BMS’s SystImmune bispecific ADC aces endpoints in Phase III for triple-negative breast cancer

Edited by Robert McTiernan··2 min read

US-based SystImmune and Bristol Myers Squibb announced positive interim topline results from a Phase III trial of izalontamab brengitecan (iza-bren), a bispecific EGFR×HER3 antibody-drug conjugate (ADC), in patients with previously treated unresectable locally advanced or metastatic triple-negative breast cancer (TNBC). The study met its dual primary endpoints of progression-free survival (PFS) and overall survival (OS), notable in a treatment setting where durable survival gains have historically been limited following progression on taxane-based therapy.

Trial specifics

The BL-B01D1-307 study (NCT06382142) is a Phase III, randomized, open-label, multicenter trial conducted in China in patients with unresectable locally advanced or metastatic TNBC whose disease progressed following prior taxane therapy. Participants were randomized to receive iza-bren or chemotherapy of physician’s choice.

In a pre-specified interim analysis, treatment with iza-bren demonstrated statistically significant improvements in both PFS and OS compared with chemotherapy, meeting the study’s dual primary endpoints. No additional efficacy or safety data were disclosed in the topline announcement. The trial sponsor, China-based Sichuan Biokin Pharmaceutical Co., Ltd., said the findings will be presented at an upcoming medical meeting.

Iza-bren was discovered by Sichuan Biokin, who partnered with BMS on the molecule’s development outside of Chinavia its wholly owned US-based subsidiary SystImmune in a 2023 deal. The molecule has received Breakthrough Therapy Designation from China’s National Medical Products Administration for multiple indications, and from the US FDA for previously treated non-small cell lung cancer (NSCLC) with EGFR mutation. Separate New Drug Applications for nasopharyngeal carcinoma and esophageal squamous cell carcinoma are currently under priority review in China.

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Research context

Izalontamab brengitecan (BL-B01D1) is a bispecific ADC designed to target both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), two signaling pathways implicated in tumor proliferation, survival, and treatment resistance across epithelial cancers. Following antibody-mediated internalization, the molecule delivers a topoisomerase I inhibitor payload intended to induce cytotoxic stress and tumor cell death.

Targeting HER3 in combination with EGFR may offer a strategy to overcome compensatory signaling mechanisms associated with resistance to EGFR-targeted therapies, particularly in aggressive tumor types such as TNBC, which lacks expression of hormone receptors and HER2 and is associated with limited targeted treatment options following progression on chemotherapy.

Approved targeted therapies in previously treated TNBC remain limited. ADCs have emerged as an important therapeutic class in this setting, including:

  • Gilead Sciences’ sacituzumab govitecan (Trodelvy), a Trop-2-directed ADC approved by the US FDA for metastatic TNBC based on the Phase III ASCENT trial.
  • AstraZeneca and Daiichi Sankyo’s trastuzumab deruxtecan (Enhertu), a HER2-directed ADC evaluated in HER2-low breast cancer populations in studies including DESTINY-Breast04.

However, bispecific ADC approaches targeting dual receptor pathways remain investigational. The BL-B01D1-307 trial is the third Phase III study in which iza-bren has met primary endpoint criteria, according to the company, though detailed results from these studies have not yet been reported.