FDA Grants Breakthrough Therapy Designation to Izalontamab Brengitecan in EGFR+ NSCLC

The FDA has granted breakthrough therapy designation to izalontamab brengitecan (iza-bren; BL-B01D1), a potential first-in-class bispecific antibody-drug conjugate (ADC), for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations who experienced disease progression on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy.1

The FDA’s decision was based on efficacy and safety data from the phase 1 BL-B01D1-101 (NCT05194982), the phase 2 BL-B01D1-203 (NCT05880706), and the phase 1 BL-B01D1-LUNG-101 (NCT05983432) studies.1 Data from these trials have revealed that iza-bren demonstrated efficacy with a manageable safety profile for the treatment of patients with EGFR-mutant NSCLC who had disease progression after third-generation EGFR TKIs and platinum-based chemotherapy.

“The FDA’s granting of breakthrough therapy designation underscores the potential of iza-bren to meaningfully improve clinical outcomes for patients with previously treated [EGFR-mutated] NSCLC,” Jonathan Cheng, MD, chief medical officer of SystImmune, the codeveloper of iza-bren, stated 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.”

Of note, iza-bren is a novel bispecific ADC that targets both EGFR and HER3, which have high expression in a variety of epithelial cancers. The dual mechanism of action can block EGFR and HER3 signals to cancer cells, and the payload can cause genotoxic stress.

BL-B01D1-101 Study Design

Investigators in the phase 1a study are evaluating the tolerability of iza-bren for the treatment of patients with locally advanced or metastatic solid tumors to identify dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD).2 The phase 1b portion of the study further evaluated 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 18 to 75 years with locally advanced or metastatic solid tumors confirmed by histopathology and/or cytology with a lack of standard treatment. The ability to provide archived tumor tissue specimens or fresh tissue samples from the primary lesion or metastases within 2 years is required; patients must have at least 1 measurable lesion per RECIST 1.1 criteria and an ECOG performance status (PS) of 0 or 1.

Approximately 570 patients on the study will be treated with iza-bren for the first cycle, which is 3 weeks. Patients who achieve clinical benefit from the agent could receive additional treatment for more cycles. However, treatment will be terminated if patients experience disease progression or intolerable toxicity, among other reasons.

The primary end points include determining the DLT and MTD, and the 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 Study Design

The phase 2 study evaluated the efficacy and safety of iza-bren in combination with osimertinib (Tagrisso) for the treatment of patients with locally advanced or metastatic NSCLC.3

The study includes patients at least 18 years of age who have locally advanced or metastatic NSCLC confirmed by histopathology and/or cytology. Additionally, patients must provide an archived tumor tissue sample or a fresh tissue sample from the primary or metastatic site within 6 months of biomarker testing, have at least 1 measurable lesion per RECIST 1.1 criteria, an ECOG PS of 0 or 1, and an expected survival time of at least 3 months.

Approximately 198 patients on the study were treated with iza-bren plus osimertinib for the first cycle of 3 weeks. Those who achieve clinical benefit could continue on treatment; 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.

BL-B01D1-LUNG-101 Study Design

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 and other solid tumors.4

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 were included. Epithelial cancers included those with NSCLC, HER2-negative breast cancer, esophageal cancer, small cell lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. Furthermore, patients were required to provide archived tumor samples from primary or metastatic sites within 2 years, have at least 1 measurable lesion per RECIST 1.1 criteria, and an ECOG PS of 0 or 1.

Approximately 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; secondary end points include ORR, DCR, PFS, time to response, and overall survival.

References

1. 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. Bristol Myers Squibb. August 18, 2025. Accessed August 18, 2025. https://news.bms.com/news/details/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. Updated August 3, 2025. Accessed August 18, 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. Updated July 2, 2025. Accessed August 18, 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. Updated August 6, 2025. Accessed August 18, 2025. https://clinicaltrials.gov/study/NCT05983432