Breast cancer remains the most prevalent malignancy among women and is the leading cause of cancer-related mortality, posing a significant threat to global women's health. Human epidermal growth factor receptor 2 (HER2) serves as a critical oncogenic driver in breast cancer, historically associated with poor prognosis and higher recurrence rates. Over the past two decades, however, targeted therapies directed against HER2 and its downstream signaling pathways have transformed treatment paradigms. For early-stage HER2-positive breast cancer, cure rates have markedly improved, while median survival for patients with advanced-stage disease has extended from less than 15 months in the pre-targeted therapy era to approximately 5 years with current regimens.On March 8, 2025, the Frontier Exploration Symposium on Breast Oncology Management was held in Shanghai under the auspices of the Breast Cancer Diagnosis and Treatment Capacity Enhancement Initiative. Renowned oncologists convened to discuss cutting-edge approaches for the management of HER2-positive breast cancer, including the optimization of neoadjuvant and adjuvant therapies in early-stage disease, recent advancements in therapeutic strategies for metastatic settings, and the accessibility of biosimilars within evolving reimbursement frameworks.Oncology Frontier has distilled key insights from this symposium, offering a comprehensive and detailed overview of the latest advancements in the management of HER2-positive breast cancer.
Advancing Neoadjuvant Therapy for HER2-Positive Breast Cancer: Refining Clinical Strategies
Professor Jian Zhang from the Fudan University Shanghai Cancer Center presented key updates on the treatment of early-stage HER2-positive breast cancer. Approximately 20% of breast cancer cases exhibit HER2 gene overexpression, which is associated with aggressive tumor biology and therapeutic challenges. As a proto-oncogene, HER2 amplification plays a critical role in tumorigenesis and disease progression, serving as both a prognostic biomarker and a therapeutic target. Since its identification as a breast cancer biomarker in 1987, extensive research has led to the development of targeted therapies. The approval of trastuzumab (Herceptin) in 1998 marked the beginning of HER2-targeted treatment, paving the way for multiple HER2-directed therapies.
Trastuzumab and pertuzumab are monoclonal antibodies that target HER2 by inhibiting its dimerization and disrupting downstream signaling pathways. Notably, pertuzumab binds to a distinct HER2 epitope compared to trastuzumab, enabling their synergistic combination to achieve more potent tumor suppression. This dual HER2 blockade has emerged as a cornerstone in the treatment of HER2-positive breast cancer and is extensively endorsed in international clinical guidelines, such as the “Guidelines for breast cancer diagnosis and treatment by China Anti-cancer Association (2024 edition) “, the “2025 CBCS & CSOBO Guidelines and Standards for the Diagnosis and Treatment of Breast Cancer“, and the “Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up （2024 edition）“.
The NeoSphere trial, a multicenter, randomized Phase II study, assessed the efficacy of dual HER2 blockade in neoadjuvant therapy for early-stage HER2-positive breast cancer. The findings demonstrated that patients treated with pertuzumab, trastuzumab, and docetaxel achieved a significantly higher pathologic complete response (pCR) rate compared to those receiving trastuzumab plus chemotherapy alone (45.8% vs. 29%, P=0.0141). Long-term follow-up data confirmed that dual HER2 blockade provided sustained benefits by further reducing the risk of disease progression and recurrence relative to single-agent therapy.
The DESTINY-Breast11 trial, the first clinical study to evaluate trastuzumab deruxtecan (T-DXd) as a neoadjuvant therapy for high-risk, early-stage HER2-positive breast cancer, is currently in progress. The primary endpoint of this study is pathological complete response (pCR). The results are highly anticipated, as they have the potential to significantly influence and refine neoadjuvant treatment strategies for this patient population.
While dual HER2 blockade in combination with chemotherapy is well established as the standard of care for high-risk patients, its necessity in low-risk cases remains a subject of ongoing debate. This has spurred increasing interest in treatment de-escalation strategies, which aim to preserve efficacy while reducing toxicity and treatment burden. These approaches emphasize minimizing chemotherapy intensity to minimize adverse effects, enhancing cost-effectiveness through the use of biosimilars, and integrating biomarker-driven precision therapy to tailor treatment regimens according to individual patient profiles.
The APHINITY trial, a large-scale Phase III multinational study, assessed the efficacy of combining trastuzumab, pertuzumab, and chemotherapy in patients with high-risk, node-positive or node-negative HER2-positive breast cancer. At the eight-year follow-up, dual HER2 blockade resulted in a 23% reduction in the risk of invasive disease recurrence compared to trastuzumab monotherapy. In node-positive patients specifically, the risk reduction reached 28%, indicating a promising trend toward improved overall survival (OS) relative to trastuzumab alone.
To expand access to HER2-targeted therapies, Qilu Pharmaceutical has developed biosimilars for trastuzumab (Anqutuo®) and pertuzumab (Ansaizhu®). These biosimilars were engineered using Chinese hamster ovary (CHO) cell lines, ensuring an identical amino acid sequence and highly similar structural and functional properties compared to the original drugs. The development process involved overcoming significant technological challenges, including the establishment of high-expression cell lines, reducing reliance on imported culture media, scaling up mammalian cell culture for large-scale production, and enhancing quality control and characterization standards. These advancements have led to two patents and recognition under China’s National Major New Drug Innovation Program.
