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根据HERA研究，HER2阳性早期乳腺癌完成一年曲妥珠单抗辅助治疗后，继续使用曲妥珠单抗延长辅助治疗并无更多获益。不过，惠氏开发、辉瑞收购、美洲狮（Puma）生物技术公司于2011年买下的奈拉替尼（来那替尼）改变了这个金标准。 奈拉替尼是一种不可逆的HER1、HER2、HER4酪氨酸激酶抑制剂，根据2016年发表于英国《柳叶刀》肿瘤学分册的ExteNET研究2年随访结果表明，2840例接受曲妥珠单抗辅助治疗后的HER2阳性乳腺癌女性，再用1年奈拉替尼（1420例）与安慰剂（1420例）相比，可以显著减少浸润病变发生风险（70例比109例，分层风险比：0.67，P=0.0091）并提高无浸润病变生存率（93.9%比91.6%）。根据ExteNET研究方案，作者对再用1年奈拉替尼的长期有效性和安全性进行了五年随访。 2017年11月13日，英国《柳叶刀》肿瘤学分册在线发表的研究报告，公布了早期乳腺癌接受曲妥珠单抗辅助治疗后再用一年奈拉替尼的五年随访结果。
该随机双盲安慰剂对照三期临床研究于2009年7月9日～2011年10月24日从欧洲、亚洲、大洋洲、北美洲和南美洲40个国家495个社区和学术医疗机构入组年龄≥18岁（日本≥20岁）早期（1～3c期，2010年2月修改为2～3c期）可手术且已完成术前新辅助和术后辅助化疗＋曲妥珠单抗治疗且入组时无疾病复发或转移证据的HER2阳性乳腺癌女性2840例，根据激素受体状态（阳性与阴性）、淋巴结状态（0、1～3、≥4个淋巴结阳性）和曲妥珠单抗辅助治疗方案（与化疗先后或同时给药）进行区组分层，通过交互语音和网络反馈系统按1∶1集中进行随机分组，分别接受奈拉替尼每天240mg口服1年（1420例）或匹配安慰剂（1420例）。治疗持续1年，除非发生疾病复发或新的乳腺癌、无法耐受的不良事件或知情同意书撤回。患者、研究者和资助者对治疗分配均盲。五年分析的预设终点为无浸润病变生存，根据意向治疗进行分析。该研究在美国政府临床研究网站的注册编号：NCT 00878709，仍在进行随访，但是不再入组。该研究资助者：惠氏、辉瑞、美洲狮生物技术公司。 结果发现，经过中位随访5.2年（四分位距：2.1～5.3），奈拉替尼组与安慰剂组相比：
根据亚组分析，对于激素受体阳性、至少累及4个淋巴结、在1年内完成曲妥珠单抗治疗、接受曲妥珠单抗序贯治疗的患者，奈拉替尼的获益似乎较大。不过，根据相互作用检验，P值并无显著统计学意义。 未采取腹泻预防措施，奈拉替尼组与安慰剂组相比，3～4级不良事件发生较多：
奈拉替尼与安慰剂相比，无证据表明奈拉替尼相关腹泻的长期不良后果或长期毒性的风险增加。 因此，根据五年随访结果，化疗和曲妥珠单抗治疗后，使用奈拉替尼延长辅助治疗一年，显著降低了有临床意义的乳腺癌复发比例（即那些可能导致死亡的乳腺癌复发，例如保留乳房之外的远处和局部区域复发）而不增加长期毒性的风险。 此外，根据计划，该研究发生248例死亡事件后，将进行总生存分析，敬请期待。 对此，德克萨斯大学MD安德森癌症中心的乳腺肿瘤内科和外科专家发表同期评论，认为该研究结果虽然为HER2阳性乳腺癌患者延长辅助治疗得出一些答案，但是带来更多问题。 问题一、ExteNET研究进行了多次修改：最初允许入组淋巴结阴性患者，但是后来将入组条件限制为高风险的淋巴结阳性患者。起初，曲妥珠单抗治疗2年内的患者符合入组条件；之后，将入组条件限制至1年。研究计划随访从5年减少至2年，将分析由事件触发改为时间触发。为了恢复原始设计，2014年修订方案，将随访时间延长至5年，获得了2840例患者的2117例（75%）再次同意。虽然再次同意与原始患者的特征相似，但是由于随访延长不完整和数据缺失，无法排除残余偏倚。 问题二、2017年7月17日，美国食品药品管理局（FDA）批准奈拉替尼用于早期HER2阳性乳腺癌患者接受曲妥珠单抗辅助治疗后进行延长辅助治疗。现在，奈拉替尼已经获批并且可以买到，是否应该进行处方？此外，无浸润病变生存的改善，相对于奈拉替尼的相关成本和副作用是否值得？这个问题是有意义的，因为在ExteNET研究中，40%的奈拉替尼治疗患者发生3级腹泻。虽然目前推荐使用洛哌丁胺（易蒙停）进行预防，并且正被PUMA-NEW-6201研究（NCT 02400476）进行评估，但是普通人群的耐受性尚不明确。 问题三、根据ExteNET研究，为何激素受体阳性与阴性肿瘤患者相比，似乎获益较多？然而新辅助治疗数据表明，激素受体阴性与阳性肿瘤相比，HER2阻断获益较大。 问题四、如果该研究仅入组与曲妥珠单抗同时治疗的患者，那么奈拉替尼是否仍可获益？根据ALTTO研究最新结果，曲妥珠单抗的序贯治疗与同时治疗相比，拉帕替尼的获益较大，正如ExteNET研究所建议的。 问题五、在帕妥珠单抗时代，奈拉替尼的使用问题可能更难以回答。对于新辅助化疗和双抗体阻断后仍有明显残留病变的患者，是否考虑使用奈拉替尼治疗？虽然FDA尚未批准使用帕妥珠单抗，但是根据APHINITY研究，延长1年的帕妥珠单抗与对照组相比，可使无浸润病变生存略有改善（94%比93%）。虽然帕妥珠单抗之后使用奈拉替尼未知能否提供额外获益尚不明确，但是是否考虑对高风险患者使用双抗体治疗序贯奈拉替尼？临床研究不太可能回答这些问题；然而，设计临床研究评估奈拉替尼对帕妥珠单抗治疗患者的效果将有深远意义。 现在，我们只能依靠数据和我们的临床判断。紫杉醇＋曲妥珠单抗治疗淋巴结阴性乳腺癌患者有良好的转归；因此，在该情况下很难证实使用奈拉替尼有效。对于淋巴结阳性乳腺癌患者，我们可能根据每位患者的个体风险对治疗方案进行增加或延长：增加治疗将使高风险患者获益较大。虽然ExteNET的亚组分析仅为探索性，但是某些医生对于曲妥珠单抗治疗1年内至少4个淋巴结阳性或激素受体阳性肿瘤患者处方奈拉替尼可能比较合适。这将是困难的权衡行为（医患共同决策过程），我们必须权衡转归的微小获益与不那么微不足道的成本和副作用。 编者按：目前，上述奈拉替尼、帕妥珠单抗在中国内陆尚未获批，仅有拉帕替尼、曲妥珠单抗可选。 Lancet Oncol. 