用EGFR酪氨酸激酶抑制剂(TKIs)治疗的EGFR突变肺癌患者出现临床耐药,最常见的是获得EGFRT790M。进化模型表明,每周两次脉冲和每日低剂量厄洛替尼的时间表可能会延迟EGFRT790M的出现。脉冲剂量埃罗替尼具有优越的中枢神经系统(CNS)穿透性,并且可导致优越的CNS疾病控制。
我们评估了毒性,药代动力学,每周两次脉冲和每日低剂量厄洛替尼的疗效。我们评估了厄洛替尼的六个递增脉冲剂量。
我们招募了34名患者;11名患者(32%)在进入研究时出现脑转移。我们在剂量递增中观察到3种剂量限制性毒性:转氨酶,粘膜炎,和皮疹。MTD为厄洛替尼1200mg第1-2天和50mg第3-7天每周一次。最常见的毒性(任何等级)是皮疹,腹泻,恶心,疲劳,和粘膜炎。观察到1个完全反应和24个部分反应(74%,95%CI60-84%)。中位无进展生存期为9.9个月(95%CI5.8-15.4个月)。在研究期间,没有患者出现未经治疗的CNS转移进展或出现新的CNS病变(0%,95%CI0-13%)。在进展时进行活检的18例患者中,EGFRT790M在78%(95%CI54-91%)中被鉴定。
这是首次临床实施联合脉冲和每日低剂量给药的抗癌TKI方案。这种基于进化建模的给药方案耐受性良好,但不能改善无进展生存期或防止EGFRT790M的出现。可能是由于厄洛替尼的峰值血清浓度不足。该给药方案防止了所有患者的未治疗或任何新的中枢神经系统转移的进展。
Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control.
We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib. We assessed six escalating pulse doses of erlotinib.
We enrolled 34 patients; 11 patients (32%) had brain metastases at study entry. We observed 3 dose-limiting toxicities in dose escalation: transaminitis, mucositis, and rash. The MTD was erlotinib 1200 mg days 1-2 and 50 mg days 3-7 weekly. The most frequent toxicities (any grade) were rash, diarrhea, nausea, fatigue, and mucositis. 1 complete and 24 partial responses were observed (74%, 95% CI 60-84%). Median progression-free survival was 9.9 months (95% CI 5.8-15.4 months). No patient had progression of an untreated CNS metastasis or developed a new CNS lesion while on study (0%, 95% CI 0-13%). Of the 18 patients with biopsies at progression, EGFR T790M was identified in 78% (95% CI 54-91%).
This is the first clinical implementation of an anti-cancer TKI regimen combining pulse and daily low-dose administration. This evolutionary modeling-based dosing schedule was well-tolerated but did not improve progression-free survival or prevent emergence of EGFR T790M, likely due to insufficient peak serum concentrations of erlotinib. This dosing schedule prevented progression of untreated or any new central nervous system metastases in all patients.