娜拉、辛巴一相逢，便胜却人间无数！

　　娜拉（Nala）是迪士尼《狮子王》辛巴的女友、妻子、王后。2011年，美洲狮（Puma）生物技术公司从辉瑞（Pfizer）旗下惠氏（Wyeth）获得人类表皮生长因子受体HER1、HER2、HER4酪氨酸激酶不可逆抑制剂奈拉替尼，用于HER2阳性早期乳腺癌术后强化辅助抗HER2治疗。2013年，美洲狮启动了NALA研究。2020年2月25日，美国食品药品监督管理局根据NALA研究结果，正式批准奈拉替尼＋卡培他滨用于HER2阳性晚期乳腺癌二线以上抗HER2治疗。

NALA: 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 (NCT01808573)

　　2020年7月17日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表西班牙乳腺癌研究协作组、巴塞罗那大学医院、中国台湾柳营奇美医院、台北三军总医院、高雄医科大学医院、台南成功大学、高雄荣民总医院、台湾大学医院、台北马偕纪念医院、香港大学李嘉诚医学院、美国洛杉矶加利福尼亚大学琼森综合癌症中心、哈佛大学麻省总医院、芝加哥西北大学综合癌症中心、德克萨斯大学西南医学中心、美洲狮生物技术公司、匹兹堡大学医疗中心、韩国蔚山大学医学院、法国古斯塔夫·鲁西癌症研究中心、日本国立大阪医院、北海道癌症中心、东京虎之门医院、久留米总医院、群马大学医学院、捷克国父纪念癌症研究中心、加拿大多伦多大学森尼布鲁克健康科学中心、芬兰赫尔辛基大学医院、新加坡国家癌症中心、意大利那不勒斯国家癌症研究所、维梅尔卡泰医院、比利时鲁汶大学医院、荷语天主教鲁汶大学、爱尔兰都柏林大学圣文森特医院的NALA研究报告全文，对奈拉替尼＋卡培他滨或拉帕替尼＋卡培他滨用于HER2阳性晚期乳腺癌≥2种抗HER2治疗方案失败患者进行了比较。

　　该国际多中心随机非安慰剂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种抗HER2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）按1∶1的比例随机分入2组：

• 奈拉替尼组307例：每天1次口服奈拉替尼240mg＋每21天前14天每天2次口服卡培他滨750mg/m²＋口服洛哌丁胺（易蒙停）预防腹泻

• 拉帕替尼组314例：每天1次口服拉帕替尼1250mg＋每21天前14天每天2次口服卡培他滨1000mg/m²

　　主要终点为集中确认的无进展生存、当地评定的总生存。次要终点为当地评定的脑转移干预率、当地评定的无进展生存、客观缓解比例、缓解持续时间、临床获益比例、安全性、健康相关生活质量。

　　结果，截至2018年9月28日，中位随访29.9个月，进展或死亡433例、死亡410例。

　　奈拉替尼组与拉帕替尼组相比：

• 进展死亡风险：低24%（风险比：0.76，95%置信区间：0.63～0.93，P=0.0059）

• 全部死亡风险：低12%（风险比：0.88，95%置信区间：0.72～1.07，P=0.2086）

• 脑转移干预率：低22%（风险比：0.78，95%置信区间：0.60～1.01，P=0.043）

• 临床获益比例：44.5%比35.6%（95%置信区间：38.3～50.8、29.8～41.6，P=0.0328）

• 客观缓解比例：32.8%比26.7%（95%置信区间：27.1～38.9、21.5～32.4，P=0.1201）

• 中位缓解时间：8.5个月比5.6个月（风险比：0.50，95%置信区间：0.33～0.74，P=0.004）

• 腹泻发生比例：83%比66%

• 恶心发生比例：53%比42%

• 治疗中断比例：13.9%比18.0%

• 健康相关生活质量评分：相似

　　因此，该研究结果表明，奈拉替尼＋卡培他滨与拉帕替尼＋卡培他滨相比，可以显著改善无进展生存、脑转移干预率、临床获益比例、持续缓解时间，未观察到新的奈拉替尼＋卡培他滨不良反应。

相关链接

NALA研究负责人、匹兹堡大学亚当·布鲁夫斯基教授

J Clin Oncol. 2020 Jul 17. Online ahead of print.

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.

Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, Brufsky A; NALA Investigators.

Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), SOLTI Breast Cancer Cooperative Group, Barcelona, Spain; Chi Mei Medical Centre, Liouying, Tainan, Taiwan; Tri-Service General Hospital, Taipei, Taiwan; Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; National Cheng Kung University, Tainan, Taiwan; Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; National Taiwan University Hospital, Taipei City, Taiwan; MacKay Memorial Hospital, Taipei, Taiwan; Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong; University of California Los Angeles/Jonsson Comprehensive Cancer Center, Los Angeles, CA; Massachusetts General Hospital Cancer Center, Boston, MA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; UT Southwestern Medical Center, Dallas, TX; Puma Biotechnology, Los Angeles, CA; Magee-Womens Hospital of UPMC, Pittsburgh, PA; University of Ulsan College of Medicine, Seoul, Korea; Gustave Roussy, Villejuif, France; National Hospital Organization, Osaka National Hospital, Osaka, Japan; National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan; Toranomon Hospital, Tokyo, Japan; JCHO Kurume General Hospital, Kurume, Japan; Gunma University, Gunma, Japan; Masaryk Memorial Cancer Institute, Brno, Czech; Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; National Cancer Centre Singapore, Singapore; National Cancer Institute Fondazione Pascale, Napoli, Italy; ASST di Vimercate, Vimercate, Italy; University Hospitals Leuven, Leuven, Belgium; KU Leuven, Leuven, Belgium; St Vincent's University Hospital, Dublin, Ireland.

PURPOSE: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.

METHODS: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).

RESULTS: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups.

CONCLUSION: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

ClinicalTrials.gov: NCT01808573

PMID: 32678716

DOI: 10.1200/JCO.20.00147