Editor's Note: With the 2026 European Society for Medical Oncology (ESMO) Congress fast approaching, the phase III randomized PANKU-Breast01 study of iza-bren (BL-B01D1), the world's first approved bispecific antibody–drug conjugate (ADC), has reached its primary endpoint. The study evaluated iza-bren in patients with HR-positive/HER2-negative (HR+/HER2−) advanced breast cancer who had previously received one or two lines of chemotherapy. The findings have been selected for a late-breaking abstract (LBA) presentation at this year's ESMO Congress and are set to be unveiled globally for the first time. This milestone signals the beginning of a new era of bispecific ADC therapy for HR+/HER2− breast cancer.Ahead of this major event, Oncology Frontier invited Professor Huihui Li of Shandong Cancer Hospital to share her academic insights into the challenges of later-line treatment for HR+/HER2− advanced breast cancer and the potential of bispecific ADCs to address these unmet needs.
The Challenge of Later-Line Treatment: The Clinical Landscape and Unmet Needs in HR+/HER2− Advanced Breast Cancer
HR+/HER2− breast cancer accounts for approximately 70% of all breast cancer cases, making it the most prevalent molecular subtype. First-line regimens, particularly endocrine therapy combined with CDK4/6 inhibitors, have significantly improved survival in patients with advanced disease. However, resistance is almost inevitable. By the later lines of treatment, patients have often received endocrine therapy, CDK4/6 inhibitors, and one or two lines of chemotherapy. Their overall physical condition may have deteriorated, and treatment options become limited, leaving substantial unmet clinical needs.
In recent years, ADCs have demonstrated potential in later-line breast cancer treatment. However, single-target ADCs rely on a single antigen as their binding target, limiting their ability to kill tumor cells with heterogeneous antigen expression or downregulated antigen levels. This creates a potential route for resistance and treatment escape. There is a clinical need for ADCs that can maintain potent antitumor activity even in heavily pretreated populations. Whether bispecific ADCs can fulfill this role has become a major focus in the field.
A Potential Breakthrough: Positive PANKU-Breast01 Results on the Horizon
Bispecific Targeting: More Than a Simple Upgrade of Single-Target ADCs
Iza-bren targets both EGFR and HER3 and offers three mechanistic advantages over single-target ADCs.
Dual-target binding makes tumor escape more difficult. Simultaneous binding to EGFR and/or HER3 can induce receptor clustering, enhance internalization and payload delivery, and block compensatory activation mediated by HER3 in advance. These mechanisms may reduce the risk of resistance associated with single-target therapy.
A stable linker enables precise payload delivery. Its proprietary, patented Ac stable linker and GGFG tetrapeptide linker help maintain stability in plasma, while lysosomal degradation within tumor cells releases the payload. The drug-to-antibody ratio (DAR) is set at 8, helping increase the effective drug concentration within the tumor.
A novel payload delivers potent activity and a strong bystander effect. The payload, Ed-04, is a novel topoisomerase I inhibitor. Compared with DXd, it has stronger antitumor activity and a more pronounced bystander effect, potentially enabling more effective local killing of heterogeneous tumor cell populations.
Study Overview: PANKU-Breast01—A Pivotal Phase III Trial in Later-Line HR+/HER2− Breast Cancer
Led by Academician Binghe Xu of the National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, PANKU-Breast01 is a randomized, multicenter phase III clinical trial designed to evaluate the efficacy and safety of iza-bren versus physician’s choice of single-agent chemotherapy—eribulin, vinorelbine, gemcitabine, or capecitabine.
The study enrolled patients with unresectable locally advanced or metastatic HR+/HER2− breast cancer who had previously received endocrine therapy and one or two lines of chemotherapy in the advanced-disease setting.
In August 2026, Sichuan Biokin Pharmaceutical announced that, according to the independent Data Monitoring Committee (iDMC), PANKU-Breast01 had met its primary endpoint of progression-free survival (PFS) at a prespecified interim analysis.
This encouraging signal raises the possibility that iza-bren could offer a new treatment option for patients with HR+/HER2− advanced breast cancer in later lines of therapy.
Early Exploration: Phase I Findings Have Already Shown Encouraging Antitumor Activity
In a multicenter phase I study published in Annals of Oncology, iza-bren demonstrated encouraging antitumor activity in 75 patients with HR+/HER2− advanced breast cancer. At a median follow-up of 11.7 months, the confirmed objective response rate (cORR) was 37.7%, the median duration of response (DOR) was 7.4 months, and median progression-free survival (mPFS) was 7.0 months.
Notably, nearly 70% of patients had previously received at least three lines of systemic therapy.
Regarding safety, adverse events were predominantly hematologic toxicities, including neutropenia, leukopenia, anemia, and thrombocytopenia. These events were clinically anticipated and could be managed with supportive care. No cases of interstitial lung disease (ILD) were observed.
Overall, the adverse-event profile was clearly characterized, predictable, and manageable, providing a foundation for further evaluation in the phase III setting.
Building Confidence: Positive Phase III Results in TNBC Raise Expectations for the HR+/HER2− Data
At this year’s ASCO Annual Meeting, results from the phase III PANKU-Breast02 study of iza-bren in patients with metastatic triple-negative breast cancer (mTNBC) who had received one or two lines of prior salvage therapy were reported.
Median PFS with iza-bren reached 8.5 months, representing an improvement of 5.4 months over chemotherapy (3.1 months; HR = 0.29, P < 0.0001). This was the most striking PFS result among ADCs with data reported to date. Median overall survival (mOS) reached 15.9 months with iza-bren, compared with just 12.5 months in the treatment-of-physician’s-choice (TPC) group (HR = 0.60, P = 0.0019).
These positive results for both endpoints confirmed the antitumor activity of iza-bren as an EGFR × HER3 bispecific ADC in breast cancer. They have further heightened expectations for the final phase III data in HR+/HER2− advanced breast cancer.
Conclusion
Significant unmet clinical needs remain in the later-line treatment of HR+/HER2− advanced breast cancer. PANKU-Breast01 has met its primary PFS endpoint and may provide a new treatment option for this patient population.
Mark your calendar for October 23 and the ESMO LBA50 presentation. Join colleagues around the world in witnessing the potential beginning of a new era of bispecific ADC therapy for patients with HR+/HER2− breast cancer!
Professor Huihui Li
