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From October 23 to 27, 2026, the European Society for Medical Oncology (ESMO) Congress was held in Madrid, Spain. At the meeting, iza-bren (BL-B01D1), an innovative EGFR×HER3 bispecific antibody–drug conjugate (BsADC) independently developed by SystImmune, made a remarkable appearance with data from its pivotal Phase III PANKU-Breast01 study. As a first-in-class, new-concept therapeutic, the agent's prespecified interim analysis results were presented in full for the first time worldwide in a late-breaking abstract (LBA).The study showed that, among patients with unresectable locally advanced or metastatic HR+/HER2− breast cancer who had previously received endocrine therapy and one to two lines of chemotherapy, iza-bren achieved a median progression-free survival (mPFS) of 8.2 months, doubling that of treatment of physician’s choice (TPC) chemotherapy (4.0 months) and reducing the risk of disease progression or death by 59%. The confirmed objective response rate (cORR) doubled to 40.5%, and 77.9% of patients experienced tumor shrinkage in target lesions. Consistent benefits were observed across subgroups, with efficacy independent of HER2 expression. As the first bispecific ADC to demonstrate a positive Phase III primary endpoint in later-line treatment of advanced HR+/HER2− breast cancer, the study enrolled a challenging population characterized by high-risk disease from an early stage, aggressive tumor biology, and poor performance status, closely reflecting real-world clinical practice. The results represent a substantial achievement in addressing this difficult-to-treat population.
As one of the major breast cancer studies presented at ESMO 2026, the full PANKU-Breast01 study was simultaneously published in the leading international journal The Lancet (impact factor: 109). In the more than 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. It has the potential to reshape the treatment landscape of advanced HR+/HER2− breast cancer and usher in a new era of bispecific ADC therapy for breast cancer.
A High-Risk, Difficult-to-Treat Study Population Closely Reflecting Real-World Clinical Practice: PANKU-Breast01 Delivers Positive Results
The PANKU-Breast01 study (BL-B01D1-306, NCT06343948), led by Academician Binghe Xu of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, was an open-label, multicenter, randomized Phase III clinical trial conducted at 72 centers across 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.
Eligible patients had unresectable locally advanced or metastatic HR+/HER2− breast cancer and had previously received endocrine therapy, a CDK4/6 inhibitor, and a taxane. They had also experienced disease progression after one to two lines of chemotherapy in the advanced-disease setting. Patients were required to have an ECOG performance status of 0–1 and measurable disease according to RECIST v1.1.
As of July 21, 2026, a total of 560 patients had been screened, and 383 were randomized 1:1 to receive iza-bren (n=190) or TPC (n=193). Patients in the iza-bren group received 2.5 mg/kg on Days 1 and 8 of each 3-week treatment cycle. Patients in the TPC group could receive eribulin, capecitabine, gemcitabine, or vinorelbine. Randomization was stratified according to the number of previous chemotherapy lines, central nervous system metastases, and HER2 expression status (IHC 0 vs. IHC 1+ vs. IHC 2+/ISH-negative). The primary endpoint was PFS assessed by blinded independent central review (BICR), and the key secondary endpoint was overall survival (OS).
Baseline characteristics were generally balanced between the two groups, and the enrolled population closely reflected real-world clinical practice. All patients (100%) had previously received CDK4/6 inhibitors; approximately 71% had received one prior line of chemotherapy and nearly 30% had received two lines in the advanced setting. Approximately 80% had previously received (neo)adjuvant treatment and anthracyclines. More than 70% had liver metastases at baseline, and 64.2% had an ECOG performance status of 1. Overall, the study population was characterized by high-risk disease from an early stage, aggressive tumor biology, multiple prior lines of treatment in the advanced setting, and relatively poor performance status.
Another Phase III Breakthrough Following mTNBC: PFS Doubles in HR+/HER2− Metastatic Breast Cancer, with Robust Results Placing Iza-bren Among the Leading Current Standard-of-Care Options
The study met its prespecified primary endpoint. Median PFS in the iza-bren group reached 8.2 months, twice that in the TPC group (4.0 months), representing a 59% reduction in the risk of disease progression or death (HR=0.41, 95% CI: 0.33–0.53; P<0.0001).
