HER2低表达乳腺癌的靶向治疗研究进展

doi:10.19401/j.cnki.1007-3639.2023.02.012

摘要/Abstract

摘要：

乳腺癌是全球女性的第一大恶性肿瘤，发病率在逐年增加。人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）在乳腺癌的生物学行为及发病机制中起着重要作用。乳腺癌HER2低表达是指HER2免疫组织化学染色1+或2+且原位杂交（in situ hybridization，ISH）阴性，占全部类型的45% ~ 55%。尽管在目前的临床实践中，HER2低表达大多数仍被报告为HER2阴性或三阴性乳腺癌，但HER2低表达与HER2未检出乳腺癌不仅在HER2蛋白表达水平上不同，在雌激素受体（estrogen receptor，ER）状态、原发肿瘤体积、淋巴结受累情况、新辅助治疗后的病理学完全缓解率（pathologic complete response，pCR）以及无病生存期（disease-free survival，DFS）等方面也存在差异。在针对早期HER2低表达乳腺癌靶向治疗的临床试验中，NSABP B-31及N9831试验表现出乳腺癌患者受益于曲妥珠单抗辅助治疗的可能性，然而，在Ⅲ期前瞻性随机对照研究NSABP B-47中，曲妥珠单抗并未改变HER2低表达乳腺癌患者的无浸润性肿瘤复发生存期（invasive disease-free survival，iDFS）、5年无远处复发间期及总生存期（overall survival，OS）。近年来针对晚期HER2低表达乳腺癌靶向治疗开展的临床试验层出不穷，主要围绕曲妥珠单抗、拉帕替尼、恩美曲妥珠单抗（trastuzumab emtansine，T-DM1）、DS-8201（又名trastuzumab deruxtecan, T-DXd, Enhertu）及SYD985等新型抗体-药物偶联物（antibody-drug conjugate，ADC）类药物。Ⅲ期临床试验CALGB9840表明曲妥珠单抗对HER2非过度表达的乳腺癌缺乏治疗效果，改变鲁妥珠单抗剂量后仍无法克服治疗窗口窄的问题。两项随机Ⅲ期试验（EGF30001和EGF100151）均发现接受拉帕替尼并未改善HER2低表达乳腺癌患者的无进展生存期（progression-free survival，PFS）。单臂Ⅱ期研究4258g及4374g初步发现HER2低表达乳腺癌患者对T-DM1的敏感性，但由于患者数量较少，结论尚不明确。Ⅲ期临床研究DESTINY-Breast04证实了DS-8201（5.4 mg/kg）与医师选择方案（2∶1随机分配）在HER2低表达转移性乳腺癌中的安全性和有效性。针对SYD985的Ⅰ期临床试验显示了其治疗HER2低表达乳腺癌的效果和安全性（1.2 mg/ kg）。除此之外，以新型ADC药物（RC48-ADC、ARX788、A166等）、双特异性抗体（KN026、ZW25、ertumaxomab等）及乳腺癌疫苗（nelipepimut-S、GP2、AE37等）为代表的一系列新型抗HER2治疗手段的临床研究也正在进行中。本文将对近年HER2低表达乳腺癌靶向治疗药物的主要临床试验进行综述。

关键词: 乳腺癌, HER2低表达, 靶向治疗

Abstract:

Breast cancer is the most common cancer in women worldwide with rising prevalence. The human epidermal growth factor receptor 2 (HER2) is crucial to the biological behavior and pathogenic mechanism of breast cancer. Approximately 45%-55% of all subtypes of breast cancer have low expression of HER2, which are classified as HER2 immunohistochemistry staining 1+ or 2+ and in situ hybridization (ISH) negative. Although in most cases, HER2 low expression (HER2-low) breast cancer is still classified as HER2 negative or triple negative in clinical practice, HER2-low differs from HER2 not detected (HER2-0) breast cancer not only in HER2 expression levels, there are also differences in terms of estrogen receptor (ER) status, primary tumor volume, lymph node involvement, and pathologic complete response (pCR) following neoadjuvant therapy and disease-free survival (DFS). In clinical trials targeting early-stage HER2-low breast cancer, the NSABP B-31 and N9831 trials demonstrated the possibilities for breast cancer patients to benefit from adjuvant trastuzumab therapy; however, in phase Ⅲ prospective randomized controlled study NSABP B-47, trastuzumab did not alter invasive disease-free survival (iDFS), 5-year interval without distant recurrence, or overall survival (OS) in patients with HER2-low breast cancer. Recent years have seen the emergence of clinical trials for targeted treatments for advanced HER2-low breast cancer, focusing mostly on trastuzumab, lapatinib, and antibody-drug conjugate (ADC), such as trastuzumab emtansine (T-DM1), DS-8201 (also known as trastuzumab deruxtecan, T-DXd, Enhertu), and SYD985. Phase Ⅲ trial CALGB9840 demonstrated a lack of therapeutic effect of trastuzumab and a narrow therapeutic window that could not be overcome by changing the dose of lumretuzumab in HER2 non-over-expressed breast cancer, respectively. Two randomized phase Ⅲ trials (EGF30001 and EGF100151) both found that receiving lapatinib did not improve progression-free survival (PFS) in patients with HER2-low breast cancer. T-DM1 sensitivity was initially observed in patients with HER2-low breast cancer in the single-arm phase Ⅱ studies 4258g and 4374g, but results were still uncertain because of the small number of patients. The phase Ⅲ clinical study DESTINY-Breast04 proved the safety and efficacy of DS-8201 (5.4 mg/kg) in HER2-low metastatic breast cancer. The phase Ⅰ clinical trial proved the efficacy and safety of 1.2 mg/kg SYD985 intravenously in HER2-low breast cancer. Additionally, there are currently ongoing clinical trials for several novel anti-HER2 therapeutics, including novel ADC drugs (RC48-ADC, ARX788, A166, etc.), bispecific antibodies (KN026, ZW25, ertumaxomab, etc.), and breast cancer vaccines (nelipepimut-S, GP2, AE37, etc.). In this paper, we will review the major clinical trials of targeted therapies for HER2-low breast cancer.

