Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib.
Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib.
复制标题
DOI：
10.1158/1078-0432.ccr-08-1455
复制
发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Kobayashi S
中科院分区：
文献类型：
--
作者：
Costa DB;Nguyen KS;Cho BC;Sequist LV;Jackman DM;Riely GJ;Yeap BY;Halmos B;Kim JH;Jänne PA;Huberman MS;Pao W;Tenen DG;Kobayashi S
大多数具有激活表皮生长因子受体(EGFR)突变的肺癌对吉非替尼有反应，但对这种酪氨酸激酶抑制剂(TKI)的耐药性总是随之而来的。T790M突变发生在50%的TKI耐药肿瘤中，MET扩增发生在20%。其他继发性突变(D761Y、L747S)很少见。我们的目标是确定erlotinib 150 mg/d对对Gefitinib 250 mg/d耐药的EGFR突变患者的疗效，因为EGFR TKI erlotinib的生物活性剂量高于Gefitinib。18例EGFR突变(外显子19缺失，L858R，L861Q)患者接受吉非替尼治疗，随后接受厄洛替尼治疗。7例患者在TKI治疗后再次采集肿瘤标本，并分析了继发性EGFR突变和MET扩增。大多数患者(14/18)对吉非替尼有反应，中位无进展生存期(PFS)为11个月(95%CI，4~16)。在吉非替尼耐药(首次耐药或获得性耐药)后，78%(14/18)的患者在服用厄洛替尼2个月后出现进展性疾病(95%可信区间2~3)。7例患者中有6例获得了T790M突变，0例获得了MET扩增。只有1名吉非替尼耐药患者的获得性L858R-L747S EGFR对厄洛替尼150 mg/天的可达血药浓度敏感，对厄洛替尼有部分反应。在对吉非替尼250 mg/天耐药的EGFR突变肿瘤中，改用厄洛替尼150 mg/天对大多数患者没有反应。这些发现与临床前模型是一致的，因为体外TKI耐药的常见机制(T790M和MET扩增)不会被临床上可达到的剂量的吉非替尼或厄洛替尼所抑制。必须评估克服TKI耐药性的替代战略。
Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib, however resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y, L747S) are rare. Our goal was to determine the effects of erlotinib 150mg/day in EGFR mutated patients resistant to gefitinib 250mg/day, since the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, L861Q) patients that were given gefitinib and subsequently erlotinib. 7 patients had tumor re-sampling after TKI therapy, and were analyzed for secondary EGFR mutations and MET amplification. Most patients (14/18) responded to gefitinib with median progression-free survival (PFS) of 11 months (95%CI,4-16). After gefitinib resistance (de novo or acquired), 78% (14/18) of these patients displayed progressive disease while on erlotinib with PFS of 2 months (95%CI,2-3). 6/7 re-sampled patients acquired the T790M mutation, and 0/3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150mg/day, achieved a partial response to erlotinib. In EGFR mutated tumors resistant to gefitinib 250mg/day, a switch to erlotinib 150mg/day does not lead to responses in most patients. These findings are consistent with pre-clinical models, since the common mechanisms of TKI-resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.