2017 Nov 13. [Epub ahead of print] Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Beverly Moy, Hiroji Iwata, Gunter von Minckwitz, Stephen K L Chia, Janine Mansi, Carlos H Barrios, Michael Gnant, Zorica Tomasevic, Neelima Denduluri, Robert Separovic, Erhan Gokmen, Anna Bashford, Manuel Ruiz Borrego, Sung-Bae Kim, Erik Hugger Jakobsen, Audrone Ciceniene, Kenichi Inoue, Friedrich Overkamp, Joan B Heijns, Anne C Armstrong, John S Link, Anil Abraham Joy, Richard Bryce, Alvin Wong, Susan Moran, Bin Yao, Feng Xu, Alan Auerbach, Marc Buyse, Arlene Chan; ExteNET Study Group. Grupo Espanol de Investigacion en Cancer de Mama (GEICAM), Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Universidad Complutense, Madrid, Spain; Texas Oncology, Houston, TX, USA; Rigshospitalet, Copenhagen, Denmark; Institut Gustave Roussy, Villejuif, France; Massachusetts General Hospital Cancer Center, Boston, MA, USA; Aichi Cancer Center, Chikusa-ku, Nagoya, Japan; Luisenkrankenhaus, German Breast Group Forschungs GmbH, Dusseldorf, Neulsenburg, Germany; BC Cancer Agency, Vancouver, BC, Canada; Guy's and St Thomas' Hospital National Health Service Foundation Trust and Biomedical Research Centre, King's College, London, UK; Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Medical University of Vienna, Vienna, Austria; Daily Chemotherapy Hospital, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia; Virginia Cancer Specialists, Arlington, VA, USA; University Hospital for Tumors, University Hospital Center "Sestre milosrdnice", Zagreb, Croatia; Ege University Faculty of Medicine, Izmir, Turkey; Auckland Hospital, Auckland, New Zealand; Hospital Universitario Virgen del Rocio, Seville, Spain; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; Lillebaelt Hospital, Vejle, Denmark; Oncology Institute of Vilnius University, Vilnius, Lithuania; Breast Oncology, Saitama Cancer Center, Kita-Adachi, Japan; Oncologianova GmbH, Recklinghausen, Germany; Amphia Hospital, Breda, Netherlands; Christie Hospital Manchester, Manchester, UK; Breastlink Medical Group Inc, Santa Ana, CA, USA; University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada; Puma Biotechnology Inc, Los Angeles, CA, USA; International Drug Development Institute, Louvain-la-Neuve, Belgium; Breast Cancer Research Centre-Western Australia, Perth, WA, Australia; Curtin University, Perth, WA, Australia. BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5.2 years (IQR 2.1-5.3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0.73, 95% CI 0.57-0.92, p=0.0083). The 5-year invasive disease-free survival was 90.2% (95% CI 88.3-91.8) in the neratinib group and 87.7% (85.7-89.4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses—ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast—without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events. FUNDING: Wyeth, Pfizer, and Puma Biotechnology. DOI: 10.1016/S1470-2045(17)30717-9 Lancet Oncol. 2017 Nov 13. [Epub ahead of print] Extended adjuvant therapy in patients with HER2-positive breast cancer: some answers, even more questions. Mariana Chavez-MacGregor, Elizabeth A Mittendorf. The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. DOI: 10.1016/S1470-2045(17)30844-6
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