Editor's Note: At the 2026 European Society for Medical Oncology (ESMO) Congress, iza-bren (BL-B01D1) made a remarkable appearance as the world's first-in-class and first approved EGFR×HER3 bispecific antibody–drug conjugate (ADC), with the strongest clinical impact in its class. The pivotal Phase III PANKU-Breast01 study, led by Academician Binghe Xu of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, was presented as a late-breaking abstract (LBA), with the full study published simultaneously in The Lancet (impact factor: 109). In the 200-year history of The Lancet, iza-bren is the first innovative Chinese drug in the breast cancer field to be published in the journal's flagship edition.Oncology Frontier specially invited Professor Bing Zhao of the Affiliated Cancer Hospital of Xinjiang Medical University, an investigator in the PANKU-Breast01 study, to provide an in-depth commentary on the study’s key findings, clinical value, and future implementation in clinical practice. The full discussion is presented below.
Overview of the PANKU-Breast01 Study
Study Background
HR+/HER2− breast cancer is the most common molecular subtype of breast cancer. Although the combination of CDK4/6 inhibitors and endocrine therapy has significantly improved patient survival, subsequent treatment options become increasingly limited as the disease progresses and resistance develops. For patients with unresectable locally advanced or metastatic HR+/HER2− breast cancer who have previously received endocrine therapy and chemotherapy, improving the objective response rate (ORR) and prolonging progression-free survival (PFS) remain important unmet clinical needs.
As the world’s first-in-class and first approved EGFR×HER3 bispecific ADC, iza-bren combines a bispecific antibody targeting EGFR and HER3 with a novel topoisomerase I inhibitor payload, Ed-04. This design enables the synergistic effects of dual-target recognition and cytotoxic payload delivery, offering a new therapeutic strategy for breast cancer. Its Phase I study had already provided preliminary evidence of its efficacy and safety in advanced HER2-negative breast cancer, laying the foundation for further investigation in advanced HR+/HER2− disease.
Study Methods
PANKU-Breast01 was a multicenter, randomized, open-label Phase III clinical trial conducted at 72 centers in China. It aimed to evaluate the efficacy and safety of iza-bren in patients with unresectable locally advanced, recurrent, or metastatic HR+/HER2− breast cancer whose disease had progressed after at least one prior line of chemotherapy.
The study enrolled 383 patients with HR+/HER2− unresectable locally advanced or metastatic breast cancer who had previously received endocrine therapy and one to two lines of chemotherapy. All patients had previously received a CDK4/6 inhibitor and a taxane.
The primary endpoint was PFS assessed by blinded independent central review (BICR). The key secondary endpoint was overall survival (OS). Other secondary endpoints included investigator-assessed PFS, ORR, disease control rate (DCR), duration of response (DoR), and safety.
Study Results
The enrolled population had challenging high-risk and refractory disease characteristics, including early-onset high-risk disease, aggressive tumor biology, multiple prior lines of treatment in the advanced setting, and relatively poor performance status.
As of July 21, 2026, the median PFS in the iza-bren group was twice that in the treatment of physician’s choice (TPC) group, reaching 8.2 months versus 4.0 months. The risk of disease progression or death was reduced by 59% (HR = 0.41, 95% CI: 0.33–0.53, P < 0.0001). Consistent and significant benefits were observed across subgroups. Patients with HER2 IHC 0, 1+, and 2+/ISH-negative tumors all experienced PFS benefits, suggesting that the efficacy of iza-bren was not restricted by HER2 expression level.
In terms of tumor response, the confirmed objective response rate (cORR) in the iza-bren group was 40.5%, twice that in the TPC group (20.2%). The DCR was 86.3% versus 63.7%, and the median duration of response (mDoR) was 6.9 months versus 4.2 months. These findings demonstrate higher tumor response rates and more durable responses with iza-bren.
Regarding safety, treatment-related adverse events (TRAEs) associated with iza-bren were primarily hematologic toxicities, including anemia, thrombocytopenia, and neutropenia. Most hematologic adverse events could be managed through routine supportive care, treatment delays, or dose adjustments. The rate of treatment discontinuation due to TRAEs was only 1.6%, indicating a low incidence. The incidence of adjudicated treatment-related interstitial lung disease (ILD) was 1.1% (two cases), comprising one Grade 1 and one Grade 2 event. Overall, the safety profile was manageable.
Study Conclusions
In patients with HR+/HER2− unresectable locally advanced or metastatic breast cancer who had received prior endocrine therapy and one to two lines of chemotherapy, PANKU-Breast01 demonstrated a doubling of both median PFS and cORR. These findings support iza-bren as a potential new standard treatment option and usher in a new era of bispecific ADC therapy for breast cancer.
