셀트리온：韩国曲妥珠单抗生物仿制药与赫赛汀的有效性和安全性相近
前情提要
2017年6月4日，英国《柳叶刀肿瘤学分册》在线发表英国伦敦帝国学院查林十字（查宁阁）医院、转化与实验医学中心、白俄罗斯明斯克临床肿瘤医院、白俄罗斯国立医科大学、亚历山德罗夫国家肿瘤学与医学放射学科学与实践中心、俄罗斯圣彼得堡临床肿瘤医院、圣彼得堡医疗专业肿瘤学临床科学与实践中心、莫斯科肿瘤医院、俄罗斯癌症研究中心、格鲁吉亚第比利斯大学医院、乌克兰文尼察地区临床肿瘤医院、外喀尔巴阡地区肿瘤医院、波兰格但斯克哥白尼肿瘤中心、罗马尼亚克卢日纳波卡肿瘤学研究所、菲律宾圣卢克医学中心、韩国赛尔群公司、美国纽约大学朗格尼医学中心劳拉和艾萨克·珀尔马特癌症中心（漫威首席执行官夫妇捐建）的研究报告，发现韩国曲妥珠单抗生物仿制药（CT-P6）对比美国基因泰克曲妥珠单抗（赫赛汀）用于HER2阳性早期乳腺癌新辅助治疗的有效性和安全性相近。
据悉，韩国最大生物制药公司、全球最大生物制药基地、全球第二大单克隆抗体生产企业赛尔群（셀트리온）的其他生物仿制药还包括：英夫利昔单抗、贝伐珠单抗（CT-P16）、依那西普（CT-P5）、西妥昔单抗（CT-P15）、帕利珠单抗（CT-P14）、阿达木单抗（CT-P17）……
该随机双盲主动对照Ⅲ期等效研究于2014年8月7日～2016年5月6日从23个国家112个中心入组549例年龄≥18岁、I～IIIa期、可手术HER2阳性乳腺癌女性。入组标准包括：美国东部肿瘤科协作组（ECOG）体力状态评分0或1、左心室射血分数正常（≥55%）、骨髓肝肾功能合格、可测量病变至少一个、已知雌激素和孕激素受体状态。排除标准包括：双侧乳腺癌、既往有乳腺癌治疗史、既往有蒽环类治疗史、妊娠或哺乳。按1∶1随机分配患者接受新辅助CT-P6或赫赛汀静脉注射（8个周期，每个周期持续3周，共24周；第1周期第1天8mg/kg，第2～8周期第1天6mg/kg）联合新辅助多西他赛（第1～4周期第1天75mg/m²）和FEC（第5～8周期第1天：氟尿嘧啶500mg/m²＋表柔比星75mg/m²＋环磷酰胺500mg/m²）。使用置换区组按临床分期、受体状态、国家进行分层随机。末次新辅助研究药物给药3～6周内进行手术，术后辅助治疗1年。患者入组结束后监测3年长期安全性和有效性。参与者和调查者对治疗方案双盲直至研究完成。各个方案人群分析的主要有效性终点为病理学完全缓解，根据手术期间获得的标本进行评定，对局部组织病理学报告进行集中盲法评审分析。该探究在美国政府临床研究网站（ClinicalTrials.gov）登记注册编号为：NCT02162667，仍在进行，但是不再入组。
结果发现，CT-P6组271例（49%）与赫赛汀组278例（51%）患者相比：
获得病理学缓解的可评估患者比例相近（46.8%比50.4%）
估算治疗结局差异（-0.04%）的95%置信区间（-0.12～0.05）在等效性界值之内。
严重治疗突发不良事件分别报告19例（7%）和22例（8%）
常见（＞1例）严重不良事件为发热性中性粒细胞减少（4例[1%]比1例[1%]）和中性粒细胞减少（1例[＜1%]比2例[1%]）
≥3级治疗相关不良事件分别为17例（6%）和23例（8%）
最常报告的不良事件为中性粒细胞减少症（10例[4%]比14例[5%]）
因此，CT-P6与赫赛汀的有效性相近、不良事件相似。曲妥珠单抗生物仿制药的可用性，能够增加获得HER2阳性早期癌症靶向疗法的机会。
Lancet Oncol. 2017 Jun 4. [Epub ahead of print]
CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial.
Justin Stebbing, Yauheni Baranau, Valeriy Baryash, Alexey Manikhas, Vladimir Moiseyenko, Giorgi Dzagnidze, Edvard Zhavrid, Dmytro Boliukh, Daniil Stroyakovskii, Joanna Pikiel, Alexandru Eniu, Dmitry Komov, Gabriela Morar-Bolba, Rubi K Li, Andriy Rusyn, Sang Joon Lee, Sung Young Lee, Francisco J Esteva.
Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK; Imperial Centre for Translational and Experimental Medicine, London, UK; Minsk City Clinical Oncological Dispensary, Minsk, Belarus; Belarusian State Medical University, Minsk, Belarus; City Clinical Oncology Dispensary, Saint Petersburg, Russia; St Petersburg Clinical Scientific and Practical Centre of Specialized Kinds of Medical Care (Oncologic), Saint Petersburg, Russia; Khechinashvili University Hospital, Tbilisi, Georgia; NN Alexandrov Republican Scientific and Practical Centre of Oncology and Medical Radiology, Minsk, Belarus; Vinnytsya Regional Clinical Oncologic Dispensary, Vinnytsya, Ukraine; Moscow City Oncology Hospital #62 of Moscow Healthcare Department, Moscow Oblast, Russia; Copernicus Wojewódzkie Centrum Onkologii Gdańsk, Gdańsk, Poland; Cancer Institute Ion Chiricuta, Cluj-Napoca, Romania; Russian Cancer Research Center, Moscow, Russia; St Luke's Medical Center, Quezon City, Philippines; Transkarpathian Regional Oncology Clinic, Uzhgorod, Ukraine; Celltrion Inc, Incheon, South Korea; Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
BACKGROUND: CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer.
METHODS: In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m² on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m²], epirubicin [75 mg/m²], and cyclophosphamide [500 mg/m²]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0.15 to 0.15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting.
FINDINGS: Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46.8%; 95% CI 40.4-53.2] of 248 patients) and reference trastuzumab (129 [50.4%; 44.1-56.7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0.04% [95% CI -0.12 to 0.05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%).
INTERPRETATION: CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer.
FUNDING: Celltrion Inc.
DOI: 10.1016/S1470-2045(17)30434-5