达沙替尼联合阿法替尼治疗表皮生长因子受体 (EGFR-) 突变型肺癌获得性酪氨酸激酶抑制剂 (TKI) 耐药的 1 期临床试验。

Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance.

机构信息

Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.

Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2, Ono-Higashi, Osakasayama, Osaka, 589-8511, Japan.

出版信息

Br J Cancer. 2019 Apr;120(8):791-796. doi: 10.1038/s41416-019-0428-3. Epub 2019 Mar 18.

BACKGROUND

Bypass activation of Src family kinases can confer resistance to EGFR tyrosine kinase inhibitors (TKIs) based on preclinical models. We prospectively assessed the safety and clinical activity of dasatinib and afatinib in combination for patients with resistant EGFR-mutant lung cancer.

METHODS

An open-label, dose-escalation phase 1/2 trial (NCT01999985) with 2-stage expansion was conducted with 25 lung cancer patients. Dose expansion required activating EGFR mutations and progression following prior EGFR TKI.

RESULTS

Patients were 72% Caucasian and received median of 2 prior lines of therapy. Maximum-tolerated dose was 30 mg afatinib with 100 mg dasatinib. New or increased pleural effusions were observed in 56% of patients. No radiologic responses were observed, although several EGFR-mutant TKI-resistant patients (26%) had prolonged stable disease over 6 months. The combination reduced the EGFR mutation and T790M variant allele frequency in cell-free DNA (p < .05). Nonetheless, the threshold for futility was met, based on 6-month progression-free survival. For EGFR TKI-resistant patients, median progression-free survival was 3.7 months (95% confidence interval (CI), 2.3-5.0) and overall survival was 14.7 months (95% CI, 8.5-20.9).

CONCLUSIONS

The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed.

背景

基于临床前模型，Src 家族激酶旁路激活可导致对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）产生耐药性。我们前瞻性评估了达沙替尼联合阿法替尼治疗耐药性 EGFR 突变型肺癌患者的安全性和临床活性。

方法

一项开放标签、剂量递增的 1/2 期试验（NCT01999985），采用 2 阶段扩展，共纳入 25 例肺癌患者。剂量扩展需要存在激活型 EGFR 突变和 EGFR-TKI 治疗后进展。

结果

患者 72%为白种人，接受中位数为 2 线的既往治疗。最大耐受剂量为 30mg 阿法替尼联合 100mg 达沙替尼。56%的患者出现新的或增加的胸腔积液。未观察到影像学反应，尽管有几个 EGFR-TKI 耐药的患者（26%）疾病稳定持续 6 个月以上。该联合方案降低了游离 DNA 中的 EGFR 突变和 T790M 变异等位基因频率（p<.05）。尽管如此，基于 6 个月无进展生存，无效的阈值已达到。对于 EGFR-TKI 耐药的患者，中位无进展生存期为 3.7 个月（95%置信区间[CI]，2.3-5.0），总生存期为 14.7 个月（95%CI，8.5-20.9）。