曲妥珠单抗仿制药用于早期乳腺癌患者新辅助治疗

　　编者按：瑞士罗氏与美国基因泰克的曲妥珠单抗原研药（商品名：赫赛汀）1988年上市以来已被证实对人类表皮生长因子受体2（HER2）阳性乳腺癌的早期术前新辅助和术后辅助、晚期转移有显著效果。不过，其欧盟专利已于2014年到期，美国专利也将于2019年到期。继印度百康、韩国赛尔群之后，位于韩国仁川的三星生物制药（官方缩写：SB）也登上了曲妥珠单抗生物仿制药舞台（官方代号：SB3）。

　　2018年1月26日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表法国、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，比较了曲妥珠单抗生物仿制药SB3或原研药赫赛汀新辅助治疗HER2阳性早期乳腺癌患者的有效性、安全性和免疫原性。

　　该III期随机双盲平行组多中心研究（NCT02149524）于2014年4月～2015年8月从97个研究中心入组II～III期HER2阳性单侧乳腺原发浸润癌患者875例，随机分组接受术前新辅助SB3（437例）或曲妥珠单抗（438例）8个周期同时化疗（多西他赛4个周期→氟尿嘧啶＋表柔比星＋环磷酰胺4个周期）随后手术，最后10个周期术后辅助SB3或曲妥珠单抗。主要终点为乳腺病理学完全缓解率的比较，预设等效范围：比值95%置信区间0.785～1.546、差值95%置信区间±13%。次要终点包括总病理完全缓解率、总缓解率、无事件生存、总生存、安全性、药代动力学和免疫原性的比较。

　　结果，完成术前新辅助治疗和手术的患者共800例，其中SB3组402例、赫赛汀组398例：

• 乳腺病理学完全缓解率：51.7%、42.0%

• 校正后率比值：1.259（95%置信区间：1.085～1.460，上、下限均符合预设等效范围）

• 校正后率差值：10.70%（95%置信区间：4.13%～17.26%，下限符合、上限超出预设等效范围）

• 总病理学完全缓解率：45.8%、35.8%

• 总缓解率：96.3%、91.2%

• 总的不良事件发生率：96.6%、95.2%

• 严重不良事件发生率：10.5%、10.7%

• 产生抗药抗体发生率：0.7%、0.0%（至第9个周期）

　　因此，根据乳腺病理学完全缓解率比值，SB3与曲妥珠单抗的有效性相似。安全性和免疫原性亦相似。

相关阅读

J Clin Oncol. 2018 Jan 26. [Epub ahead of print]

Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer.

Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J.

University Hospital Jean Minjoz, Institut National de la Santé et de la Recherche Médicale, Besancon, France; State Institution Dnipropetrovsk Medical, Academy of the Ministry of Health of Ukraine, Communal Institution Dnipropetrovsk City Multifield Clinical Hospital No. 4 of Dnipropetrovsk Regional Council, Dnipropetrovsk; Communal Healthcare Institution Kharkiv, Regional Clinical Oncological Center, Kharkiv; Lviv State Oncological Regional Treatment and Diagnostic Center, Lviv, Ukraine; Centrum Onkologii-Instytutim. M. Sklodowskiej Curie; Magodent, Warsaw; Comprehensive Cancer Center, Medical University, Bialystok, Poland; BHI of Omsk Region, Clinical Oncology Dispensary, Omsk; SBHI Leningrad Regional Oncology Dispensary; SBHI Saint Petersburg Scientific and Practical Center of Specialized Methods of Medical Help; FSI Scientific and Research Institution of Oncology n.a. N.N. Petrov of Ministry of Healthcare and SD of RF, St Petersburg, Russia; Asan Medical Center; Seoul National University Hospital, Seoul; Samsung Bioepis, Incheon, Republic of Korea; Tata Medical Centre, Kolkata, India; St Luke's Medical Center, Quezon City, Philippines.

PURPOSE: This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2-positive early breast cancer in the neoadjuvant setting (ClinicalTrials.gov identifier: NCT02149524).

PATIENTS AND METHODS: Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference was within ± 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity.

RESULTS: Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCR rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259 (95% CI, 1.085 to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8% and the overall response rates were 96.3% and 91.2% with SB3 and TRZ, respectively. Overall, 96.6% and 95.2% of patients experienced one or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively.

CONCLUSION: Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCR rates. Safety and immunogenicity were comparable.

PMID: 29373094

DOI: 10.1200/JCO.2017.74.0126