exon 20 insertions and KRAS G12C mutations in NSCLC also showed favorable responses.3

In metastatic ESCC, phase 1b/2 data (NCT05262491) demonstrated a confirmed ORR of 39.6% and a disease control rate (DCR) of 79.2% at the recommended phase 2 dose of 2.5 mg/kg every 3 weeks. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 63.3% of patients and were primarily hematologic (anemia, leukopenia, thrombocytopenia, neutropenia).1,2

For patients with locally advanced/metastatic urothelial carcinoma, phase 2 data (BL-B01D1-201) showed a confirmed ORR (cORR) of 44.1% and DCR of 88.2% at 2.2 mg/kg every 3 weeks. Median progression-free survival (PFS) was 7.3 months and median duration of response (DOR) was 11.3 months. Hematologic toxicity was common but manageable.3

In NSCLC with driver mutations, phase 1b expansion cohorts showed a cORR up to 85.7% in patients with EGFR exon 20 insertion and 37.5% in KRAS G12C. Hematologic toxicity and rare interstitial lung disease were manageable.4,5 

Among 50 patients with EGFR-mutated NSCLC who had received prior EGFR tyrosine kinase inhibitor (TKI) therapy but no chemotherapy and were treated with iza-bren at 2.5 mg/kg on days 1 and 8 of a 3-week cycle, the ORR was 66%, with a median PFS of 12.5 months. The median DOR was 13.7 months. However, median overall survival (OS) was not reached (12-month OS 80.3%).6

Potent but Tolerable Toxicity

Iza-bren demonstrated a manageable safety profile primarily characterized by hematologic toxicities such as anemia, leukopenia, neutropenia, and thrombocytopenia. Grade 3 or higher events occurred in 32% to 47% of patients, slightly more than with some other ADCs due to the potent Ed-04 payload.1,4 Nonhematologic events, including nausea, stomatitis, diarrhea, and alopecia, were generally mild, and interstitial lung disease was rare but requires monitoring.2,4 Only 1.2% of patients discontinued treatment because of an adverse event, and no treatment-related deaths were observed. The pharmacokinetic data confirmed stable linker-payload integrity and slow toxin release, supporting the feasibility of this bispecific approach.1

Compared with monospecific ADCs, such as datopotamab deruxtecan for TROP2, patritumab deruxtecan for HER3, and MRG003 for EGFR, bispecific ADCs like iza-bren may offer broader efficacy and overcome resistance mechanisms by dual targeting, although at the cost of increased hematologic toxicity.7,8 The dual targeting strategy is particularly relevant for tumors with heterogeneous receptor expression or acquired resistance to EGFR TKIs.

Clinical Implications

For patients with EGFR-mutated NSCLC who have progressed on TKIs, iza-bren may represent a potential new therapeutic option given the high response rate and durable responses in this early-phase data. In addition, the bispecific targeting of EGFR and HER3 is a novel approach, possibly enabling deeper or different targeting in EGFR-mutated disease. 

Compared with other EGFR-targeting ADCs, iza-bren demonstrates a notably higher incidence of hematologic toxicities, while nonhematologic adverse events and discontinuation rates remain relatively low and manageable. Hematologic toxicity will need monitoring in larger studies. Phase 3 data will be crucial in determining whether this treatment becomes part of standard care.

Other EGFR-targeting ADCs, such as MRG003 and cetuximab sarotalocan, also show hematologic and hepatic toxicities, but the rates of severe (grade 3 or higher) hematologic events are generally lower than those seen with iza-bren. For example, MRG003 reports grade 3 or higher adverse events in 31% of patients, primarily liver and hematologic toxicities. Cetuximab sarotalocan is associated with a high rate of grade 3 or higher TRAEs (63.3%), but these are not predominantly hematologic.1,8 In early-phase studies, other bispecific ADCs (eg, tilatamig samrotecan, GEN1286) and EGFR-directed ADCs with microtubule inhibitor payloads (eg, M1231) have exhibited lower incidence and severity of hematologic toxicity compared with iza-bren.8

Considerations and Limitations

The early-phase data include a relatively small and selected patient population (pool of chemotherapy-naïve patients with prior TKI use only). A broader patient population, such as those with prior chemotherapy treatment, different EGFR mutation subtypes, and brain metastases, will need to be explored, and long-term safety and survival benefit beyond 12 months remains to be defined.

Future Directions: Optimizing Bispecific ADC Design

EGFR–HER3 bispecific ADCs with Ed-04 payloads, such as iza-bren, demonstrate promising efficacy and manageable safety in advanced solid tumors, particularly in patients refractory to standard therapies. Ongoing phase 2/3 trials will further define their role in clinical practice.2-5 Phase 3 trials are ongoing in ESCC and NSCLC (NCT05262491, NCT05194982), aiming to confirm efficacy and further refine patient selection and biomarker strategies. A phase 3 registrational study of iza-bren as monotherapy in EGFR-mutated NSCLC after progression on a third-generation EGFR TKI is ongoing in China.