A multicenter, randomized, double-blind, active-controlled Phase III trial evaluated Anqutuo® against reference trastuzumab in treatment-naïve patients with HER2-positive metastatic breast cancer. The results confirmed that Anqutuo® exhibited clinical efficacy and safety equivalent to the originator trastuzumab. Similarly, a large-scale Phase III trial of Ansaizhu®, conducted across 52 medical centers in China, demonstrated that its efficacy and safety profile were comparable to reference pertuzumab. These findings reinforce the viability of biosimilars as an alternative for HER2-targeted therapy, thereby enhancing treatment accessibility for patients.
Expanding Evidence-Based Treatment Options for Advanced HER2-Positive Breast Cancer
Professor Shu Liu from The Affiliated Hospital of Guizhou Medical University presented the latest advancements in the treatment of advanced HER2-positive breast cancer. This subtype is highly aggressive, with a five-year survival rate that is 44% lower than that of HER2-negative breast cancer, posing significant challenges for patient prognosis and quality of life.
The evolution of HER2-targeted therapies, encompassing monoclonal antibodies, small molecule inhibitors, and antibody-drug conjugates (ADCs), in conjunction with innovative combination strategies, have markedly enhanced survival outcomes for patients. Notably, the dual HER2 blockade utilizing trastuzumab and pertuzumab has been established as the first-line standard of care for HER2-positive metastatic and advanced-stage breast cancer, a regimen that is strongly endorsed by multiple international clinical guidelines.
The CLEOPATRA trial, a Phase III randomized, double-blind, placebo-controlled study, enrolled 808 patients with HER2-positive metastatic breast cancer to evaluate the potential benefits of adding pertuzumab to trastuzumab plus chemotherapy. The results demonstrated that the combination of pertuzumab, trastuzumab, and docetaxel achieved a median progression-free survival (mPFS) of 18.5 months, establishing a new standard for disease control. The objective response rate (ORR) was 80.2%, compared to 69.3% in the control group, underscoring the superior efficacy of dual HER2 blockade over trastuzumab monotherapy.
Subgroup analyses within the CLEOPATRA study demonstrated that patients who had previously received trastuzumab as neoadjuvant or adjuvant therapy continued to derive clinical benefit from dual HER2 blockade, thereby underscoring its sustained long-term therapeutic value. In 2014, data presented at the European Society for Medical Oncology (ESMO) conference revealed that the median overall survival (mOS) for patients receiving dual HER2 blockade reached 56.5 months, reflecting a 16-month improvement compared with trastuzumab monotherapy. Furthermore, retrospective analyses suggested that pertuzumab may contribute to delaying the onset of brain metastases, with patients receiving dual HER2 blockade exhibiting a trend toward improved survival following the development of brain metastases.
The PERUSE study, a global multicenter, single-arm trial, evaluated the efficacy of combining pertuzumab, trastuzumab, and three taxane-based chemotherapy agents (docetaxel, paclitaxel, and nab-paclitaxel) as a first-line treatment for HER2-positive locally recurrent or metastatic breast cancer (LR/mBC). The results confirmed that dual HER2 blockade remained highly effective irrespective of the specific taxane utilized, with a median overall survival (OS) exceeding five years across all treatment regimens.
Further reinforcing these results, the PUFFIN study, a Chinese bridging trial, assessed the efficacy and safety of pertuzumab-based therapy in a Chinese patient population. The results were consistent with those of the CLEOPATRA trial, demonstrating that dual HER2 blockade was equally effective in Chinese patients. This provides robust evidence supporting the use of this regimen in diverse populations.
The DESTINY-Breast07 trial, a Phase Ib/II multicenter, open-label, modular study, is currently evaluating the combination of trastuzumab deruxtecan (T-DXd) and pertuzumab as a first-line treatment for HER2-positive metastatic breast cancer. Preliminary results demonstrate promising efficacy, with an objective response rate (ORR) of 84% observed in the T-DXd + pertuzumab combination group, compared to 76% in the T-DXd monotherapy group. Furthermore, the 12-month progression-free survival (PFS) rate was 89.4% in the combination therapy group, compared to 80.8% in the T-DXd monotherapy group, suggesting that this dual-targeting approach may enhance treatment outcomes for patients with HER2-positive metastatic breast cancer.
These findings underscore the expanding range of treatment options for advanced HER2-positive breast cancer, with dual HER2 blockade continuing to serve as a cornerstone therapy. Meanwhile, emerging ADC-based strategies present promising opportunities for enhancing long-term survival outcomes. The incorporation of these innovative approaches into clinical practice has the potential to transform the treatment landscape, providing renewed hope for patients with advanced-stage disease.
