The human epidermal growth factor receptor 2 (HER2) is a known important molecular target in breast cancer. As one of the proto-oncogenes, HER2 is often associated with aggressiveness, recurrence, metastasis, and poor prognosis. The clinical application of the anti-HER2 drug trastuzumab has significantly improved the diagnosis and treatment patterns and prognosis of HER2-positive breast cancer, marking a milestone in anti-HER2 targeted therapy for breast cancer.
Patients with HER2-positive advanced breast cancer should undergo anti-HER2 treatment as early as possible, except in cases of contraindications. This article introduces the classification and research progress of targeted therapies for HER2-positive advanced breast cancer, aiming to provide new ideas for research in targeted treatment of advanced breast cancer.
1 Monoclonal Antibodies
1.1 Trastuzumab
Trastuzumab is an antibody drug targeting HER2 that was approved by the FDA in 1998, marking the beginning of the era of precision treatment for breast cancer. It binds to the HER2 molecule, blocking HER2 signal transduction, enhancing antibody-dependent cellular cytotoxicity (ADCC) effects, and promoting tumor cell apoptosis. The H0648g study in 2001 showed that trastuzumab combined with chemotherapy significantly improved disease control rates and survival in HER2-positive breast cancer patients. Subsequent studies such as M77001 and BCIRG 007 confirmed its cornerstone status in first-line treatment of HER2-positive breast cancer. Trastuzumab has also been combined with endocrine therapy to improve the prognosis of triple-positive breast cancer patients, promoting the development of the “de-chemotherapy” treatment concept, providing better survival benefits for patients with metastatic breast cancer (MBC).
1.2 Pertuzumab
Pertuzumab is a recombinant humanized monoclonal antibody approved by the FDA in 2012 for HER2-positive MBC, which can enhance the efficacy of anti-HER2 treatment when combined with trastuzumab. The CLEOPATRA study showed that the combination of pertuzumab, trastuzumab, and docetaxel significantly improved the median progression-free survival (PFS) and overall survival (OS) of patients with HER2-positive MBC. The PUFFIN study further confirmed the advantages of the dual-target + chemotherapy regimen. The PERTAIN study showed that pertuzumab also improved efficacy in patients with advanced triple-positive breast cancer (ABC). In HER2-positive MBC patients treated with the dual-target first-line therapy, even if PFS was shortened, OS could still be maintained, and tolerance was good. Therefore, dual-target therapy has an important position in HER2-positive MBC and will continue to promote the development of anti-HER2 targeted therapy.
1.3 Inizumab
Inizumab is a domestically developed anti-HER2 monoclonal antibody in China, with modifications at the amino acid sites in its Fc region, resulting in a stronger ADCC effect. The HOPES study showed that Inizumab combined with vinorelbine significantly improved median PFS, objective response rate (ORR), and disease control rate (DCR) in HER2-positive MBC. Phase II clinical trials presented at SABCS indicated that Inizumab combined with pyrotinib and chemotherapy was effective in HER2-positive MBC patients resistant to trastuzumab. ASCO’s Phase II study results showed that Inizumab combined with pertuzumab, paclitaxel, and carboplatin was effective in neoadjuvant therapy for HER2-positive locally advanced ABC patients. These studies confirm the potential of Inizumab in the treatment of HER2-positive breast cancer, making it a promising first-line treatment option.
1.4 Margetuximab
Margetuximab is an Fc-optimized monoclonal antibody that enhances ADCC effects to kill HER2-positive tumor cells. The SOPHIA study showed that margetuximab combined with chemotherapy significantly prolonged median PFS in HER2-positive MBC patients, especially in patients with the CD16A (FcγRⅢa) 158F allele. A bridging study in China further confirmed the advantages of margetuximab in the treatment of HER2-positive MBC. The FDA approved margetuximab in 2020 for the treatment of HER2-positive MBC patients who have received multiple anti-HER2 treatment regimens. Studies have shown that margetuximab combined with chemotherapy also demonstrated survival benefits in patients resistant to TKIs, providing a new treatment option for HER2-positive MBC patients.