Key Ongoing Trials Involving EGFR-Targeting ADCs

  1. NCT05751512: an ongoing phase 3 trial in HNSCC, comparing MRG003, an EGFR-targeting ADC, with a monomethyl auristatin E (MMAE) payload, to standard therapies such as cetuximab or methotrexate.8,9 
  2. The ECLIPSE phase 3 trial (NCT06699212): evaluating cetuximab sarotalocan (RM-1929), which combines cetuximab with a photoactivatable payload (IRDye700DX), plus pembrolizumab in recurrent HNSCC.8  
  3. The EGRET phase 1 study (NCT05647122): evaluating tilatamig samrotecan (AZD9592), a bispecific ADC targeting EGFR and c-MET delivering a topoisomerase I inhibitor payload, is ongoing in NSCLC and HNSCC.8,10 
  4. NCT06685068: GEN1286 (PRO1286) is another bispecific ADC targeting EGFR and c-MET, in early-phase clinical investigation.8  
  5. NCT04695847: M1231 is a bispecific ADC targeting EGFR and MUC1, currently in phase 1 trials for HNSCC.8  
  6. NCT06515990: A first-in-human trial looking at DM005, a bispecific ADC targeting EGFR and c-MET, with a DNA topoisomerase I inhibitor payload, is actively recruiting in Australia, the United States, and China.11 
  7. ABBV-321 (serclutamab talirine): a next-generation EGFR-targeted ADC with a pyrrolobenzodiazepine (PBD) dimer toxin, currently in phase 1 trials for advanced EGFR-expressing malignancies.12 
  8. Other notable agents such as patritumab deruxtecan (HER3-directed), and additional bispecific ADCs targeting EGFR/HER3 or EGFR/c-MET, are in development for EGFR-mutant NSCLC and other solid tumors.13-15

References

  1. Ma Y, Huang Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study. Lancet Oncol. 2024;25(7):901–911. doi:10.1016/S1470-2045(24)00159-1
  2. Liu C, Liu D, Ji Y, et al. A bispecific antibody-drug conjugate targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma: a phase 1b trial. Nat Med. 2025;31(10):3485–3491. doi:10.1038/s41591-025-03792-7
  3. Ma W, Li Y, Lu Y, et al. A multicenter retrospective study: impact of first-line treatment strategies on second-line efficacy and safety of regorafenib with or without PD-1 inhibitors in unresectable hepatocellular carcinoma. J Hepatocell Carcinoma. 2025;12:2123–2137. doi:10.2147/JHC.S456712. eCollection 2025
  4. Bian X, Yang T, Yin H, et al. Efficacy and safety of BL-B01D1 in patients with locally advanced or metastatic urothelial carcinoma: a phase II clinical trial. J Clin Oncol. 2025;43(32):3505–3515. doi:10.1200/JCO-25-00109
  5. Li Z, Ma Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFR×HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: results from a first-in-human phase 1 study. J Clin Oncol. 2023;41(16_suppl):3001. doi:10.1200/JCO.2023.41.16_suppl.3001
  6. Martin C. New antibody-drug conjugate shows promising efficacy in EGFR-mutated NSCLC patients 2025 [2025 Sep 6]. www.iaslc.org/iaslc-news/press-release/new-antibody-drug-conjugate-shows-promising-efficacy-egfr-mutated-nsclc
  7. Waissengrin B, Reckamp KL. An evaluation of patritumab deruxtecan for the treatment of EGFR-mutated non-small cell lung cancer. Expert Opin Biol Ther. 2025;25(6):583–591. doi:10.1080/14712598.2025.2507833
  8. Hwang W, Ahn JS, Jung HA, et al. Emerging EGFR-targeted therapy in head and neck cancer: a review. JAMA Oncol. 2025. doi:10.1001/jamaoncol.2025.3136
  9. Qiu MZ, Zhang Y, Guo Y, et al. Evaluation of safety of treatment with anti-epidermal growth factor receptor antibody drug conjugate MRG003 in patients with advanced solid tumors: a phase 1 nonrandomized clinical trial. JAMA Oncol. 2022;8(7):1042–1046. doi:10.1001/jamaoncol.2022.0503
  10. Aggarwal C, Azzoli CG, Spira A, et al. EGRET: A first-in-human study of the novel antibody-drug conjugate (ADC) AZD9592 as monotherapy or combined with other anticancer agents in patients (pts) with advanced solid tumors. J Clin Oncol. 2023;41(Suppl 16):TPS3156. doi:10.1200/JCO.2023.41.16_suppl.TPS3156
  11. Wei H, Dai W, Shen Y, et al. DM005: An anti-EGFR/c-MET bispecific antibody-drug conjugate for advanced solid tumors. J Clin Oncol. 2025;43(Suppl 16):e15010. doi:10.1200/jco.2025.43.16_suppl.e15010
  12. Anderson MG, Falls HD, Mitten MJ, et al. Targeting multiple EGFR-expressing tumors with a highly potent tumor-selective antibody-drug conjugate. Mol Cancer Ther. 2020;19(10):2117–2125. doi:10.1158/1535-7163.MCT-20-0149
  13. Meyer ML, Fitzgerald BG, Paz-Ares L, et al. New promises and challenges in the treatment of advanced non-small-cell lung cancer. Lancet. 2024;404(10454):803–822. doi:10.1016/S0140-6736(24)01029-8
  14. High P, Guernsey C, Subramanian S, et al. The evolving paradigm of antibody-drug conjugates targeting the ErbB/HER family of receptor tyrosine kinases. Pharmaceutics. 2024;16(7). doi:10.3390/pharmaceutics16070890
  15. Jimenez-Labaig P, Rullan A, Hernando-Calvo A, et al. A systematic review of antibody-drug conjugates and bispecific antibodies in head and neck squamous cell carcinoma and nasopharyngeal carcinoma: charting the course of future therapies. Cancer Treat Rev. 2024;128:102772. doi:10.1016/j.ctrv.2024.102772