昨天，《美国医学会杂志》主编、执行主编、副主编、助理主编、哈佛、布莱根、达纳法伯为了这项研究连发两篇社论！
编者按：2014年1月，亚洲最大生物技术公司印度百康（Biocon）宣布，与美国迈兰（Mylan）合作开发，在印度推出全球首个曲妥珠单抗生物仿制药（代号：Myl1401O，商品名：CANMAb）。2013年11月，该药已获印度药物监管机构批准；2013年7月，印度专利局撤销了罗氏的曲妥珠单抗专利；随后，罗氏发表声明，决定不再寻求曲妥珠单抗在印度的专利申请，此举为印度仿制药商生产便宜的曲妥珠单抗生物仿制药铺平了道路。罗氏在声明中称，这一决定是出于对印度专利保护和知识产权环境的总体考虑。而当时，印度政府已经在考虑，针对曲妥珠单抗发布一份强制许可。
2016年12月1日，《美国医学会杂志》在线发表加美国（利福尼亚大学旧金山分校、约翰霍普金斯大学、迈兰）、印度（百康、维杰亚瓦达市立癌症中心、居里马纳瓦塔癌症中心）、德国（弗莱堡大学）、西班牙（德克塞伍斯吉隆大学附属医院）、俄罗斯（圣彼得堡市立临床肿瘤中心、喀山地区临床肿瘤中心）、乌克兰（第聂伯罗彼得罗夫斯克国立医学院、苏梅州立大学）、格鲁吉亚（临床肿瘤学研究所、金羊毛廿一世纪健康之家）、菲律宾（圣卢克医疗中心、拉仙道斯枢机主教医疗中心）、泰国（诗里拉吉医院、朱拉隆功大学朱拉隆功国王纪念医院）、智利（苏尔临床肿瘤学研究所）的随机临床研究报告，比较了曲妥珠单抗生物仿制药＋紫杉、曲妥珠单抗＋紫杉一线治疗HER2阳性转移性乳腺癌患者的总有效率和安全性。研究代号：继承（HERiTAge）。
该多中心双盲随机平行组Ⅲ期等效研究于2012年12月～2015年8月入组500例未经治疗的转移性乳腺癌女性患者，按1∶1随机接受生物仿制药＋紫杉或曲妥珠单抗＋紫杉，化疗至少24周，随后单用抗体，直至发生不可耐受的毒性反应或疾病进展。
主要结局指标为24周总有效率，定义为完全或部分缓解。生物仿制药与曲妥珠单抗等效定义：总有效率之比90%置信区间为0.81～1.24、总有效率差异90%置信区间为-15%～15%。次要结局指标包括肿瘤进展时间、第48周的无进展生存和总生存、不良事件。
结果，在500例被随机分配的女性中，符合意向治疗人群458例（生物仿制药＋紫杉230例，曲妥珠单抗＋紫杉228例，平均年龄：53.6±11.11岁）、符合安全性分析人群493例女性。
458例女性一线用药24周时，生物仿制药＋紫杉、曲妥珠单抗＋紫杉的总有效率分别为69.6%、64.0%（95%置信区间分别为：63.62%～75.51%、57.81% %～70.26%）。总有效率之比为1.09（90%置信区间：0.974～1.211），总有效率差异为5.53（95%置信区间：-3.08～14.04），均在预设的等效范围内。
第48周，生物仿制药＋紫杉、曲妥珠单抗＋紫杉的肿瘤进展（41.3%比43.0%，-1.7%，95%置信区间：-11.1%～6.9%）、无进展生存（44.3%比44.7%，-0.4%，95%置信区间：-9.4%～8.7%）、总生存（89.1%比85.1%，4.0%，95%置信区间：-2.1%～10.3%）均无统计学显著差异。生物仿制药＋紫杉、曲妥珠单抗＋紫杉分别有239例（98.6%）和233例（94.7%）发生至少1个不良事件，最常见的包括中性粒细胞减少（57.5%比53.3%）、周围神经病变（23.1%比24.8%）、腹泻（20.6%比20.7%）。
因此，作者认为在接受紫杉的HER2阳性转移性乳腺癌女性中，生物仿制药与曲妥珠单抗相比，在24周时总有效率相似。虽然需要进一步研究以确定长期临床结局和安全性，但是临床有效的曲妥珠单抗生物仿制药，可能使乳腺癌患者更广泛地获得这种治疗。
对此，《美国医学会杂志》主编、执行主编、副主编发表社论：以科学证据和经济学责任确保获得治疗癌症的生物仿制药。哈佛医学院、布莱根女子医院、达纳法伯癌症研究所的肿瘤学家和《美国医学会杂志》助理主编发表社论：HER2阳性乳腺癌的生物仿制药疗法是否足够相近？
JAMA. 2016 Dec 1. [Epub ahead of print]
Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial.