The PFS curves began to separate early during follow-up (before 3 months), with the difference maintained at subsequent assessment time points. The 6-, 9-, and 12-month PFS rates were 62.8% versus 24.2%, 41.8% versus 14.4%, and 26.5% versus 9.2%, respectively, consistently favoring iza-bren over TPC. These findings suggest that a greater proportion of patients receiving iza-bren can maintain disease control without progression over an extended period.
Regarding tumor response, the cORR assessed by BICR was 40.5% in the iza-bren group, doubling that in the TPC group (20.2%), indicating a substantially higher tumor response rate. The DCR was also higher with iza-bren (86.3% vs. 63.7%), demonstrating improved disease control.
In terms of depth of tumor shrinkage, 77.9% of patients in the iza-bren group experienced a reduction in target lesion size, with a median reduction of 37.4%. The corresponding figures in the TPC group were 60.6% and 24.5%, respectively. Median DoR was 6.9 months with iza-bren versus 4.2 months with TPC. The doubling of cORR and longer DoR indicate deeper tumor shrinkage and more durable responses. Following its results in metastatic triple-negative breast cancer (mTNBC), the strong tumor-shrinking activity of iza-bren has now been further demonstrated in HR+/HER2− metastatic breast cancer (mBC).
At a median follow-up of 17.8 months, OS data remained immature at the prespecified interim analysis.
Efficacy Independent of HER2 Expression: Innovative Dual-Targeting Design Redefines the Clinical Decision-Making Framework for HR+/HER2− Metastatic Breast Cancer
Subgroup analyses demonstrated consistent and significant PFS benefits with iza-bren across all prespecified subgroups. In patients with HER2 IHC 0, IHC 1+, and IHC 2+/ISH-negative tumors, the HRs were 0.41 (95% CI: 0.28–0.62), 0.53 (95% CI: 0.36–0.76), and 0.32 (95% CI: 0.19–0.53), respectively. These findings suggest that its efficacy is not restricted by HER2 expression level.
In HR+/HER2− breast cancer, the use of ADCs has long been strongly influenced by HER2 expression status. Patients with IHC 0, IHC 1+, and IHC 2+/ISH-negative tumors have traditionally been considered distinct populations, with treatment pathways differing accordingly. However, this established framework based on HER2 expression levels is gradually being challenged.
In PANKU-Breast01, HER2 expression status (IHC 0, IHC 1+, and IHC 2+/ISH-negative) was incorporated as a prespecified stratification factor during randomization. The results showed consistent benefits across all subgroups, with no significant differences in efficacy according to HER2 expression level. This suggests that HER2 expression level is no longer a prerequisite for selecting iza-bren.
In other words, in later-line treatment of HR+/HER2− breast cancer, the benefits of iza-bren are independent of HER2 expression stratification. The logic of clinical decision-making is shifting from “stratification according to expression level” toward “treatment selection based on efficacy data.” Efficacy evidence, rather than HER2 expression level, is becoming the central consideration in treatment decisions.
The study also demonstrated a clearly defined and predictable adverse event profile for iza-bren, supported by established clinical management approaches. No new safety signals emerged, and the adverse events were consistent with those observed in previous studies. Hematologic adverse events were predominant and could be effectively managed with standard supportive care. The rate of treatment discontinuation due to treatment-related adverse events (TRAEs) was only 1.6%.
The median number of treatment cycles (10 vs. 6) and median treatment duration (7.3 vs. 4.3 months) were both longer in the iza-bren group, suggesting that patients could tolerate prolonged treatment and maintain good treatment adherence.
Non-hematologic adverse events were predominantly low-grade. Patient-reported or clinically noticeable adverse events such as oral mucositis, diarrhea, and nausea occurred at relatively low rates, supporting the potential for sustained treatment. Regarding interstitial lung disease (ILD), only two treatment-related cases were reported (1.1%), substantially lower than the rates associated with ADCs carrying a DXd payload. Overall, the safety profile was manageable.
