众所周知，曲妥珠单抗的问世改变了HER2阳性早期乳腺癌患者生存结局。不过，根据HERA研究长达11年随访数据，HER2阳性早期乳腺癌术后完成1年曲妥珠单抗辅助治疗，仍有高达31%的患者出现复发或死亡。
奈拉替尼（又被误译为来那替尼）是人类表皮生长因子受体HER1、HER2、HER4酪氨酸激酶的不可逆抑制剂，还可抑制雌激素受体信号传导。
英国《柳叶刀》肿瘤学分册分别于2016年和2017年发表的ExteNET研究结果表明，对于HER2阳性早期乳腺癌术后完成曲妥珠单抗辅助治疗的2840例患者，每天口服奈拉替尼240毫克与安慰剂相比，浸润病变或死亡风险显著较低：
2年浸润病变或死亡风险低33%（风险比：0.67，95%置信区间：0.50～0.91，P=0.009）
5年浸润病变或死亡风险低27%（风险比：0.73，95%置信区间：0.57～0.92，P=0.008）
ExteNET: A Randomized, Double-Blind, Placebo-Controlled Trial Of Neratinib (HKI-272) After Trastuzumab In Women With Early-Stage HER-2/Neu Overexpressed/Amplified Breast Cancer (NCT00878709)
因此，美国食品药品管理局于2017年7月17日批准奈拉替尼用于HER2阳性早期乳腺癌术后完成曲妥珠单抗辅助治疗患者的强化治疗。
此外，根据ExteNET研究预设亚组分析2年结果，激素受体阳性与激素受体阴性亚组患者相比，奈拉替尼的疗效更高：
激素受体阳性：2年浸润病变或死亡风险低49%（风险比：0.51，95%置信区间：0.33～0.77）
激素受体阴性：2年浸润病变或死亡风险低 7%（风险比：0.93，95%置信区间：0.60～1.43）
完成曲妥珠单抗辅助治疗1年内与1年后开始强化治疗的患者相比，奈拉替尼的疗效也更高。
因此，欧洲药品管理局于2018年9月12日批准奈拉替尼用于HER2阳性且激素受体阳性早期乳腺癌术后完成曲妥珠单抗辅助治疗1年内患者的强化治疗。
2018年美国圣安东尼奥乳腺癌大会和2019年美国癌症研究学会《癌症研究》共同发表了奥地利维也纳医科大学、西班牙马德里大学、莱里达大学、拉斯帕尔马斯大学、巴塞罗那大学、美国德克萨斯肿瘤科协作组、哈佛大学麻省总医院、国际药品开发研究所、辛辛那提基督教医院、旧金山加利福尼亚大学、美洲狮生物技术公司、德国乳腺癌协作组、奥芬巴赫萨纳医院、加拿大不列颠哥伦比亚癌症中心、日本爱知癌症中心、自治医科大学、英国伦敦大学国王学院、皇家马斯登医院、法国古斯塔夫·鲁西癌症研究中心、意大利卡坦扎罗大学、丹麦奥尔堡大学医院、哥本哈根大学王国医院、巴西肿瘤研究中心、澳大利亚科廷大学的ExteNET研究亚组分析报告5年结果，检验了奈拉替尼用于HER2阳性且激素受体阳性早期乳腺癌术后完成曲妥珠单抗辅助治疗1年内患者的5年生存获益。
该国际多中心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40个国家495家医院入组HER2阳性早期乳腺癌完成术前新辅助或术后辅助化疗＋曲妥珠单抗治疗患者2840例，按1∶1的比例随机分为两组，每组各1420例，每天口服奈拉替尼240毫克或安慰剂连续1年。根据激素受体状态、淋巴结状态和曲妥珠单抗治疗方案对随机分组进行分层。激素受体阳性乳腺癌患者可以进行内分泌治疗。主要终点为无浸润病变生存，通过生存曲线法和多因素比例风险回归模型，计算浸润病变或死亡风险比及其95%置信区间，通过双侧对数秩检验分析统计学意义。次要终点为无病变生存＋导管原位癌、远处复发时间、无远处病变生存、中枢神经系统复发。首次分析于2年时进行，敏感性分析于5年时进行。
结果，其中1631例（57%）患者激素受体阳性（奈拉替尼组816例、安慰剂组815例），大多数（93%）入组时正在进行内分泌治疗。
1334例（82%）激素受体阳性患者完成曲妥珠单抗辅助治疗1年内入组：奈拉替尼组670例与安慰剂组664例患者相比：
2年无浸润病变生存获益高4.5%
2年浸润病变或死亡风险低51%（风险比：0.49，95%置信区间：0.30～0.78，P=0.002）
5年无浸润病变生存获益高5.1%
5年浸润病变或死亡风险低42%（风险比：0.58，95%置信区间：0.41～0.82，P=0.002）
因此，该研究结果表明，对于完成曲妥珠单抗辅助治疗1年内开始治疗的HER2阳性且激素受体阳性乳腺癌患者，奈拉替尼的疗效可能更强而持久。
据悉，国家药品监督管理局已于2020年4月27日正式批准奈拉替尼进入中国内陆市场，商品名：贺俪安，由美洲狮生物技术授权北海康成在大中华区独家开发和商业化。
相关链接
Cancer Res. 2019;79(4 Suppl):P2-13-01.
Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early-stage breast cancer: Subgroup analyses from the phase III ExteNET trial.
Gnant M, Martin M, Holmes FA, Jackisch C, Chia SK, Iwata H, Moy B, Martinez N, Mansi J, Morales S, Ruiz-Borrego M, von Minckwitz G, Buyse M, Delaloge S, Bhandari M, Murias-Rosales A, Galeano T, Fujita T, Luczak A, Barrios CH, Saura C, Rugo HS, Chien J, Johnston SR, Spencer M, Xu F, Barnett B, Chan A, Ejlertsen B.
Medical University of Vienna, Vienna, Austria; Universidad Complutense, Madrid, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain; Hospital Universitari Arnau de Vilanova de Lleida, Lleida, Spain; Hospital Universitario Virgen del Rocio, Seville, Spain; Compejo Hospitalario Materno Insular de Las Palmas, Las Palmas, Spain; Vall d'Hebron University Hospital, Barcelona, Spain; Texas Oncology, Houston, TX; Massachusetts General Hospital Cancer Center, Boston, MA; International Drug Development Institute, San Francisco, CA; Christ Hospital of Cincinnati, Cincinnati, OH; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Puma Biotechnology Inc., Los Angeles, CA; Sana Klinikum Offenbach, Offenbach, Germany; German Breast Group, Neu-Isenburg, Germany; British Columbia Cancer Agency, Vancouver, Canada; Aichi Cancer Center Hospital, Chikusa-ku Nagoya, Japan; Jichi Medical University Hospital, Tochigi, Japan; King's College London, London, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom; Institut Gustave Roussy, Villejuif, France; Magna Graecia University, Catanzaro, Italy; Aalborg Sygehus, Aalborg, Denmark; Rigshospitalet, Copenhagen, Denmark; Centro de Pesquisa em Oncologia, Porto Alegre, Brazil; Curtin University, Nedlands, Australia.
BACKGROUND: The international, randomized, placebo-controlled phase III ExteNET trial showed that 1 year (yr) of neratinib 240 mg/day after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in 2840 patients with early-stage HER2+ breast cancer at 2 yr (hazard ratio 0.67; 95% CI 0.50-0.91; p=0.009) [Chan 2016] and 5 yr (hazard ratio 0.73; 95% CI 0.57-0.92; p=0.008) [Martin 2017]. A prespecified subgroup analysis by hormone receptor (HR) status suggested enhanced efficacy with neratinib in patients with HR+ (2-yr hazard ratio 0.51; 95% CI 0.33-0.77) vs. HR- tumors (2-yr hazard ratio 0.93; 95% CI 0.60-1.43). The efficacy of neratinib was also greater in patients who initiated treatment within 1 yr of prior trastuzumab compared with those who started neratinib later. The European Medicines Agency's Committee for Medicinal Products for Human Use recently recommended neratinib for use in patients with HR+ tumors who initiate treatment within 1 yr of completing trastuzumab-based adjuvant therapy. Subgroup analyses from ExteNET examining iDFS benefits in this patient population are presented here.
METHODS: Patients with early-stage HER2+ breast cancer who completed trastuzumab-based (neo)adjuvant therapy were assigned to oral neratinib 240 mg/day or placebo for 1 yr. Randomization was stratified by HR status (determined locally before trial entry), nodal status, and trastuzumab regimen. Endocrine therapy was allowed in patients with HR+ disease. The primary endpoint, iDFS, was tested by 2-sided log-rank test and hazard ratios (95% CI) were estimated using Cox proportional hazards models. Kaplan-Meier methods were used to estimate iDFS rates. Secondary endpoints were DFS-DCIS, time to distant recurrence, distant DFS, and CNS recurrences. The primary analysis was conducted at 2 yr, and a sensitivity analysis conducted at 5 yr.
RESULTS: Of the 2840 patients (neratinib, n=1420; placebo, n=1420), 1631 (57%) had HR+ disease (neratinib, n=816; placebo, n=815). Most (93%) HR+ patients were receiving endocrine therapy at baseline. 1334 of 1631 (82%) patients with HR+ tumors were randomized to start neratinib within 1 yr of last trastuzumab dose (neratinib, n=670; placebo, n=664). iDFS benefits from neratinib in this population are shown in the table. Secondary endpoints were also improved with neratinib vs. placebo in this population. Safety data in this subset will be presented at the meeting.
CONCLUSIONS: Neratinib may have enhanced and sustained efficacy in patients with HR+ disease who initiate treatment within 1 yr of trastuzumab-based adjuvant therapy.
Clinicaltrials.gov: NCT00878709
DOI: 10.1158/1538-7445.SABCS18-P2-13-01
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