Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York 10065, USA.
Clin Cancer Res. 2011 Oct 1;17(19):6298-303. doi: 10.1158/1078-0432.CCR-11-1468. Epub 2011 Aug 19.
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 that mandated TKI discontinuation before 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 epidermal growth factor receptor TKIs, discontinuation of erlotinib or gefitinib before 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.
与细胞毒性化疗相比，用酪氨酸激酶抑制剂（TKI）治疗致癌基因成瘾的癌症患者在生物学和临床上有所不同。我们观察到，一些表皮生长因子受体（EGFR）突变型肺癌患者对厄洛替尼或吉非替尼（初始获益后 RECIST 进展）产生获得性耐药，在停止 TKI 治疗后疾病迅速进展。为了检验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厄洛替尼或吉非替尼获得性耐药治疗药物临床试验的患者。
我们评估了参加要求在研究治疗前停止 TKI 治疗的获得性耐药试验的 EGFR 突变型肺癌患者。疾病爆发定义为在洗脱期内因疾病进展而住院或死亡。
61 例患者中有 14 例（23%；95%CI：14-35）发生疾病爆发。TKI 停药后疾病爆发的中位时间为 8 天（范围 3-21）。与疾病爆发相关的因素包括初始 TKI 进展时间更短（P=0.002）以及存在胸膜（P=0.03）或中枢神经系统（CNS）疾病（P=0.01）。获得性耐药时存在 T790M 与疾病爆发无关。
在 EGFR 突变型肺癌和表皮生长因子受体 TKI 获得性耐药的患者中，在开始研究治疗前停止厄洛替尼或吉非替尼与加速疾病进展的临床显著风险相关。该患者人群的临床试验必须尽量减少方案规定的洗脱期。