2 Tyrosine Kinase Inhibitors (TKIs)
Small molecule tyrosine kinase inhibitors and monoclonal antibodies can both bind to specific targets to produce anti-tumor effects, but their mechanisms of action differ. TKIs inhibit tyrosine kinase phosphorylation by binding to the intracellular tyrosine kinase of HER2 and interfering with adenosine triphosphate (ATP) binding, thereby achieving anti-tumor effects through multiple pathways.
Additionally, small molecule TKIs are widely used in patients with HER2-positive ABC brain metastases due to their unique ability to cross the blood-brain tumor barrier (the penetration and accumulation of drugs within the tumor is hindered). The TKIs currently used in breast cancer mainly include lapatinib, pyrotinib, neratinib, and tucatinib.
2.1 Pyrotinib
Pyrotinib is a pan-HER tyrosine kinase inhibitor that irreversibly binds to the intracellular ends of HER1, HER2, and HER4, similar to neratinib. The PHOEBE study showed that pyrotinib combined with capecitabine in the second-line treatment of HER2-positive breast cancer significantly prolonged median PFS and duration of response (DoR) compared to lapatinib combined with capecitabine, and improved ORR. The PHILA study further confirmed the efficacy of pyrotinib in first-line treatment. The PRETTY study validated the clinical applicability of pyrotinib in Chinese HER2-positive breast cancer patients. The PERMEATE study confirmed the efficacy of pyrotinib in controlling brain metastases. Furthermore, Chinese scholars have explored the combination of pyrotinib with endocrine therapy, including its use in a Phase II clinical study with letrozole and dalpiciclib. In summary, pyrotinib provides multiple treatment options for HER2-positive breast cancer patients, including targeted combination chemotherapy and fully oral de-chemotherapy regimens, bringing new hope to patients.
2.2 Lapatinib
Lapatinib is an oral TKI drug targeting both HER1 and HER2, suitable for HER2-driven tumors that are not sensitive to trastuzumab. The EGF100151 and EGF104900 studies showed that lapatinib combined with trastuzumab in the treatment of HER2-positive breast cancer significantly prolonged the median PFS and OS of patients and improved clinical objective response rates. This indicates that dual-target therapy with lapatinib and trastuzumab may be a new option for patients after trastuzumab resistance. Additionally, lapatinib exerts anti-cancer effects by inhibiting the phosphorylation of p95 HER2, reducing downstream activation of AKT and mitogen-activated protein kinase (MAPK), providing another treatment option for patients after trastuzumab treatment failure.
2.3 Neratinib
Neratinib is an oral TKI drug that irreversibly binds to the intracellular ends of HER1, HER2, and HER4, blocking tyrosine kinase activity and exerting anti-cancer effects. The FDA approved it for long-term maintenance therapy after postoperative trastuzumab adjuvant therapy in early HER2-positive breast cancer, as well as in combination with capecitabine for adult patients with metastatic advanced HER2-positive breast cancer who have received two or more treatment regimens. The NALA study showed that neratinib combined with capecitabine significantly prolonged the median PFS of patients, especially those with high HER2 expression levels. Neratinib also has certain therapeutic value in HER2-positive MBC patients after progression.
2.4 Tucatinib
Tucatinib is a highly HER2-selective TKI drug. The HER2CLIMB trial showed that tucatinib combined with trastuzumab and capecitabine in the treatment of HER2-positive ABC patients significantly prolonged median OS (24.7 months vs 19.2 months) compared to placebo, especially extending median OS by 9.1 months in patients with brain metastases. Additionally, tucatinib combined treatment significantly reduced the risk of death in patients with brain metastases. The TLP trial demonstrated the safety and efficacy of tucatinib combined with letrozole and palbociclib in HR/HER2-positive MBC, showcasing the safety and efficacy of a fully oral, de-chemotherapy regimen. Future studies should further explore the efficacy of tucatinib in HER2-positive ABC patients and its combination therapies.
