奈拉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，已被ExteNET研究证实对HER2阳性早期乳腺癌强化辅助治疗有效，并被NALA研究证实对HER2阳性晚期乳腺癌患者具有全身疗效和颅内活性。不过，目前关于奈拉替尼治疗HER2阳性乳腺癌的有效性和安全性证据主要来自西方患者。由于乳腺癌的肿瘤生物学特征存在种族差异，可能导致不同结局，而且治疗模式也因地区而异，故有必要对奈拉替尼治疗晚期乳腺癌亚洲患者的有效性和安全性进行分析。
2021年9月23日，施普林格自然旗下《乳腺癌研究与治疗》在线发表中国台北三总医院、台南奇美医院、柳营奇美医院、彰化基督教医院、台北台大医院、花莲慈济医院、台北马偕纪念医院、台中光田综合医院、义大癌治疗医院、台北荣总医院、台北北海康成、高雄医学大学附设中和纪念医院、中国香港大学李嘉诚医学院、伊利沙伯医院、屯门医院、日本国立大阪医院、北里大学医学院、新加坡国立癌症中心、OncoCare癌症中心、新加坡国立大学癌症研究所、韩国国立癌症中心、首尔峨山医院、延世大学医学院延世癌症中心、美国洛杉矶美洲狮生物技术的NALA研究亚组分析报告，对奈拉替尼＋卡培他滨、拉帕替尼＋卡培他滨治疗HER2阳性晚期乳腺癌亚洲患者的有效性和安全性进行了比较。
NALA (NCT01808573): A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting
该国际多中心非盲非安慰剂随机对照三期临床研究于2013年5月29日～2017年7月21日从欧洲、美洲、亚洲、大洋洲28个国家地区203家医院入组集中确认的HER2阳性晚期乳腺癌≥2种HER2靶向治疗方案失败患者621例（其中包括病情稳定的无症状脑转移患者101例、亚洲患者202例）按1∶1的比例随机分为2组：
奈拉替尼组307例（其中亚洲患者104例）每天口服奈拉替尼240毫克＋每21天前14天每天2次口服卡培他滨每平方米体表面积750毫克＋口服洛哌丁胺（易蒙停）预防腹泻
拉帕替尼组314例（其中亚洲患者98例）每天口服拉帕替尼1250毫克＋每21天前14天每天2次口服卡培他滨每平方米体表面积1000毫克
共同主要终点为集中评定的无进展生存和总生存。次要终点包括中枢神经系统病变干预时间、客观缓解率、缓解持续时间、临床获益率和安全性。
结果，奈拉替尼组与拉帕替尼组的亚洲患者相比：
中位无进展生存时间显著较长：7.0比5.4个月（P=0.0011）
脑转移总累积发生率显著较低：27.9%比33.8%（P=0.039）
中位总生存时间较长：23.8比18.7个月（P=0.185）
中位缓解持续时间显著较长：11.1比4.2个月（P<0.0001）
两组亚洲患者的3或4级治疗相关不良事件、导致停药的治疗相关不良事件发生率相似，腹泻和手足综合征是最常见的治疗相关不良事件，发生率和严重程度与整体人群相似。
因此，该研究亚组分析结果表明，HER2阳性晚期乳腺癌≥2种HER2靶向治疗方案失败的亚洲患者与整个研究人群的疗效特征一致，也可对奈拉替尼＋卡培他滨显著获益，而且未见新的安全问题。
相关链接
Breast Cancer Res Treat. 2021 Sep 23. Online ahead of print.
Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens.
Dai MS, Feng YH, Chen SW, Masuda N, Yau T, Chen ST, Lu YS, Yap YS, Ang PCS, Chu SC, Kwong A, Lee KS, Ow S, Kim SB, Lin J, Chung HC, Ngan R, Kok VC, Rau KM, Sangai T, Ng TY, Tseng LM, Bryce R, Bebchuk J, Chen MC, Hou MF.
Tri-Service General Hospital, Taipei, Taiwan; Chi Mei Medical Center-Yongkang Branch, Tainan, Taiwan; Chi Mei Medical Center-LiouYing Branch, Tainan, Taiwan; Changhua Christian Hospital, Changhua, Taiwan; National Taiwan University Hospital, Taipei, Taiwan; Hualien Tzu Chi Hospital, Hualien, Taiwan; Mackay Memorial Hospital, Taipei, Taiwan; Kuang Tien General Hospital Cancer Center, Taichung, Taiwan; E-Da Cancer Hospital, Kaohsiung, Taiwan; Taipei Veterans General Hospital, Taipei, Taiwan; CANbridge Pharmaceuticals Inc., Taipei, Taiwan; Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan; The University of Hong Kong, Hong Kong, Hong Kong; The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong; Queen Elizabeth Hospital, Hong Kong, Hong Kong; Tuen Mun Hospital, Hong Kong, Hong Kong; National Hospital Organization Osaka National Hospital, Osaka, Japan; Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; National Cancer Centre Singapore, Singapore, Singapore; OncoCare Cancer Centre, Singapore, Singapore; National University Cancer Institute, Singapore, Singapore; National Cancer Center, Goyang-si, Korea; Asan Medical Center, Seoul, Korea; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; Puma Biotechnology Inc., Los Angeles, USA.
PURPOSE: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein.
METHODS: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety.
RESULTS: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity.
CONCLUSION: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted.
CLINICAL TRIAL REGISTRATION: NCT01808573
KEYWORDS: Brain metastases; CNS metastases; HER2-positive breast cancer; Lapatinib; Neratinib; Tyrosine kinase inhibitor
PMID: 34553296
DOI: 10.1007/s10549-021-06313-5
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