2019年12月，美国《新英格兰医学杂志》和圣安东尼奥乳腺癌大会同时公布的KATHERINE研究结果表明，对于HER2阳性早期乳腺癌术前新辅助化疗＋HER2靶向治疗后残留浸润病变患者，术后恩美曲妥珠单抗与曲妥珠单抗辅助治疗相比，浸润病变或死亡风险减少50%（95%置信区间：0.39～0.64，P<0.001）。不过，对于晚期乳腺癌，亚洲与非亚洲患者相比，恩美曲妥珠单抗所致血小板减少发生率较高。那么，恩美曲妥珠单抗对中国早期乳腺癌患者的安全性和有效性如何？
2021年6月，施普林格自然旗下《乳腺癌研究与治疗》正式发表中国台湾大学附属医院黄俊升、中国医药大学台中荣民总医院杨阳生、香港大学玛丽医院邝霭慧、长庚大学桃园长庚纪念医院陈训彻、台北荣民总医院曾令民、辜公亮基金会和信治癌中心医院刘美瑾、上海交通大学医学院附属瑞金医院沈坤炜、中山大学肿瘤医院王树森、香港屯门医院吴廷英、复旦大学附属肿瘤医院邵志敏等学者的KATHERINE研究中国患者亚组分析报告，比较了恩美曲妥珠单抗与曲妥珠单抗对中国HER2阳性早期乳腺癌术前新辅助化疗＋HER2靶向治疗后残留浸润病变患者的安全性和有效性。
KATHERINE (NCT01772472): A Randomized, Multicenter, Open-Label Phase III Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy for Patients With HER2-Positive Primary Breast Cancer Who Have Residual Tumor Present Pathologically in the Breast or Axillary Lymph Nodes Following Preoperative Therapy
该国际多中心双组非盲随机对照三期临床研究于2013年4月～2015年12月从28个国家地区273家医疗机构入组HER2阳性早期乳腺癌术前曲妥珠单抗＋紫杉类新辅助化疗后残留浸润病变患者1486例，其中101例（6.8%）来自中国大陆、中国香港、中国台湾，按1∶1的比例随机分为两组进行14轮术后辅助治疗。主要终点为无浸润病变生存。次要终点包括无病变生存、总生存、无远处复发间隔、安全性。
结果，对于中国患者，恩美曲妥珠单抗组51例与曲妥珠单抗组50例相比：
中位随访时间：42.8个月比37.1个月
浸润病变或死亡事件：17.6%比28.0%
无浸润病变生存比例：83.8%比70.4%
浸润病变或死亡风险：减少43%（风险比：0.57，95%置信区间：0.25～1.31）
病变或死亡事件：17.6%比28.0%
无病变生存比例：83.8%比70.4%
病变或死亡风险：减少43%（风险比：0.57，95%置信区间：0.25～1.31）
总死亡事件：5.9%比8.0%
总生存比例：93.6%比90.2%
总死亡风险：减少32%（风险比：0.68，95%置信区间：0.15～3.04）
远处复发事件：11.8%比16.0%
无远处复发率：89.5%比82.3%
远处复发风险：减少32%（风险比：0.68，95%置信区间：0.24～1.97）
由于曲妥珠单抗组1例患者未接受治疗，故恩美曲妥珠单抗组51例与曲妥珠单抗组49例相比：
≥3级不良事件：39.2%比4.1%
严重不良事件：19.6%比2.0%
不良事件所致停药：27.5%比0%
血小板减少：52.9%（全球患者为28.5%）比4.1%
≥3级血小板减少：21.6%（全球患者为5.7%）比0%
出血：39.2%（全球患者为29.2%）比8.2%
≥3级出血：2.0%（全球患者为0.4%）比0%
因此，KATHERINE研究中国患者亚组分析结果表明，恩美曲妥珠单抗与曲妥珠单抗相比，疗效较高，≥3级不良事件和不良事件所致停药发生率也较高，主要由于血小板减少发生率较高所致。
相关链接
Breast Cancer Res Treat. 2021 Jun;187(3):759-768.
Trastuzumab emtansine (T-DM1) versus trastuzumab in Chinese patients with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy for HER2-positive breast cancer in the phase 3 KATHERINE study.
Huang CS, Yang Y, Kwong A, Chen SC, Tseng LM, Liu MC, Shen K, Wang S, Ng TY, Feng Y, Sun G, Yan IR, Shao Z.
National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Taichung Veterans General Hospital and School of Medicine, China Medical University, Taichung City, Taiwan; Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong; Chang Gung Memorial Hospital, Chang Gung University Medical College, Taoyuan, Taiwan; Taipei Veterans General Hospital, Taipei, Taiwan; Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan; Shanghai Jiaotong University School of Medicine, Ruijin Hospital, Shanghai, China; Sun Yat-Sen University Cancer Center, Guangdong Sheng, China; Tuen Mun Hospital, Tuen Mun, Hong Kong; Roche (China) Holding Ltd., Shanghai, China; Fudan University Shanghai Cancer Center, Shanghai, China.
PURPOSE: In the KATHERINE study (NCT01772472), patients with HER2-positive early breast cancer (EBC) and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy who were treated with adjuvant trastuzumab emtansine (T-DM1) had a 50% reduction in the risk of an invasive disease-free survival (IDFS) event compared to patients treated with adjuvant trastuzumab. In metastatic disease, T-DM1 has resulted in higher rates of thrombocytopenia in Asian versus non-Asian patients. Here, we report safety and efficacy in Chinese patients from KATHERINE.
METHODS: Patients with HER2-positive EBC and residual invasive disease after taxane- and trastuzumab-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 or trastuzumab. The primary endpoint was time to an IDFS event.
RESULTS: Among Chinese patients (T-DM1 n = 51, trastuzumab n = 50), T-DM1 treatment resulted in a 43% reduction in risk of an IDFS event compared to trastuzumab (HR = 0.57; 95% CI 0.25-1.31), with similar results for secondary endpoints. As in the global population, Chinese patients receiving T-DM1 versus trastuzumab had more grade ≥ 3 adverse events (AEs; 39.2% versus 4.1%) and AEs leading to treatment discontinuation (27.5% versus 0%). The most common grade ≥ 3 AE with T-DM1 was thrombocytopenia (21.6%), a frequency higher than the frequency in the global population (5.7%). Grade ≥ 3 hemorrhage was reported in 1 patient (T-DM1 arm).
CONCLUSIONS: In the KATHERINE study, T-DM1 demonstrated increased efficacy compared to trastuzumab in Chinese patients. Consistent with previous data in Asian patients, T-DM1 was associated with more grade ≥ 3 AEs, and AEs leading to discontinuation, which was driven by an increase in thrombocytopenia.
KEYWORDS: Chinese; Early breast cancer; HER2-positive; Invasive disease-free survival (IDFS); Thrombocytopenia; Trastuzumab emtansine (T-DM1)
PMID: 33860389
DOI: 10.1007/s10549-021-06166-y
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