3 Antibody-Drug Conjugates (ADCs)
Currently, although dual-target therapies and small molecule TKIs show significant effects, the survival bottleneck after resistance to anti-HER2 treatment still fails to meet clinical needs. ADCs are a new type of targeted drug that, compared to traditional targeted drugs, have higher antibody selectivity and drug activity. In 2013, the FDA approved the first ADC drug targeting HER2 for solid tumors (T-DM1), and subsequently, new ADCs have been continuously developed by selecting different targets and small molecule toxic agents, as well as updating the connection methods, rapidly advancing the personalized precision treatment of breast cancer.
3.1 Trastuzumab Emtansine (T-DM1)
T-DM1 is an antibody-drug conjugate (ADC) composed of trastuzumab linked to the cytotoxic agent DM1, used for treating HER2-positive breast cancer. The EMILIA and TH3RESA studies showed that T-DM1 significantly improved median OS and PFS in second-line and later treatments.
The KATE2 study explored the efficacy of T-DM1 combined with the immune checkpoint inhibitor atezolizumab; although no significant improvement was observed in the overall population, potential benefits were seen in the PD-L1 positive subgroup. The KATE3 study is ongoing to further evaluate the efficacy and safety of T-DM1 combined with atezolizumab in PD-L1 positive HER2-positive breast cancer patients.
3.2 Deruxtecan (DS-8201)
DS-8201 is a novel ADC drug that shows significant efficacy against HER2-positive advanced breast cancer, with its stable and uniform drug payload enhancing tumor-killing effects. In patients after multiple lines of treatment, DS-8201 significantly improved response rates and survival. Compared to T-DM1, DS-8201 shows advantages in PFS and OS, and is effective in patients with brain metastases. Approved in China in 2023, DS-8201 challenges the standard of first-line dual-target therapy, providing new treatment options for HER2-positive breast cancer patients and changing the treatment landscape.
3.3 RC-48
RC-48 is the first ADC drug to receive breakthrough therapy designation from the FDA and the National Medical Products Administration (NMPA) in China, targeting HER2-positive and low-expressing breast cancer patients, demonstrating high efficacy and safety. It has shown excellent performance in clinical trials for gastric cancer, urothelial carcinoma, and breast cancer. Data from the 2021 American Society of Clinical Oncology (ASCO) annual meeting indicated that RC-48 exhibited good efficacy in HER2-positive breast cancer patients, with the 2.0 mg/kg dose group selected as the recommended dose.
The 2023 European Society for Medical Oncology (ESMO) conference further confirmed the efficacy and safety of RC-48, especially in the HER2-positive subgroup, where it extended PFS when used alone or in combination with other anti-tumor drugs, providing a new option for post-line treatment of HER2-positive breast cancer and indicating future development directions for ADC drugs.
3.4 Trastuzumab Duocarmazine (SYD985)
SYD985 is an ADC drug targeting HER2 that induces tumor cell death by internalizing and activating the payload, theoretically reducing side effects. In the Phase III TULIP trial, SYD985 significantly prolonged PFS in HER2-positive MBC patients who had previously failed treatment, but there were no significant differences in OS, ORR, and quality of life.
In terms of safety, the adverse events associated with SYD985 led to a high discontinuation rate, including severe interstitial lung disease/pneumonitis. Although it has received fast track designation from the FDA, its drug efficacy, safety, and dosage still need further confirmation.
3.5 ARX788
ARX788 is a novel anti-HER2 ADC drug that achieves precise treatment through optimized antibody conjugation technology, with no bystander effect. In a Phase I clinical study, it showed good safety, pharmacokinetics, and anti-tumor activity in Chinese HER2-positive breast cancer patients, with an ORR of 65.5% and a DCR of 100%, and a median PFS of 17.02 months. The Phase II ACE-Breast-03 study evaluated the efficacy of ARX788 in HER2-positive MBC patients after treatment with T-DM1, DS-8201, etc., showing a certain response rate. ARX788 may provide new treatment options for HER2-positive breast cancer patients.
