紫丁香研究与乳腺癌仿制药之争妍
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，已被证实对人表皮生长因子受体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之后，美国安进与艾尔建的ABP980也加入了赫赛汀仿制药大军，于2013年启动了挑战赫赛汀的随机双盲对照研究，代号：紫丁香（LILAC）。与其他赫赛汀仿制药不同的是，该研究为术前新辅助＋术后辅助治疗，而且除了研究组、对照组，还设置了转换组。
2018年6月4日，英国《柳叶刀》肿瘤学分册在线发表德国乳腺癌研究协作组、博特罗普妇产科医院、马里安医院、意大利米兰大学欧洲肿瘤研究所、西班牙莱里达大学阿诺德维拉诺瓦医院、巴西血液学肿瘤学研究中心、塞尔维亚肿瘤学放射学研究所、美国安进的LILAC研究报告，比较了ABP980与赫赛汀用于术前新辅助＋术后辅助治疗HER2阳性早期乳腺癌患者的临床安全性和有效性。
Lilac: Efficacy and Safety Study of ABP 980 Compared With Trastuzumab in Subjects With HER2 Positive Early Breast Cancer (NCT01901146)
该多中心随机双盲主动对照3期等效研究（Lilac）于2013年4月29日～2015年9月29日从主要位于欧洲和南美洲的20个国家97个研究中心，入组年龄≥18岁、经组织学证实为HER2阳性早期浸润性乳腺癌、东部肿瘤学组（ECOG）体力状态评分为0或1、计划接受新辅助化疗和乳腺肿瘤以及前哨淋巴结或腋窝淋巴结切除手术女性725例。蒽环类化疗4个周期后，根据区组置换设计（4个区组）通过计算机生成随机化方案，将患者按1∶1分配接受ABP980（364例）或赫赛汀（361例）。根据肿瘤大小分期、淋巴结状态、激素受体状态、紫杉醇给药方案计划、地理区域对随机分组进行分层。术前新辅助治疗方案为首次在90分钟内静脉注射紫杉醇175mg/m²＋ABP980或赫赛汀负荷剂量8mg/kg，随后每3周1次，每次在30分钟内静脉注射紫杉醇175mg/m²＋ABP980或赫赛汀维持剂量6mg/kg，共3次（或者根据当地治疗标准，每周1次，每次紫杉醇80mg/m²，共12次）。末次新辅助治疗给药后3～7周完内成手术，术后辅助治疗方案为每3周1次，每次ABP980或赫赛汀维持剂量6mg/kg，直至首次新辅助治疗用药后1年。患者入组时被随机分配术后辅助治疗时继续APB980、继续赫赛汀、赫赛汀转换为APB980。共同主要有效性终点为乳腺组织和腋窝淋巴结病理完全缓解率的风险差和风险比，由当地实验室对随机分配接受任何数量研究产品术前新辅助治疗并接受手术的所有患者进行评定。对随机分配接受任何数量研究产品的所有患者评定安全性。该临床研究查询编号：NCT 01901146（美国）、CT 2012-004319-29（欧盟）。
最终，可评定主要终点患者共计696例（ABP980组358例、赫赛汀组338例）。
由当地实验室评定的病理完全缓解率：
紫丁香：172/358（48%，95%置信区间：43%～53%）
赫赛汀：137/338（41%，95%置信区间：35%～46%）
风险差：7.3%（90%置信区间：1.2%～13.4%，上限超过预设等效临界值13%）
风险比：1.188（90%置信区间：1.033～1.366，上限超过预设等效临界值1.318）
由中心实验室评定的病理完全缓解率：
紫丁香：162/339（48%）
赫赛汀：138/330（42%）
风险差：5.8%（90%置信区间：-0.5%～12.0%）
风险比：1.142（90%置信区间：0.993～1.312）
术前新辅助治疗期间≥3级不良事件：
紫丁香：54/364（15%）
赫赛汀：51/361（14%）
最常见的≥3级不良事件为中性粒细胞减少，两组患者各发生21例（6%）。
术后辅助治疗期间≥3级不良事件：
继续紫丁香：30/349（9%）
继续赫赛汀：11/171（14%）
换为紫丁香：13/171（8%）
最常见的≥3级不良事件（继续ABP980、继续赫赛汀、换为ABP980）：
内部和外部感染：4/349（1%）、2/171（1%）、2/171（1%）
中性粒细胞减少：3/349（1%）、2/171（1%）、1/171（1%）
输液反应：2/349（1%）、2/171（1%）、3/171（2%）
2例患者死于与研究产品无关的不良事件：1例术前接受ABP980新辅助治疗时死于肺炎，另1例术前接受赫赛汀新辅助治疗术后转换为ABP980辅助治疗时死于感染性休克。
因此，根据当地实验室对肿瘤标本的评定，虽然风险比和风险差的90%置信区间下限表明了非劣效性，但是上限超过预设等效临界值，意味着非优效性不确定。根据中心实验室对肿瘤标本的评估，两种药物的敏感性分析推算值均在预设等效范围内，表明有效性相似。该研究的术前新辅助治疗和术后辅助治疗期间，ABP980与赫赛汀安全性结局相似。
对此，马德里大学肿瘤内科教授、格雷戈里奥·马拉尼翁医院肿瘤内科主任、西班牙乳腺癌研究协作组组长、癌症网络生物医学研究中心主任米格尔·马丁发表同期评论：紫丁香研究与抗癌生物仿制药之争妍。
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Lancet Oncol. 2018 Jun 4. [Epub ahead of print]
Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial.
Gunter von Minckwitz, Marco Colleoni, Hans-Christian Kolberg, Serafin Morales, Patricia Santi, Zorica Tomasevic, Nan Zhang, Vladimir Hanes.
German Breast Group, Neu-Isenburg, Germany; Istituto Europeo di Oncologia, Milan, Italy; Marienhospital Bottrop, Klinik fur Gynakologie und Geburtshilfe, Bottrop, Germany; Hospital Universitario Arnau de Vilanova, Lleida, Spain; Centro de Estudos de Hematologia e Oncologia, Sao Paulo, Brazil; Institute for Oncology and Radiology of Serbia, Belgrade, Serbia; Amgen, Thousand Oaks, CA, USA.
BACKGROUND: ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer.
METHODS: We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with ClinicalTrials.gov, number NCT01901146 and Eudra, number CT 2012-004319-29.
FINDINGS: Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43-53) of 358 patients in the ABP 980 group and 137 (41%, 35-46) of 338 in the trastuzumab group (risk difference 7.3%, 90% CI 1.2-13.4; RR 1.188, 90% CI 1.033-1.366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1.318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5.8%, 90% CI -0.5 to 12.0, and RR 1.142, 90% CI 0.993 to 1.312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab.
INTERPRETATION: Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study.
FUNDING: Amgen.
DOI: 10.1016/S1470-2045(18)30241-9
Lancet Oncol. 2018 Jun 4. [Epub ahead of print]
The LILAC trial and the blooming of anticancer biosimilars.
Miguel Martin.
Instituto de Investigacion Sanitaria Gregorio Maranon, Ciberonc, Geicam, Universidad Complutense, Madrid.
Complex biosimilars (ie, monoclonal antibodies) are entering the oncology market in Europe and the USA. These drugs present a unique opportunity for the health-care system to remain sustainable. In The Lancet Oncology, Gunter von Minckwitz and colleagues1 report the results of the LILAC trial, which provides evidence that the biosimilar ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is not inferior to trastuzumab, according to the US Food and Drug Administration and European Medicines Agency requirements.
DOI: 10.1016/S1470-2045(18)30290-0
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