赫赛汀仿制药治疗乳腺癌长期随访

　　去年，美国临床肿瘤学会《临床肿瘤学杂志》发表法国、乌克兰、俄罗斯、波兰、俄罗斯、韩国、印度、菲律宾的III期研究报告，比较了HER2阳性早期乳腺癌患者术前曲妥珠单抗生物仿制药SB3或原研药赫赛汀新辅助治疗的有效性、安全性和免疫原性（相关链接：曲妥珠单抗仿制药用于早期乳腺癌患者新辅助治疗）。

NCT02149524: A Phase III Randomised, Double-Blind, Parallel Group, Multicentre Study to Compare the Efficacy, Safety, Pharmacokinetics and Immunogenicity Between SB3 (Proposed Trastuzumab Biosimilar) and Herceptin in Women With Newly Diagnosed HER2 Positive Early or Locally Advanced Breast Cancer in Neoadjuvant Setting (SB3-G31-BC)

　　2019年8月21日，欧洲癌症治疗研究组织、欧洲癌症组织、欧洲乳腺癌专科医师学会《欧洲癌症杂志》在线发表法国保罗施特劳斯癌症中心、美国斯坦福大学医学院综合癌症研究所、西雅图华盛顿大学福瑞德哈金森癌症研究中心、西班牙巴塞罗那大学拉蒙卡哈尔医院、沃尔德希布伦肿瘤研究所、德国柏林大学医院、意大利米兰大学欧洲肿瘤研究院、乌克兰第聂伯罗彼得罗夫斯克医学院、韩国三星生物制药的研究报告，对曲妥珠单抗生物仿制药SB3或原研药赫赛汀术前新辅助治疗HER2阳性早期乳腺癌患者的3期研究长期有效性和心脏安全性进行了3年随访。

NCT02771795: A Long-term Follow-up Study for Cardiac Safety in the Patients With HER2 Positive Early or Locally Advanced Breast Cancer Who Have Completed the SB3-G31-BC (SB3-G31-BC-E)

　　该扩展研究从完成3期研究的患者入组367例，其中仿制药186例、原研药181例，自2016年4月开始随访。随访结局包括有症状充血性心力衰竭发生率、无症状左室射血分数显著减少、其他心脏事件发生率、无事件生存和总生存。通过多因素比例风险回归模型，对无事件生存相关因素进行事后分析。

　　结果，仿制药组、原研药组相比：

• 中位随访时间：40.8、40.5个月

• 无症状左室射血分数显著减少：1、2例

• 有症状充血性心力衰竭发生率：0、0

• 其他心脏事件发生率：0、0

• 左室射血分数恢复至≥50%：100%、100%

• 三年无事件生存率：91.9%、85.2%

• 事件发生率：9.1%、17.1%（风险比：0.47，95%置信区间：0.26～0.87）

　　根据多因素分析，无事件生存显著相关因素包括：

• 抗体依赖性细胞介导细胞毒性（ADCC）活性

• 乳房病理完全缓解率

　　因此，该扩展研究结果表明结论，对于HER2阳性早期乳腺癌患者，仿制药与原研药相比，术前新辅助治疗后3年的心脏毒性反应极少且相似、无事件生存率较高，事后分析表明ADCC活性较低为显著相关因素之一。

Eur J Cancer. 2019 Aug 21;120:1-9.

Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2-positive breast cancer.

Pivot X, Pegram M, Cortes J, Lüftner D, Lyman GH, Curigliano G, Bondarenko I, Yoon YC, Kim Y, Kim C.

Paul Strauss Center, Strasbourg, France; Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Vall D'Hebron Institute of Oncology (VHIO), Barcelona and Ramon y Cajal University Hospital, Madrid, Spain; Charité Campus Benjamin Franklin, Humboldt University, Berlin, Germany; Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Istituto Europeo di Oncologia, University of Milan, Milan, Italy; Dnipropetrovsk Medical Academy, Dnipro, Ukraine; Samsung Bioepis Co., Ltd., Incheon, Korea.

HIGHLIGHTS

• Cardiotoxicity was rare and similar between SB3 (a trastuzumab biosimilar) and Herceptin (trastuzumab [TRZ]) up to 3 years.

• Three-year event-free survival (EFS) was significantly higher in SB3 compared with TRZ.

• In some TRZ lots, a downward drift in antibody-dependent cell-mediated cytotoxicity-related quality attributes was observed.

• Post hoc analyses suggest a downward drift in TRZ could have affected EFS difference.

• Three-year EFS and overall survival were comparable between SB3 and non-drifted TRZ.

BACKGROUND: We assessed long-term cardiac safety and efficacy in patients with human epidermal growth factor receptor 2-positive early breast cancer treated with a trastuzumab biosimilar (SB3) or its reference product, trastuzumab (TRZ), in a phase 3 study.

METHODS: Patients who completed the phase 3 study could be enrolled in this extension study. The outcomes included the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival. In post hoc analysis, the Cox proportional hazards regression model was used to assess factors associated with EFS.

RESULTS: A total of 367 patients were enrolled in the study (SB3, n = 186; TRZ, n = 181). The median follow-up duration from the main study enrolment was 40.8 and 40.5 months for SB3 and TRZ, respectively. During the two-year follow-up after adjuvant therapy, incidence of asymptomatic significant LVEF decrease was rare (SB3, n = 1; TRZ, n = 2), with all patients recovering with LVEF ≥ 50%, and no cases of symptomatic CHF or other cardiac events were reported. At 3 years, the EFS was 91.9% with SB3 and 85.2% with TRZ. The number of patients with events was 17 (9.1%) with SB3 and 31 (17.1%) with TRZ [hazard ratio: 0.47, 95% confidence interval: 0.26-0.87]. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity and the breast pathologic complete response rate were the factors associated with EFS.

CONCLUSION: Cardiotoxicity was rare in this extension study. EFS was higher with SB3 versus TRZ, with post hoc analysis suggesting that a downward drift in ADCC activity was a contributing factor.

CLINICAL TRIAL REGISTRATION NUMBERS: NCT02771795 (EudraCT 2015-005663-17)

KEYWORDS: SB3, Trastuzumab, Biosimilar, Antibody-dependent cell-mediated cytotoxicity, Long-term extension study

PMID: 31445454

DOI: 10.1016/j.ejca.2019.07.015

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