A Phase I-II Study of Combined Blockade of the ErbB Receptor Network with Trastuzumab and Gefitinib in Patients with HER2 (ErbB2)-Overexpressing Metastatic Breast Cancer
A Phase I-II Study of Combined Blockade of the ErbB Receptor Network with Trastuzumab and Gefitinib in Patients with HER2 (ErbB2)-Overexpressing Metastatic Breast Cancer
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DOI：
10.1158/1078-0432.ccr-08-0482
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发表时间：
2008-10-01
影响因子：
11.5
通讯作者：
Davidson, Nancy E.
中科院分区：
文献类型：
--
作者：
Arteaga, Carlos L.;O'Neill, Anne;Davidson, Nancy E.
目的：确定表皮生长因子受体酪氨酸激酶抑制剂吉非替尼联合曲妥珠单抗治疗 HER2 阳性转移性乳腺癌患者的安全性和有效性。实验设计：HER2 过表达乳腺癌患者接受曲妥珠单抗 2 mg/kg/周和吉非替尼 250 至 500 mg/天的治疗。该研究的主要终点是将未接受化疗的患者的 6 个月无进展比例从 50% 提高到 65%，将之前接受过化疗的转移性患者的 3 个月无进展比例从 50% 提高到 70%。结果：在 I 期研究中，所有接受吉非替尼 500 mg/天治疗的患者均出现 3 级腹泻。 11 期研究使用曲妥珠单抗和吉非替尼 250 毫克/天进行。 1 名患者实现完全缓解，2 名患者部分缓解，6 名患者病情稳定，总体缓解率为 9%，临床受益率为 28%（32 名患者中有 9 名）。对于既往未接受全身治疗的转移性患者 (n = 23)，中位进展时间 (TTP) 为 3 个月（95% 置信区间，2.3-4.1）。在既往接受过全身治疗的患者 (n = 9) 中，中位 TTP 为 5.3 个月（95% 置信区间，2.8-8.1）。总体中位生存期为 27 个月。与 EGFR 阴性患者相比，EGFR 阳性患者的 TTP 相似。结论：吉非替尼 250 mg/天是每周一次与曲妥珠单抗安全给药的最大剂量。中期疗效分析表明，与单独使用曲妥珠单抗相比，联合用药不太可能带来临床益处。这些结果不支持在 HER2 阳性乳腺癌患者中使用该组合。
Purpose: To determine the safety, and efficacy of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in combination with trastuzumab in patients with metastatic HER2-positive metastatic breast cancer.Experimental Design: Patients with HER2-overexpressing breast cancer were treated with trastuzumab 2 mg/kg/week and gefitinib 250 to 500 mg/day. The primary end point of the study was to increase the proportion progression-free from 50% to 65% at 6 months in chemotherapynaive patients and from 50% to 70% at 3 months in patients previously treated with chemotherapy in the metastatic setting. Results: In the phase I study, all patients treated with gefitinib 500 mg/day developed grade 3 diarrhea. The phase 11 study was conducted using trastuzumab and gefitinib 250 mg/day. One patient achieved a complete response, 2 had a partial response, and 6 had stable disease for an overall response rate of 9% and a clinical benefit rate of 28% (9 of 32). Median time to progression (TTP) was 3 months (95% confidence interval, 2.3-4.1) in patients with no prior systemic therapy in the metastatic setting (n = 23). In patients treated with prior systemic therapy (n = 9), the median TTP of 5.3 months (95% confidence interval, 2.8-8.1). Overall median survival was 27 months. TTP was similar in EGFR-positive compared with EGFR-negative patients.Conclusions: Gefitinib 250 mg/day was the maximal dose that can be safely administered with weekly trastuzumab. Interim analysis of the efficacy suggested that the combination was unlikely to result in clinical benefit compared with trastuzumab alone. These results do not support the use of this combination in patients with HER2-positive breast cancer.