The Role of Pertuzumab in the Treatment of HER2-Positive Breast Cancer
On December 23, 2024, China’s National Medical Products Administration (NMPA) officially approved QL1209, a pertuzumab biosimilar developed by Qilu Pharmaceutical, for the treatment of HER2-positive breast cancer. As the world’s first approved pertuzumab biosimilar, the introduction of Ansaizhu® has expanded the range of available treatment options, improving accessibility and offering more diverse choices for patients with HER2-positive breast cancer.
On December 23, 2024, China’s National Medical Products Administration (NMPA) officially approved QL1209, a pertuzumab biosimilar developed by Qilu Pharmaceutical, for the treatment of HER2-positive breast cancer. As the world’s first approved pertuzumab biosimilar, Ansaizhu® has not only expanded the range of available treatment options but also enhanced treatment accessibility for patients with HER2-positive breast cancer, providing more diverse therapeutic choices.
Professor Huihui Li from Shandong Cancer Hospital&Institute delivered a presentation titled “The Accessibility of Biologic Therapies Under New Healthcare Reimbursement Models,” which explored the economic advantages of biosimilars in breast cancer treatment. Biologic therapies are a cornerstone of standard treatment for many diseases; however, their high cost can pose a barriers for patients. The development of biosimilars has played a crucial role in enhancing patient access to these essential treatments. Although pertuzumab is currently included in China’s healthcare insurance system, the long-term financial burden of treatment remains a challenge for some patients. Advances in biotechnology have provided innovative solutions to improve affordability, making biosimilars a viable option for reducing financial barriers and expanding access to care.
With the expiration of the pertuzumab patent, the approval of Qilu Pharmaceutical’s biosimilar offers patients a high-quality and cost-effective alternative. Throughout the drug development process, Qilu Pharmaceutical strictly adhered to international biosimilar evaluation standards, conducting comprehensive clinical trials to demonstrate that QL1209 exhibits equivalent efficacy, safety, and pharmacokinetics (PK) compared to the reference pertuzumab. Structurally, QL1209 possesses an identical amino acid sequence and comparable biological characteristics to the reference drug, thereby ensuring therapeutic equivalence.
A Phase I randomized, double-blind, parallel-controlled study was conducted in healthy male volunteers to evaluate the pharmacokinetics, safety, tolerability, and immunogenicity of QL1209. The results demonstrated that QL1209 exhibited pharmacokinetic properties, safety, and immunogenicity comparable to those of the reference drug, thereby establishing a solid foundation for subsequent clinical research.
To assess therapeutic equivalence, a multicenter, randomized, double-blind, parallel-group Phase III clinical trial was conducted in patients with HER2-positive, ER/PR-negative early or locally advanced breast cancer. A total of 517 patients were enrolled and randomly assigned to receive either QL1209 or the reference drug pertuzumab, both in combination with trastuzumab and docetaxel as neoadjuvant therapy. This was followed by adjuvant chemotherapy and dual HER2 blockade with trastuzumab and pertuzumab or QL1209.
The results of this Phase III trial demonstrated a high degree of consistency between QL1209 and the reference pertuzumab in terms of both efficacy and safety. The pathologic complete response (pCR) rate, as assessed by an Independent Review Committee (IRC), was 42.75% for QL1209 and 45.17% for the reference pertuzumab, with a relative risk (RR) of 0.95 (90% CI: 0.80–1.11), confirming equivalence within the predefined margin. Specifically, breast pCR rates were 50.00% and 51.74%, respectively, while investigator-assessed objective response rates (ORR) were 82.49% and 81.85%. These findings further demonstrate comparable clinical efficacy between the two treatment groups. Additionally, imaging-based complete response (CR) and partial response (PR) rates were nearly identical, reinforcing the similarity between QL1209 and the originator pertuzumab.
The safety profile of QL1209 was highly consistent with that of the reference pertuzumab. The incidence of treatment-emergent adverse events (TEAEs) was 95.3% in the QL1209 group and 96.1% in the reference pertuzumab group. The proportion of patients experiencing Grade ≥3 treatment-related adverse events (TRAEs) was 27.2% for QL1209 and 28.2% for the reference pertuzumab, with comparable rates observed for neutropenia (10.9% vs. 12.7%) and leukopenia (5.1% vs. 6.9%). Discontinuation due to TRAEs was infrequent, occurring in 0.4% of patients treated with QL1209 and 0.8% of those receiving the reference pertuzumab.
Pharmacokinetic analysis revealed no significant differences between the two groups, with both treatments maintaining stable minimum serum drug concentrations throughout the study period. Immunogenicity testing further confirmed that QL1209 did not present an increased risk of immunogenicity compared to the reference drug, as evidenced by comparable rates of anti-drug antibody (ADA) formation in both groups.
Through comprehensive clinical validation, QL1209 has demonstrated an efficacy and safety profile equivalent to that of the reference pertuzumab, positioning it as a high-quality, cost-effective alternative for patients with HER2-positive breast cancer. Compared to originator biologics, biosimilars such as QL1209 enhance treatment accessibility by offering more personalized treatment options while reducing overall healthcare costs. By alleviating financial burdens, biosimilars improve patient adherence to long-term therapy, which may ultimately contribute to better clinical outcomes and an enhanced quality of life for individuals with HER2-positive breast cancer globally.
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