Izalontamab Brengitecan Earns FDA Breakthrough Designation in EGFR+ NSCLC

The US FDA has granted breakthrough therapy designation (BTD) to izalontamab brengitecan (iza-bren), a bispecific antibody-drug conjugate (ADC), for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR mutations.¹

The designation, announced by co-developers SystImmune Inc. and Bristol Myers Squibb, is for patients with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed after treatment with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy.

This designation underscores the significant and persistent clinical unmet need for this patient population. While third-generation EGFR TKIs like osimertinib (Tagrisso) have revolutionized first-line treatment, resistance is nearly universal, often developing within 18 months. Subsequent standard-of-care options typically involve platinum-based chemotherapy, which provides limited efficacy and is associated with substantial toxicities, highlighting the urgent need for more effective and tolerable therapeutic alternatives.

“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," said Jonathan Cheng, MD, chief medical officer of SystImmune, in a press 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."

Iza-bren, a potential first-in-class agent, is a bispecific ADC that simultaneously targets both EGFR and HER3. Both receptors are frequently overexpressed in various epithelial cancers, including NSCLC, and are known to promote cancer cell proliferation and survival. By engaging both targets, iza-bren aims to provide a more comprehensive blockade of tumor signaling pathways. Upon binding and internalization, the ADC releases its therapeutic payload, a potent topoisomerase 1 inhibitor, which induces DNA damage and genotoxic stress, ultimately leading to targeted cancer cell death.

The FDA's decision was based on compelling efficacy and safety data from a trio of ongoing clinical trials: 2 conducted in China by Sichuan Biokin Pharmaceutical Co (BL-B01D1-101 and BL-B01D1-203) and a global study led by SystImmune (BL-B01D1-LUNG-101). In these trials, iza-bren demonstrated an encouraging safety profile and evidence of improved clinical outcomes in patients with EGFR-mutant NSCLC who had exhausted prior TKI and platinum-based chemotherapy regimens. Data from the BL-B01D1-101 study (NCT05194982) showed an overall response rate of 63.2% in patients with EGFR-mutated NSCLC, a highly promising result in this difficult-to-treat setting.

About BL-B01D1-LUNG-101

The phase 1 BL-B01D1-LUNG-101 study is a global, multicenter study evaluating iza-bren in patients with metastatic or unresectable NSCLC and other solid tumors.² Patients are randomized to receive iza-bren administered on days 1 and 8 or on day 1 of each 3-week cycle.

The primary end points are incidence of dose-limiting toxicities and adverse events and determining the maximum tolerated dose. Secondary end points include pharmacokinetics, overall response rate, time to response, disease control rate, progression-free survival, and overall survival.

The study is currently recruiting and aims to enroll 260 patients. The estimated study completion date is March 21, 2028.

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. SystImmune Inc. August 18, 2025. Accessed August 18, 2025. https://tinyurl.com/58pzbsz2

2. 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