编者按：1988年，瑞士罗氏与美国基因泰克的曲妥珠单抗（商品名：赫赛汀）上市以来，已被证实对HER2阳性乳腺癌的早期术前新辅助和术后辅助、晚期转移治疗有显著效果。不过，其欧盟专利已于2014年到期，美国专利也将于2019年到期。继印度百康与美国迈兰的MYL1401O、韩国赛尔群的CT-P6、韩国三星的SB3、美国安进与艾尔建的ABP980之后，宇宙第一大药厂美国辉瑞的PF-05280014也加入了赫赛汀仿制药大军，并且低调地公布了早期乳腺癌术前新辅助治疗三期研究全文。
2018年7月13日，英国癌症研究基金会和英国《自然》旗下《英国癌症杂志》在线发表美国梅哈里医学院、匈牙利塞麦尔维斯大学、意大利罗马天主教大学、美国辉瑞的研究报告，对曲妥珠单抗生物仿制药PF-05280014与赫赛汀新辅助治疗可手术HER2阳性乳腺癌进行了比较。
该随机双盲三期研究（REFLECTIONS B327-04、NCT02187744）于2014～2017年在欧洲10个国家67个单位对辉瑞曲妥珠单抗仿制药（PF-05280014）与欧盟曲妥珠单抗对照药（赫赛汀）新辅助治疗可手术HER2阳性乳腺癌的药物代谢动力学、有效性、安全性和免疫原性。226例患者根据原发肿瘤大小和激素受体状态进行分层、按1∶1随机分配接受PF-05280014或赫赛汀（负荷剂量8mg/kg，随后6mg/kg）＋多西他赛＋卡铂，每3周1次，共6个治疗周期。主要终点为第5个周期（第6个周期给药前）血药浓度谷值>20μg/ml的患者百分比。有效性终点包括病理学完全缓解率和客观缓解率。如果第5个周期血药浓度谷值>20μg/ml患者百分比组间相差95%置信区间下限高于预设非劣效临界值-12.5%，那么表明PF-05280014与赫赛汀相比非劣效。
结果，PF-05280014与赫赛汀相比：
血药谷浓度达标率：92.1%比93.3%（组间分层相差95%置信区间：-8.02%～6.49%，下限高于预设非劣效临界值-12.5%）
病理学完全缓解率：47.0%比50.0%
放射学客观缓解率：88.1%比82.0%（集中复核评定）
治疗后不良事件率：38.1%比45.5%（不论因果关系、3～4级）
抗药物抗体产生率：0%比0.89%
因此，该研究结果表明，对于接受新辅助化疗的可手术HER2阳性乳腺癌患者，PF-05280014与赫赛汀相比，药物代谢动力学非劣效，有效性、安全性、免疫原性能够相提并论。
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读者调查
Br J Cancer. 2018 Jul 13. [Epub ahead of print]
Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer.
Philip E. Lammers, Magdolna Dank, Riccardo Masetti, Richat Abbas, Fiona Hilton, Jennifer Coppola, Ira Jacobs.
Meharry Medical College, Nashville, TN, USA; Semmelweis University, Budapest, Hungary; Catholic University of Rome, Rome, Italy; Pfizer Inc., Collegeville, PA, USA; Pfizer Inc., Groton, CT, USA; Pfizer Inc., New York, NY, USA.
BACKGROUND: This randomised, double-blind study compared pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 (potential trastuzumab biosimilar) and trastuzumab reference product (Herceptin) sourced from the European Union (trastuzumab-EU) as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
METHODS: Patients (N=226), stratified by primary tumour size and hormone receptor status, were randomised 1:1 to PF-05280014 or trastuzumab-EU (8mg/kg loading dose; 6mg/kg thereafter), each with docetaxel and carboplatin, every 3 weeks for six treatment cycles. Primary endpoint was percentage of patients with trough plasma concentration (Ctrough) >20μg/ml at Cycle 5 (Cycle 6 predose). Efficacy endpoints included pathological complete response and objective response rate. Non-inferiority of PF-05280014 to trastuzumab-EU was declared if the lower limit of the 95% confidence interval for the stratified difference between groups in the percentage of patients with Cycle 5 Ctrough >20μg/ml was above the prespecified non-inferiority margin of -12.5%.
RESULTS: For PF-05280014 vs trastuzumab-EU patients, respectively, 92.1% vs 93.3% had Cycle 5 Ctrough >20μg/ml; the lower limit of the 95% confidence interval (-8.02%, 6.49%) for the stratified difference between groups was above the non-inferiority margin (-12.5%). Pathological complete response (47.0% vs 50.0%) and central radiology review-assessed objective response (88.1% vs 82.0%) rates were comparable. Incidence of all-causality, grade 3-4 treatment-emergent adverse events was 38.1% vs 45.5%; antidrug antibody rates were 0% vs 0.89%.
CONCLUSIONS: PF-05280014 demonstrated non-inferior pharmacokinetics and comparable efficacy, safety and immunogenicity to trastuzumab-EU in patients with operable HER2-positive breast cancer receiving neoadjuvant chemotherapy.
DOI: 10.1038/s41416-018-0147-1
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