On October 21, 2026, information published by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) confirmed that the marketing application for iza-bren for HR+/HER2− breast cancer had been formally accepted. The proposed indication is for patients with unresectable locally advanced, recurrent, or metastatic HR+/HER2− breast cancer whose disease has progressed after at least one prior line of chemotherapy. This may soon provide clinicians with a new treatment option.
ESMO 2026 Expert Insights
Professor Bing Zhao: As an investigator in the PANKU-Breast01 clinical trial, I was extremely encouraged to hear the results presented at the congress for the first time. PANKU-Breast01 is the first positive Phase III study of the world’s first EGFR×HER3 bispecific ADC, iza-bren, in advanced HR+/HER2− breast cancer.
The enrolled population represents a particularly challenging group in clinical practice: patients who have already received endocrine therapy, developed resistance to CDK4/6 inhibitors, and subsequently undergone one to two lines of chemotherapy. For a long time, chemotherapy has been the mainstay of treatment for patients with unresectable locally advanced or metastatic HR+/HER2− breast cancer in this setting. However, its efficacy is limited, and treatment options remain scarce, leaving a substantial unmet clinical need.
The study showed that median PFS reached 8.2 months in the experimental group, compared with 4.0 months in the control group, with an HR of 0.41, representing a 59% reduction in the risk of disease progression or death. The cORR was 40.5%, compared with 20.2% in the chemotherapy group, demonstrating a substantial improvement in tumor shrinkage. Furthermore, consistent trends in benefit were observed across different HER2 expression subgroups, providing robust evidence.
These findings provide strong evidence that iza-bren delivers significant clinical benefits in patients who have previously received endocrine therapy and one to two lines of chemotherapy, offering new Phase III evidence to support later-line treatment of advanced HR+/HER2− breast cancer.
Unlike conventional single-target ADCs directed against HER2 or TROP2, iza-bren uses a dual-target EGFR×HER3 design to address a key mechanism of endocrine resistance: HER3 pathway activation and compensatory bypass signaling. This provides a novel mechanism of action and a new therapeutic option. The consistent benefits observed across different HER2 expression subgroups further broaden the potential application of ADCs. Iza-bren has the potential to reshape the later-line treatment landscape of advanced HR+/HER2− breast cancer and usher in a new era of bispecific ADC therapy.
Based on these findings, I believe its clinical value can be understood from several perspectives:
First, It Addresses a Major Gap in Later-Line Treatment
After developing resistance to multiple lines of endocrine therapy, CDK4/6 inhibitors, and PI3K/AKT inhibitors, patients with HR+/HER2− breast cancer have historically had limited treatment options, with chemotherapy remaining the mainstay. Highly active targeted ADCs have been lacking in this setting.
Although TROP2 ADCs have demonstrated efficacy in this population, their applicability has certain limitations. Iza-bren, by contrast, does not depend on TROP2 expression, opening up a new therapeutic pathway for patients with treatment-resistant disease.
Second, It Broadens the Targeting Strategy for ADC Development
Unlike single-target ADCs directed against HER2 or TROP2, this EGFR×HER3 bispecific ADC directly addresses the HER3-mediated compensatory bypass pathway associated with resistance.
The positive results of this study provide high-level clinical evidence supporting HER3 as a valuable therapeutic target in endocrine-resistant HR-positive breast cancer. They also offer important support for future basic and translational research into mechanisms of treatment resistance.
Third, It Reshapes the Clinical Decision-Making Pathway in Later-Line Treatment
In the future, when these patients experience disease progression, chemotherapy will no longer be the only available option. Clinicians will be able to stratify and select treatments based on tumor biomarkers, the number of previous treatment lines, and patients’ performance status, choosing among chemotherapy, TROP2 ADCs, and this first-in-class bispecific ADC.
In particular, for patients with prominent symptoms, high tumor burden, or an urgent need for tumor shrinkage, the 40.5% cORR makes iza-bren an attractive treatment option.
Fourth, It Provides Directions for Future Research
At present, OS data remain immature, and we need to await the final OS results, further DoR data, and long-term safety findings.
It is also worth exploring the potential of moving iza-bren into earlier lines of treatment, particularly in patients who have developed resistance to CDK4/6 inhibitors but have not yet received chemotherapy. Its potential in combination with endocrine therapy and other targeted agents also warrants further investigation.
Professor Bing Zhao
