Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain.
Clin Cancer Res. 2021 Feb 15;27(4):992-1002. doi: 10.1158/1078-0432.CCR-20-1690. Epub 2020 Oct 12.
We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive -mutant non-small cell lung cancer (NSCLC).
This open-label, single-arm phase I study enrolled patients with T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.
Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with ( = 10) and without central nervous system (CNS) metastasis ( = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6-21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.
Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive -mutant NSCLC..
我们报告了 JVDL（NCT02789345）的最终分析结果，该研究评估了 EGFR 酪氨酸激酶抑制剂（TKI）奥希替尼联合血管内皮生长因子受体 2 导向抗体雷莫芦单抗在 T790M 阳性突变型非小细胞肺癌（NSCLC）患者中的疗效。
这项开放标签、单臂 I 期研究纳入了 T790M 阳性 NSCLC 患者，这些患者在接受 EGFR TKI 治疗后进展，但未接受第三代 EGFR TKI 治疗。在必要时进行剂量调整的剂量限制毒性（DLT）期后，进行了扩展队列研究。患者每日口服奥希替尼和静脉注射雷莫芦单抗，每 2 周一次，直至疾病进展或停药。
共纳入 25 例患者。未观察到 DLT。中位随访时间为 25.0 个月。常见的 3 级或更高级别的治疗相关不良事件（TRAEs）为高血压（8%）和血小板计数降低（16%）；1 例患者发生 5 级 TRAE（硬膜下血肿）。有（n=10）和无（n=15）中枢神经系统（CNS）转移的患者具有相似的安全性结局。5 例患者仍在接受治疗。客观缓解率（ORR）为 76%。中位缓解持续时间为 13.4 个月[90%置信区间（CI）：9.6-21.2]。中位无进展生存期（PFS）为 11.0 个月（90%CI：5.5-19.3）。在有和无 CNS 转移的患者中均观察到疗效（ORR 分别为 60%和 87%；中位 PFS 分别为 10.9 和 14.7 个月）。循环肿瘤 DNA 的探索性生物标志物分析表明，基线时可检测到的治疗期间 EGFR 外显子 19 缺失或 L858R 突变的丢失与更长的 PFS相关，但 T790M 的丢失则没有。疾病进展后出现的新的遗传改变包括 C797S、MET 扩增和 EGFR 扩增。
雷莫芦单抗联合奥希替尼在 T790M 阳性突变型 NSCLC 中显示出令人鼓舞的安全性和抗肿瘤活性。
