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.
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。