BACKGROUND Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC). METHODS Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety. RESULTS The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C. CONCLUSION We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases. TRIAL REGISTRATION EudraCT Number: 2013-003894-87; registered 09-September-2013.

中文翻译：

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一项针对 HER2 阳性转移性乳腺癌患者进行依帕替尼加曲妥珠单抗联合或不联合化疗的 I/II 期研究。


背景 Epertinib (S-222611) 是一种有效的 HER2、EGFR 和 HER4 可逆抑制剂。该试验评估了每日口服依帕替尼联合曲妥珠单抗（A 组）、曲妥珠单抗加长春瑞滨（B 组）或曲妥珠单抗加卡培他滨（C 组）治疗 HER2 阳性转移性乳腺癌患者的安全性、耐受性、药代动力学和抗肿瘤活性。癌症（MBC）。方法 符合条件的患者，无论是否患有脑转移，均已接受过先前的 HER2 靶向治疗。剂量递增阶段确定了每种组合的耐受性并确定了进一步研究的剂量。此外，我们还招募了 3 个组的患者来扩大队列，以进一步探索疗效和安全性。结果 A、B、C 组的依帕替尼推荐剂量分别为 600 mg、200 mg 和 400 mg。最常见的 3/4 级不良事件 (AE) 是所有手臂中的腹泻，这可以通过医疗干预和剂量调整来控制。在接受过重度治疗的 HER2 阳性 MBC 患者中，使用推荐剂量的依帕替尼联合曲妥珠单抗的客观缓解率（完全缓解 [CR] 加部分缓解 [PR]）为 67% (N = 9)，而曲妥珠单抗加长春瑞滨的客观缓解率为 67% (N = 9)。 0% (N = 5)，曲妥珠单抗加卡培他滨为 56% (N = 9)。值得注意的是，之前接受 T-DM1 治疗的 6 名患者中有 4 名在 A 组扩展队列（埃珀替尼加曲妥珠单抗）中出现反应。在 C 组扩展队列（依帕替尼加曲妥珠单抗加卡培他滨）中，尽管之前曾接触过卡培他滨，但 7 名患者中有 4 名有反应。在接受 A 组和 C 组治疗的 CNS 靶病变患者中观察到脑转移瘤明显消退。 结论 我们观察到依培替尼联合曲妥珠单抗或曲妥珠单抗联合卡培他滨的安全性、耐受性和令人鼓舞的抗肿瘤活性。这支持在患有或不患有脑转移的既往 HER2 阳性 MBC 患者中进一步评估这些组合。试用注册 EudraCT 编号：2013-003894-87；注册日期：2013 年 9 月 9 日。