Key words: Breast cancer, HER2-low expression, Targeted therapies

中图分类号:

R737.9

郭晴, 张剑. HER2低表达乳腺癌的靶向治疗研究进展[J]. 中国癌症杂志, 2023, 33(2): 181-190.

GUO Qing, ZHANG Jian. Advances in targeted therapy for HER2-low breast cancer[J]. China Oncology, 2023, 33(2): 181-190.

图/表 1

表1

抗HER2药物及HER2低表达乳腺癌相关临床试验概览"

Drug	Clinical trials	Phase	Inclusion criteria	Primary outcome	Results
ADC
RC48-ADC	NCT04400695	Ⅲ	Participants with HER2-low, unresectable, locally advanced, or metastatic breast cancer who had previously been treated with an anthracycline and received 1 or 2 systemic chemotherapy regimens after relapse or metastasis	PFS	Ongoing
ARX788	NCT05018676	Ⅱ	Unresectable and/or metastatic HER2-low breast cancer. Patients with recurrent or metastatic disease should receive≥2 lines of systemic chemotherapy regimens; Hormone receptor-positive objects need to have received ≥2-line endocrine therapy±targeted therapy (including neoadjuvant/adjuvant therapy)	ORR	Ongoing
A166	CTR20181301	Ⅰ	Patients with HER2-expressing locally advanced or metastatic solid tumors (51 HER2-positive (3+ or 2+/ISH+), 6 HER2-low (1+ or 2+/ISH-)	ORR	The efficacy of 36 HER2-positive breast cancer patients with measurable disease was evaluated; the best ORR was 59.1% (13/22) and 71.4% (10/14) in the 4.8 and 6.0 mg/kg cohorts, respectively. Corneal epitheliopathy (73.7%), blurred vision (59.6%), peripheral sensory neuropathy (26.3%), dry eye (21.1%), anemia (19.3%), and hyponatremia (19.3%) were the most common TRAEs. Corneal epitheliopathy (17.5%), hypophosphatemia (5.3%), and dry eye (5.3%) were the most common grade 3 TRAEs
Bispecific antibody
KN026	NCT04165993	Ⅱ	Patients with HER2-low and hormone receptor positive MBC failed standard chemotherapy and hormone therapy; patients with HER2-low and hormone receptor negative/weak positive MBC failed standard chemotherapy	ORR; DOR	Ongoing
ZW25	NCT02892123	Ⅰ	Patients with HER2-expressing cancer that was locally advanced (unresectable) or metastatic	DLTs	Ongoing
Ertumaxomab	NCT00522457	Ⅱ	Enrolled patients had advanced breast cancer that was ER and/or PgR positive with low HER2 expression (IHC 1+ or 2+ and FISH negative). Patients were required to have PD after hormonal therapy that included at least one aromatase inhibitor, but no prior chemotherapy for advanced disease	ORR	The evaluable population's median TTP was 65.5 days (95% CI: 43-98). Pyrexia (74.1%), headache (40.7%), chill (33.3%), and vomitting (29.6%) were the most frequently observed AEs. The majority (73.8%) of AEs were mild or moderate in severity and resolved within one day
Vaccine
Nelipepimut-S	NCT01479244	Ⅲ	Patients with HER2/neu-positive, node-positive, or high-risk node-negative breast cancer	Disease recurrence	At the interim analysis with the median follow-up (16.8 months), there was no discernible between-arms difference in DFS events. Imaging identified 54.1% of recurrence episodes in NP-S participants as opposed to 29.2% in the placebo group (P = 0.069). Injection-related erythema (84.3%), induration (55.8%), and pruritus (54.9%) were the most prevalent
GP2	NCT00524277	Ⅱ	Breast cancer patients with tumors expressing HER2 (IHC 1-3+) who were clinically disease-free, node-positive, and high-risk node-negative were enrolled	Disease recurrence	The 5-year DFS rate in the ITT analysis was 88% (95% CI: 78%-94%) in the vaccine-eligible patients versus 81% (95% CI: 69%-89%) (P = 0.43), in the control group
AE37	NCT00524277	Ⅱ	Patients with tumors expressing any level of HER2 (IHC 1-3+) who were node-positive and high-risk node-negative for breast cancer and were clinically disease-free	Disease recurrence	Relative risk decreased 12%, HR = 0.885, 95% CI: 0.472-1.659, P = 0.70; recurrence rate in the immunized group was 12.4% against 13.8% in the control group. Vaccinated patients had a 5-year DFS rate of 80.8%, compared to 79.5% for control patients. The 5-year DFS was 77.2% in patients who received the vaccine (n = 76) compared to 65.7% in those who received a placebo (n = 78) in planned subset analyses of patients with IHC 1+/2+ HER2-expressing tumors (P = 0.21). DFS was 77.7% in the vaccinated patients (n = 25) against 49.0% in the control patients (n = 25) in patients with TNBC (HER2 IHC 1+/2+ and hormone receptor negative) (P = 0.12)

表1

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