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Abstract：
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.
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.
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).
The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed.
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.
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).
The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed.
摘要：
基于临床前模型,Src家族激酶的旁路激活可以赋予对EGFR酪氨酸激酶抑制剂(TKIs)的抗性。我们前瞻性评估了达沙替尼和阿法替尼联合用于耐药EGFR突变肺癌患者的安全性和临床活性。
开放标签，对25例肺癌患者进行了剂量递增1/2期试验(NCT01999985),同时进行了2期扩展.剂量扩大需要激活EGFR突变和先前EGFRTKI后的进展。
患者为72％的白种人，接受了2种先前疗法的中位数。最大耐受剂量为30mg阿法替尼和100mg达沙替尼。在56％的患者中观察到新的或增加的胸腔积液。没有观察到放射学反应，尽管有几名EGFR突变TKI耐药患者(26%)的病情稳定时间超过6个月.该组合降低了无细胞DNA中的EGFR突变和T790M变体等位基因频率(p<.05)。尽管如此，达到了徒劳的门槛，基于6个月无进展生存期。对于EGFRTKI耐药患者，中位无进展生存期为3.7个月(95%可信区间(CI),2.3-5.0），总生存期为14.7个月（95%CI，8.5-20.9）。
该组合具有可控制的毒性特征和体内T790M调制，但没有观察到客观的临床反应。
开放标签，对25例肺癌患者进行了剂量递增1/2期试验(NCT01999985),同时进行了2期扩展.剂量扩大需要激活EGFR突变和先前EGFRTKI后的进展。
患者为72％的白种人，接受了2种先前疗法的中位数。最大耐受剂量为30mg阿法替尼和100mg达沙替尼。在56％的患者中观察到新的或增加的胸腔积液。没有观察到放射学反应，尽管有几名EGFR突变TKI耐药患者(26%)的病情稳定时间超过6个月.该组合降低了无细胞DNA中的EGFR突变和T790M变体等位基因频率(p<.05)。尽管如此，达到了徒劳的门槛，基于6个月无进展生存期。对于EGFRTKI耐药患者，中位无进展生存期为3.7个月(95%可信区间(CI),2.3-5.0），总生存期为14.7个月（95%CI，8.5-20.9）。
该组合具有可控制的毒性特征和体内T790M调制，但没有观察到客观的临床反应。
