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对于人类表皮生长因子受体HER2阳性晚期乳腺癌，根据CLEOPATRA研究结果，多西他赛＋曲妥珠单抗＋帕妥珠单抗已被指南推荐为首选联合治疗方案。不过，多西他赛的水肿、周围神经病变等不良反应发生比例较高。艾立布林是一种人工合成的软海绵素类化疗药物，可抑制肿瘤细胞的有丝分裂和转移能力，2010年、2011年、2019年先后被美国、欧盟、日本、中国批准用于至少两种化疗方案失败的晚期乳腺癌。 2020年8月24日，德国施普林格旗下《新药研究》在线发表日本神奈川癌症中心、松山红十字医院、大阪国立医院、旭川医科大学、横滨市立大学、爱知癌症中心、大阪国际癌症研究所、大阪労災医院、关西电力医院、熊本红十字医院、千叶大学、筑波大学、长崎大学、弘前市立医院、千叶癌症中心、鹿儿岛相良医院、京都大学、日本癌症研究基金会有明医院的日本乳腺癌研究协作组JBCRG-M03研究报告，探讨了艾立布林＋帕妥珠＋曲妥珠单抗一线或二线治疗HER2阳性晚期乳腺癌的有效性和安全性。 该多中心单组非盲二期临床研究于2013年11月～2016年4月从日本全国入组曾经接受过曲妥珠单抗＋紫杉类术后辅助化疗或晚期一线化疗的HER2阳性晚期乳腺癌患者50例，每21天周期的第1天和第8天静脉注射艾立布林，每3周静脉注射帕妥珠单抗＋曲妥珠单抗。主要终点为无进展生存，次要终点为缓解率和安全性。 结果，其中49例符合安全性分析标准；46例患者符合有效性分析标准；一线治疗8例（16%）、二线治疗41例（84%）；局部晚期11例（23.9%）、远处转移35例（76.1%）。 全部患者的中位无进展生存为9.2个月（95%置信区间：7.0～11.4）。 44例患者病变可测量，完全缓解率为17.4%，部分缓解率为43.5%。 3～4级不良事件为5例（10.2%）中性粒细胞减少包括2例（4.1%）中性粒细胞减少伴发热、3例高血压（6.1%）、1例其他。左心室射血分数平均值未见明显下降。未见有症状的左心室收缩功能障碍。 因此，该研究结果表明，对于HER2阳性晚期乳腺癌患者中，艾立布林＋帕妥珠单抗＋曲妥珠单抗联合治疗的抗肿瘤活性显著、安全性可接受，故研究者已经启动随机对照三期临床研究，对艾立布林或紫杉类＋帕妥珠单抗＋曲妥珠单抗联合治疗HER2阳性晚期乳腺癌进行比较。 Invest New Drugs. 2020 Aug 24. Online ahead of print. Efficacy of the eribulin, pertuzumab, and trastuzumab combination therapy for human epidermal growth factor receptor 2-positive advanced or metastatic breast cancer: a multicenter, single arm, phase II study (JBCRG-M03 study). Yamashita T, Kawaguchi H, Masuda N, Kitada M, Narui K, Hattori M, Yoshinami T, Matsunami N, Yanagihara K, Kawasoe T, Nagashima T, Bando H, Yano H, Hasegawa Y, Nakamura R, Kashiwaba M, Morita S, Ohno S, Toi M. Kanagawa Cancer Center, Yokohama, Japan; Matsuyama Red Cross Hospital, Matsuyama, Japan; Osaka National Hospital, Osaka, Japan; Asahikawa Medical University Hospital, Asahikawa, Japan; Yokohama City University Medical Center, Yokohama, Japan; Aichi Cancer Center, Nagoya, Japan; Osaka International Cancer Institute, Osaka, Japan; Osaka Rosai Hospital, Sakai, Japan; Kansai Electric Power Hospital, Osaka, Japan; Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan; Chiba University Hospital, Chiba, Japan; University of Tsukuba, Tsukuba, Japan; Nagasaki University, Nagasaki, Japan; Hirosaki Municipal Hospital, Hirosaki, Japan; Chiba Cancer Center, Chiba, Japan; Sagara Hospital, Kagoshima, Japan; Kyoto University, Kyoto, Japan; The Cancer Institute Hospital of JFCR, Tokyo, Japan. PURPOSE: To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast cancer (AMBC), this multicenter, open-label, phase II trial presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab. METHODS: We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013-April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety. RESULTS: Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients [95% confidence interval (CI): 7.0-11.4]. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed. CONCLUSIONS: In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC. TRIAL REGISTRATION ID: UMIN-CTR: UMIN000012232 KEYWORDS: Anti-HER2 drug; Chemotherapy; Eribulin; Metastatic breast cancer; Pertuzumab PMID: 32833136 DOI: 10.1007/s10637-020-00991-6
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