FDA Grants Breakthrough Therapy Designation to Izalontamab Brengitecan for EGFR-Mutated NSCLC

The FDA has granted Breakthrough Therapy Designation (BTD) to SystImmune and Bristol Myers Squibb’s izalontamab brengitecan (iza-bren) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy.¹

Breakthrough Therapy Designation supported by multiple trials

The BTD is based on data from three clinical trials evaluating iza-bren: BL-B01D1-101 (NCT05194982), BL-B01D1-203 (NCT05880706), and BL-B01D1-LUNG-101 (NCT05983432).

Iza-bren is a bispecific antibody-drug conjugate (ADC) which acts by targeting both epidermal growth factor receptor and human epidermal growth factor receptor 3 (EGFRxHER3) with a topoisomerase 1 inhibitor payload. The potential first-in-class therapy is being developed by Biokin in China and jointly developed by SystImmune and Bristol Myers Squibb under a collaboration and exclusive license agreement outside of China.

In a press release, Jonathan Cheng, MD, Chief Medical Officer of SystImmune, said: “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. 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.”

Expanded results presented at ASCO 2025

Earlier in May, SystImmune announced it would be presenting positive data from the Phase I BL-B01D1-101 study at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting. Expanded results included data from patients with advanced stages of SCLC and NSCLC with driver genomic alterations outside of classic EGFR mutations and having multiple lines of prior therapies.²

Key results in NSCLC patient population

In the NSCLC patient population, data from BL-B01D1-101 showed:³

• As of December 5, 2024, 73 patients with NSCLC and genomic alterations were enrolled.
• Five patients were still on treatment but excluded from analysis due to insufficient follow-up.
• Among seven patients with EGFR exon 20 insertions, 85.7% (6 of 7) achieved confirmed partial responses.
• Among eight patients with KRAS G12C mutations, three confirmed partial responses and one pending partial response were observed.

Outcomes in small cell lung cancer

In SCLC participants, data from the trial showed:⁴

• As of December 5, 2024, 58 patients with SCLC were enrolled, all of whom received at least one dose of iza-bren.
• The median follow-up was 16.4 months. Overall response rate (ORR) was 55.2%, confirmed ORR was 44.8%, median progression-free survival (PFS) was 4.0 months, and median overall survival (OS) was 12.0 months.
• Among 52 patients treated at 2.5 mg/kg, 20 had received only one prior line of PD-(L)1 plus platinum-based chemotherapy.
  • In this subgroup, ORR was 80.0%, confirmed ORR was 75.0%, median duration of response was 5.6 months, median PFS was 6.9 months, and median OS was 15.1 months.

No new safety signals were observed across either patient population in this readout.

In a press release from the time of when these ASCO presentations were announced, Cheng said: "Recent data have bolstered our confidence in iza-bren's safety profile while highlighting its encouraging efficacy across tumors that have been difficult to treat. Iza-bren emerges as a promising therapeutic option, potentially fulfilling the unmet need of patients with few treatment alternatives. Our commitment to advancing this therapy through a series of comprehensive clinical trials remains steadfast, as we explore its potential both as a standalone treatment and in combination with other agents to improve cancer patient outcomes globally."

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/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. SystImmune, Inc. to Present New izalontamab brengitecan (iza-bren) Data in Small Cell Lung Cancer and Non-Small Cell Lung Cancer with Driver Genomic Alterations (GA) outside of Classic EGFR Mutations at ASCO Congress 2025. News release. SystImmune. May 23, 2025. Accessed August 18, 2025. https://systimmune.com/news---systimmune-inc-asco-congress-2025

3. Yunpeng Yang et al. Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with driver genomic alterations (GA) outside of classic EGFR mutations.. JCO 43, 3001-3001(2025). DOI:10.1200/JCO.2025.43.16_suppl.3001 https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3001

4. Yan Huang et al. Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic small cell lung cancer (SCLC).. JCO 43, 3002-3002(2025). https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3002 DOI:10.1200/JCO.2025.43.16_suppl.3002