"Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer
"Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer
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DOI：
10.1093/neuonc/nor121
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发表时间：
2011-12-01
期刊：
影响因子：
15.9
通讯作者：
Lassman, Andrew B.
中科院分区：
文献类型：
--
作者：
Grommes, Christian;Oxnard, Geoffrey R.;Lassman, Andrew B.
厄洛替尼对表皮生长因子受体（EGFR）突变型肺癌有效，但标准日剂量的CNS渗透有限。我们以前报道过，高剂量（1500 mg）厄洛替尼每周一次的间歇性“脉冲”给药是可以耐受的，并且在软脑膜转移患者的脑脊液中达到的浓度超过EGFR突变型肺癌细胞的半数最大抑制浓度;我们现在将这种范例扩展到9例患者。我们回顾性地确定了接受脉冲厄洛替尼治疗的EGFR突变型肺癌患者，尽管常规每日厄洛替尼或其他EGFR酪氨酸激酶抑制剂治疗，但仍发生CNS转移（脑和/或软脑膜）。可用肺和CNS组织中的突变与疗效相关。厄洛替尼单药治疗，中位剂量为每周1500 mg。67%（6/9，包括2例孤立的软脑膜转移）的最佳中枢神经系统放射学反应为部分反应，11%（1/9）的疾病稳定，22%（2/9）的疾病进展。中位CNS进展时间为2.7个月（范围：0.8-14.5个月），中位总生存期为12个月（范围：2.5个月-未达到）。治疗耐受性良好。在4名患者的中枢神经系统转移中未发现EGFR获得性耐药突变，其中1名患者在中枢神经系统外携带T790 M。脉冲厄洛替尼可控制EGFR突变型肺癌在标准日剂量失败后的CNS转移。中枢神经系统疾病可能不会产生系统性的获得性耐药突变。计划进行前瞻性试验。
Erlotinib is effective for epidermal growth factor receptor (EGFR) mutant lung cancer, but CNS penetration at standard daily dosing is limited. We previously reported that intermittent "pulsatile" administration of high-dose (1500 mg) erlotinib once weekly was tolerable and achieved concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung cancer cells in a patient with leptomeningeal metastases; we now expand this paradigm to a series of 9 patients. We retrospectively identified patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases (brain and/or leptomeningeal) that occurred despite conventional daily erlotinib or other EGFR tyrosine kinase inhibitors. Mutations in available lung and CNS tissue were correlated with efficacy. Erlotinib was administered as monotherapy at a median dose of 1500 mg weekly. Best CNS radiographic response was partial in 67% (6/9, including 2 with isolated leptomeningeal metastases), stable disease in 11% (1/9), and progressive disease in 22% (2/9). Median time to CNS progression was 2.7 months (range, 0.8-14.5 months) and median overall survival was 12 months (range, 2.5 months-not reached). Treatment was well tolerated. No acquired resistance mutations in EGFR were identified in the CNS metastases of 4 patients, including 1 harboring T790M outside the CNS. Pulsatile erlotinib can control CNS metastases from EGFR mutant lung cancer after failure of standard daily dosing. CNS disease may not harbor acquired resistance mutations that develop systemically. A prospective trial is planned.