3.6 Other HER2-targeted ADCs
MRG002, A166, and FS-1502 are new generation HER2-targeted ADC drugs that have shown efficacy and safety in early studies for HER2-positive breast cancer. The Phase I clinical trial of MRG002 reported an ORR of 50% and a DCR of 81%, and it is currently undergoing Phase III clinical trials. The Phase I clinical trial of A166 showed an ORR of up to 73.91% during the dose expansion phase, with a median PFS of 12.3 months, and it is currently in Phase II clinical trials. The Phase I study of FS-1502 demonstrated good safety and tolerability, with an ORR of 66.7%, and it is undergoing Phase III studies comparing it with T-DM1. The development of these ADC drugs provides more treatment options for HER2-positive breast cancer patients.
4 Bispecific Antibodies
Bispecific antibodies such as ZW25 and KN026 achieve dual signal blockade by targeting two different epitopes of HER2, enhancing anti-cancer effects. ZW25 combined with docetaxel showed high ORR and PFS in HER2-positive advanced breast cancer.
KN026 demonstrated preliminary efficacy in HER2-positive MBC patients in Phase I studies, and Phase II studies showed good clinical benefits when combined with docetaxel for first-line treatment of HER2-positive breast cancer. ZW49, as a bispecific ADC, is undergoing Phase I studies. These bispecific antibodies provide new treatment options for HER2-positive breast cancer patients.
5 CAR-T Cell Immunotherapy
CAR-T cell immunotherapy modifies the patient’s own immune cells to fight tumors, achieving significant results in the treatment of hematological malignancies and gradually advancing in solid tumor treatment.HER2-targeted CAR-T cells can inhibit HER2-positive breast cancer both in vitro and in vivo, penetrating tumor stroma and eradicating resistant tumor cells.HER2-targeted CAR-T therapy can overcome antibody resistance and is effective against brain metastases.Currently, clinical studies of CAR-T targeting HER2-positive solid tumors are ongoing, showing its potential as a new immunotherapy method.
Conclusion
HER2, as an important prognostic biomarker in breast cancer, has revolutionized the treatment of HER2-positive breast cancer, greatly improving the prognosis of HER2-positive breast cancer patients. However, advanced patients still experience disease progression due to resistance. The emergence of various anti-HER2 targeted drugs has changed the treatment landscape for HER2-positive ABC, bringing survival hope to advanced patients.
Currently, treatment options can include first-line dual-target therapy, small and large molecule targeted therapies, trastuzumab treatment, second-line DS-8201, and third-line and beyond can involve sequential ADC drugs or sequential TKIs, margetuximab, or other trastuzumab combination treatment regimens.
However, in the actual clinical environment, as the number of treatment lines increases, treatment rates and patient physical conditions decline, and a reasonable treatment sequence may maximize the survival benefits of anti-HER2 targeted therapy for HER2-positive ABC patients. Currently, the sequencing of TKIs and ADC drugs, the mechanisms of resistance to HER2-targeted therapy, and the treatment of brain metastases remain urgent issues to be further explored.
In the future, it is essential to continue to explore and initiate clinical research based on clinical realities, including representative patient populations, addressing clinical pain points in the HER2-positive ABC field, and exploring the therapeutic efficacy of various anti-HER2 targeted drugs.
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References
[1] Jiang Mingxia, Li Qiao, Xu Binghe. Classification and Clinical Research Progress of Targeted Therapy Drugs for HER2-Positive Advanced Breast Cancer [J]. China Oncology, 2024, 33(07): 583-595.
Disclaimer: The WuXi AppTec content team focuses on introducing global biopharmaceutical health research progress. This article is for informational exchange purposes only, and the views expressed do not represent the position of WuXi AppTec, nor do they represent WuXi AppTec’s support or opposition to the views expressed. This article is not a treatment recommendation. For treatment guidance, please visit a formal hospital.
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