From Innovation in Dual-Targeting Mechanisms to Phase III Evidence Across Molecular Subtypes: Iza-bren Leads Breast Cancer into a New Era of Bispecific ADC Therapy
HR+/HER2− breast cancer is the most common breast cancer subtype. Although endocrine therapy combined with CDK4/6 inhibitors has improved patient outcomes, many patients experience disease progression after two to three years. For patients whose disease progresses following endocrine therapy, TROP2 ADCs have achieved certain advances, but the magnitude of benefit remains limited. The benefits of HER2-targeted ADCs, meanwhile, are restricted to patients with HER2-low or HER2-ultralow tumors and depend heavily on accurate pathological assessment. Further optimization of treatment strategies is therefore urgently needed.
Against this background, iza-bren demonstrates the distinctive therapeutic potential of an EGFR×HER3 bispecific ADC. Both EGFR and HER3 belong to the ERBB receptor family and are associated with tumor cell growth signaling and treatment resistance. They can form heterodimers that drive tumor cell proliferation and survival.
Iza-bren simultaneously recognizes and binds EGFR and HER3. This design may enhance tumor cell internalization while reducing, at the source, the risk of acquired resistance resulting from target heterogeneity or dynamic changes in target expression. Combined with a cleavable linker and the novel Ed-04 payload, this approach offers a new strategy for addressing tumor heterogeneity and overcoming the limitations of single-target ADCs.
Previous Phase Ib studies demonstrated that iza-bren had favorable antitumor activity in HER2-negative locally advanced or metastatic breast cancer, achieving a cORR of 37.3% and an mPFS of 7.0 months.
Building on these findings, the Phase III PANKU-Breast01 study enrolled a difficult-to-treat population that had received one to two prior lines of chemotherapy and included patients with liver metastases and endocrine therapy resistance. Its design closely reflected real-world clinical practice and provided high-level evidence for this patient population.
Importantly, PANKU-Breast01 incorporated HER2 expression status as a randomization stratification factor, enrolling patients across different HER2 expression categories. Subgroup analyses showed consistent and significant trends toward survival benefit with iza-bren, regardless of whether patients had HER2-low, HER2-ultralow, or HER2-non-expressing tumors.
Through its prospective randomized design, PANKU-Breast01 therefore provides direct evidence supporting the conclusion that the efficacy of iza-bren is independent of HER2 expression level. Based on these high-quality clinical data, iza-bren has the potential to reshape the treatment landscape of advanced HR+/HER2− breast cancer.
Previously, the Phase III PANKU-Breast02 study, whose positive results for both co-primary endpoints of PFS and OS were presented at the 2026 ASCO Annual Meeting, validated the efficacy of iza-bren in triple-negative breast cancer. The positive PFS results from PANKU-Breast01 further advance its therapeutic potential in advanced HR+/HER2− breast cancer to the level of randomized Phase III evidence, expanding the clinical evidence base across different molecular subtypes of breast cancer.
Meanwhile, the global multicenter Phase III IZABRIGHT-Breast01 study is ongoing to evaluate the efficacy and safety of iza-bren as first-line treatment in patients with advanced triple-negative breast cancer who are not suitable candidates for PD-(L)1 inhibitors.
From nasopharyngeal carcinoma and esophageal squamous cell carcinoma to triple-negative breast cancer and HR+/HER2− breast cancer, iza-bren continues to expand the therapeutic landscape of bispecific ADCs.
Looking ahead, further follow-up of PANKU-Breast01 is expected to clarify long-term outcomes, including OS. As the body of clinical evidence continues to grow, information published by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration on October 21, 2026, 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.
We look forward to the early approval of this indication, its implementation in clinical practice, and updates to authoritative guidelines in China and internationally. These developments may bring longer survival and improved quality of life to patients in China and around the world.
This was not a head-to-head comparative study; the results should be interpreted with caution.
Study Investigators
Professor Binghe Xu
Professor Lanbo
