曲妥珠单抗-美坦新偶联物（T-DM1）联合 S-1 治疗曲妥珠单抗预处理的 HER2 阳性晚期或转移性乳腺癌患者：一项 Ib 期研究。

Trastuzumab Emtansine (T-DM1) Plus S-1 in Patients with Trastuzumab-Pretreated HER2-Positive Advanced or Metastatic Breast Cancer: A Phase Ib Study.

机构信息

Division of Breast and Endocrine Surgery, Department of Surgery, St. Marianna University School of Medicine, Kawasaki, Japan,

Division of Breast and Endocrine Surgery, Department of Surgery, St. Marianna University School of Medicine, Kawasaki, Japan.

出版信息

Oncology. 2019;96(6):309-317. doi: 10.1159/000497276. Epub 2019 Mar 20.

DOI:10.1159/000497276

PMID:30893699

Abstract

BACKGROUND

In treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, the efficacy of capecitabine combined with HER2-directed agents such as trastuzumab and lapatinib is supported by some evidence. The combination of T-DM1 and S-1, another oral 5-FU, may be a safe alternative treatment for metastatic breast cancer.

OBJECTIVES

The optimal dose of S-1 was evaluated in combination with T-DM1 for patients with HER2-positive advanced or metastatic breast cancer. The safety and clinical response of this combination treatment were also assessed.

METHODS

This 3 + 3 dose-escalation study of S-1 given for the first 2 of 3 weeks, in combination with T-DM1 (3.6 mg/kg given every 3 weeks) to patients with trastuzumab-pretreated HER2-positive advanced or metastatic breast cancer was designed to evaluate the dose-limiting toxicity (DLT) occurrence in the first cycle. We also evaluated the safety and clinical activity of this combination treatment in multiple cycles. Two different dose levels of S-1 (65 and 80 mg/m2/day) were planned, although the capecitabine arm was abandoned because of slow recruitment.

RESULTS

Twelve out of the 13 patients enrolled were evaluable for DLT. One DLT (grade ≥3 non-hematological adverse events) occurred at dose level 0, leading to the expansion of this cohort to 6 patients, with an additional DLT (≥7 days discontinuation of medication), while no DLT occurred at dose level 1. As a result, the maximum tolerable dose of S-1 was determined to be 80 mg/m2/day for 14 days with T-DM1 3.6 mg/kg, repeated every 3 weeks. Two patients had grade 3 thrombocytopenia at dose level 0, and 1 patient at dose level 1.

CONCLUSIONS

S-1 can be safely combined with the clinically relevant dose of T-DM1 in patients with HER2-positive advanced or metastatic breast cancer. Further evaluation with a larger sample size is required for efficacy assessment.

摘要

背景

在治疗人表皮生长因子受体 2（HER2）阳性转移性乳腺癌方面，卡培他滨联合曲妥珠单抗和拉帕替尼等 HER2 靶向药物的疗效得到了一些证据的支持。T-DM1 和 S-1（另一种口服 5-FU）的联合治疗可能是转移性乳腺癌的一种安全替代治疗方法。

目的

评估 S-1 与 T-DM1 联合用于 HER2 阳性晚期或转移性乳腺癌患者的最佳剂量。还评估了这种联合治疗的安全性和临床反应。

方法

这项 S-1 剂量递增 3 + 3 研究，S-1 在 3 周的前 2 周给予，与 T-DM1（每 3 周给予 3.6 mg/kg）联合用于曲妥珠单抗预处理的 HER2 阳性晚期或转移性乳腺癌患者，旨在评估第一个周期的剂量限制毒性（DLT）发生情况。我们还评估了这种联合治疗在多个周期中的安全性和临床活性。计划了两种不同剂量水平的 S-1（65 和 80 mg/m2/天），尽管由于招募缓慢而放弃了卡培他滨组。

结果

13 名入组患者中有 12 名可评估 DLT。1 例 DLT（≥3 级非血液学不良事件）发生在剂量水平 0，导致该队列扩大至 6 例患者，出现另 1 例 DLT（≥7 天停药），而剂量水平 1 未发生 DLT。因此，确定 S-1 的最大耐受剂量为 T-DM1 3.6 mg/kg，每 3 周重复一次，S-1 剂量为 80 mg/m2/天，14 天。2 例患者在剂量水平 0 时出现 3 级血小板减少症，1 例患者在剂量水平 1 时出现 3 级血小板减少症。