Iza-Bren Receives FDA Breakthrough Therapy Designation for EGFR-Mutated NSCLC

The FDA granted a breakthrough therapy designation to izalontamab brengitecan (iza-bren, formerly BL-B01D1; Bristol Myers Squibb, SystImmune) for the treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations. This indication is specifically for those whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy.¹

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Iza-bren is a bispecific antibody-drug conjugate (ADC) that targets both EGFR and HER3 targets, which are highly expressed in various epithelial cancers and are known to be associated with cancer cell proliferation and survival. The ADC’s dual mechanism of action blocks both EGFR and HER3 signals to cancer cells, therefore reducing proliferation and survival signals. Additionally, upon antibody-mediated internalization, the therapeutic payload is released, causing genotoxic stress that leads to cancer cell death in patients treated with iza-bren.¹

According to the manufacturers, the FDA’s decision is based on safety and efficacy data from 3 ongoing trials: BL-B01D1-101 (NCT05194982)², BL-B01D1-203 (NCT05880706)³, and BL-B01D1-LUNG-101 (NCT05983432).⁴

BL-B01D1-101 Clinical Trial

The phase 1a study is currently evaluating the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of iza-bren for the treatment of patients with locally advanced or metastatic solid tumors. This trial aims to identify dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD), and the phase 1b portion specifically will further evaluate the safety and tolerability of iza-bren, with the goal of determining the recommended phase 2 dose (RP2D). Patients included in the study are aged between 18 and 75 years with locally advanced or metastatic solid tumors confirmed by histopathology and/or cytology with a lack of standard treatment.²

An estimated 570 patients in the study will be treated with iza-bren for the first 3-week cycle, and those who achieve clinical benefit from the agent could receive further treatment for additional cycles; however, treatment will be terminated if patients experience disease progression or intolerable toxicity, among other reasons.

The primary end points include DLT, MTD, and RP2D. Secondary end points include treatment-emergent adverse effects (TEAEs), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).

BL-B01D1-203 Clinical Trial

This phase 2 study evaluated the efficacy and safety of iza-bren in combination with osimertinib (Tagrisso; AstraZeneca) for the treatment of patients with locally advanced or metastatic NSCLC. BL-B01D1-203 includes patients who are at least 18 years of age who have locally advanced or metastatic NSCLC confirmed by histopathology and/or cytology. A total of 198 patients in the study were treated with iza-bren plus osimertinib for the first 3-week cycle, and those who achieved clinical benefit can continue on treatment, whereas those who have disease progression, intolerable toxicity, or other reasons discontinued treatment. Notably, the primary end points are the RP2D and ORR. Secondary end points include PFS, DCR, DOR, and TEAEs.³

BL-B01D1-LUNG-101 Clinical Trial

The global, multicenter, phase 1 study assesses the safety, tolerability, pharmacokinetics, and preliminary efficacy of iza-bren for the treatment of metastatic or unresectable NSCLC as well as other solid tumors. Patients at least 18 years of age with a life expectancy of at least 3 months and histologically documented, incurable, locally advanced, or metastatic epithelial origin cancer (eg, HER2– breast cancer, esophageal cancer, small cell lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma) were enrolled in the trial. About 260 patients were randomly assigned to receive either iza-bren on days 1 and 8 every 3 weeks or iza-bren on day 1 every 3 weeks. The primary end point is safety, and secondary end points include ORR, DCR, PFS, time to response, and overall survival.⁴

The manufacturer reports that NSCLC accounts for approximately 80% of all lung cancer cases, and it remains the leading cause of cancer-related death worldwide. Among patients with NSCLC, about 10% to 15% in Western populations and up to 50% in Asian populations harbor activating EGFR mutations. These tumors—which are most commonly of nonsquamous histology—initially respond to EGFR TKIs; however, resistance is nearly universal and often occurs after about 18 months, meaning that treatment options beyond TKIs and platinum-based chemotherapy provide limited clinical benefit with significant toxicities. For these reasons, there is a significant need for new and effective therapies for this patient population.¹

“The FDA’s granting of breakthrough therapy designation underscores the potential of iza-bren to meaningfully improve clinical outcomes for patients with previously treated epidermal growth factor receptor mutation NSCLC,” Jonathan Cheng, MD, chief medical officer of SystImmune, said in a news release. “The data we have generated to date suggest that iza-bren could address a critical unmet need in patient care, and we look forward to working closely with the FDA to conduct the relevant clinical studies and seek regulatory approval.”¹

REFERENCES

1. Bristol Myers Squibb. Izalontamab Brengitecan (EGFRxHER3 ADC) Granted Breakthrough Therapy Designation by U.S. FDA for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer. News release. August 18, 2025. Accessed August 27, 2025. https://news.bms.com/news/corporate-financial/2025/Izalontamab-Brengitecan-EGFRxHER3-ADC-Granted-Breakthrough-Therapy-Designation-by-U-S--FDA-for-Patients-with-Previously-Treated-Advanced-EGFR-Mutated-Non-Small-Cell-Lung-Cancer/default.aspx

2. A Study of BL-B01D1 in Patients With Locally Advanced or Metastatic Solid Tumor. ClinicalTrials.gov identifier: NCT05194982. Updated August 3, 2025. Accessed August 27, 2025. https://clinicaltrials.gov/study/NCT05194982

3. A Study of BL-B01D1 and BL-B01D1 in Combination With Osimertinib Mesylate Tablets in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer. ClinicalTrials.gov identifier: NCT05880706. Updated July 2, 2025. Accessed August 27, 2025. https://www.clinicaltrials.gov/study/NCT05880706

4. Evaluate BL-B01D1 in Patients With Metastatic or Unresectable Non-Small Cell Lung Cancer (NSCLC) and Other Solid Tumors. ClinicalTrials.gov identifier: NCT05983432. Updated August 6, 2025. Accessed August 27, 2025. https://clinicaltrials.gov/study/NCT05983432