Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design.
Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design.
复制标题
DOI：
10.1158/1078-0432.ccr-11-1468
复制
发表时间：
2011-10-01
期刊：
影响因子：
--
通讯作者：
Riely GJ
中科院分区：
文献类型：
--
作者：
Chaft JE;Oxnard GR;Sima CS;Kris MG;Miller VA;Riely GJ
用酪氨酸激酶抑制剂（TKI）治疗癌基因成瘾性癌症患者在生物学和临床上与细胞毒性化疗不同。我们观察到，一些EGFR突变型肺癌患者对厄洛替尼或吉非替尼获得性耐药（初始获益后RECIST进展），在停用TKI后病情进展加速。为了检查这一观察结果并确定TKI停药后患者的病程，我们系统地评估了参加治疗厄洛替尼或吉非替尼获得性耐药药物临床试验的患者。我们评估了EGFR突变型肺癌患者，这些患者参加了获得性耐药患者的试验，这些试验要求在研究治疗给药前停用TKI。疾病发作定义为“洗脱”期间因疾病进展导致的住院或死亡。61例患者中有14例（23%; 95% CI 14-35%）发生疾病发作。TKI停药后至疾病发作的中位时间为8天（范围3-21）。与疾病发作相关的因素包括初始TKI时至进展时间较短（p=0.002）和存在胸膜（p=0.03）或CNS疾病（p=0.01）。在获得性耐药时，疾病爆发与T790 M的存在之间没有关联。在EGFR突变型肺癌和EGFR TKI获得性耐药患者中，在开始研究治疗前停用厄洛替尼或吉非替尼与具有临床意义的疾病进展加速风险相关。在该患者人群中进行的临床试验必须尽量缩短方案规定的洗脱期。
Treatment of patients with oncogene-addicted cancers with tyrosine kinase inhibitors (TKI) is biologically and clinically different than with cytotoxic chemotherapy. We have observed that some patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib (RECIST progression after initial benefit) have accelerated progression of disease after discontinuation of TKI. To examine this observation and define the course of patients following TKI discontinuation, we systematically evaluated patients enrolled on clinical trials of agents to treat acquired resistance to erlotinib or gefitinib. We evaluated patients with EGFR-mutant lung cancer who participated in trials for patients with acquired resistance which mandated TKI discontinuation prior to administration of study therapy. Disease flare was defined as hospitalization or death attributable to disease progression during the “washout” period. Fourteen of 61 patients (23%; 95% CI 14-35%) experienced a disease flare. The median time to disease flare after TKI discontinuation was 8 days (range 3-21). Factors associated with disease flare included shorter time to progression on initial TKI (p=0.002) and the presence of pleural (p=0.03) or CNS disease (p=0.01). There was no association between disease flare and the presence of T790M at the time of acquired resistance. In patients with EGFR-mutant lung cancer and acquired resistance to EGFR TKIs, discontinuation of erlotinib or gefitinib prior to initiation of study treatment is associated with a clinically significant risk of accelerated disease progression. Clinical trials in this patient population must minimize protocol mandated washout periods.