Hope S. Rugo; Abhijit Barve; Cornelius F. Waller; Miguel Hernandez-Bronchud; Jay Herson; Jinyu Yuan; Rajiv Sharma; Mark Baczkowski, RPh; Mudgal Kothekar; Subramanian Loganathan; Alexey Manikhas; Igor Bondarenko; Guzel Mukhametshina; Gia Nemsadze; Joseph D. Parra; Maria Luisa T. Abesamis-Tiambeng; Kakhaber Baramidze; Charuwan Akewanlop; Ihor Vynnychenko; Virote Sriuranpong; Gopichand Mamillapalli; Sirshendu Ray; Eduardo P. Yanez Ruiz; Eduardo Pennella; for the Heritage Study Investigators.
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco; Biocon Research Limited, Bangalore, India; Mylan Inc, Canonsburg, Pennsylvania; University of Freiburg, Freiburg, Germany; Quiron-Dexeus, Barcelona, Spain; Johns Hopkins University, Baltimore, Maryland; City Clinical Oncology Dispensary, Saint Petersburg, Russia; Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine; Regional Clinical Oncological Center, Kazan, Russia; Institute of Clinical Oncology, Tbilisi, Georgia; St Luke's Medical Center Global City, Taguig City, Philippines; Cardinal Santos Medical Center, Manila, Philippines; Golden Fleece 21 Century Health House Ltd, Tbilisi, Georgia; Siriraj Hospital, Bangkok, Thailand; Sumy State University, Sumy, Ukraine; King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand; City Cancer Center, Vijayawada, India; Curie Manavata Cancer Centre, Nasik, India; Instituto Clinico Oncologico del Sur, Temuco, Chile.
Key Points
Question: Are the effects of a proposed trastuzumab biosimilar equivalent to those of trastuzumab in the treatment of ERBB2 (formerly HER2 or HER2/neu)-positive metastatic breast cancer?
Findings: In this randomized clinical trial that included 458 women, the overall response rate to the proposed biosimilar plus a taxane at 24 weeks was 69.6% (95% CI, 63.62%-75.51%) compared with 64.0% (95% CI, 57.81%-70.26%) for trastuzumab plus a taxane, which was within predefined equivalence boundaries.
Meaning: Although further assessment is needed to establish long-term clinical outcomes and safety, the availability of a clinically effective biosimilar treatment option for trastuzumab may lead to broader access to this therapy for patients with breast cancer.
Abstract
Importance: Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)-positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy.
Objective: To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer.
Design, Setting, and Participants: Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred.
Interventions: Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane.
Main Outcomes and Measures: The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and -15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events.
Results: Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, -3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; -1.7%; 95% CI, -11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; -0.4%; 95% CI, -9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, -2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%).
Conclusions and Relevance: Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome.
Trial Registration: clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42
DOI: 10.1001/jama.2016.18305
JAMA. 2016 Dec 1. [Epub ahead of print]
Scientific Evidence and Financial Obligations to Ensure Access to Biosimilars for Cancer Treatment.
Howard Bauchner; Phil B. Fontanarosa; Robert M. Golub.
Editor in Chief, JAMA; Executive Editor, JAMA; Deputy Editor, JAMA.
DOI: 10.1001/jama.2016.18743
JAMA. 2016 Dec 1. [Epub ahead of print]
Biosimilar Therapy for ERBB2 (HER2)-Positive Breast Cancer: Close Enough?
Harold J. Burstein; Deborah Schrag.
Dana-Farber Cancer Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts; Associate Editor, JAMA.
DOI: 10.1001/jama.2016.18979
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