Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
School of Cancer Medicine, La Trobe University School of Cancer Medicine, Melbourne, Australia.
Clin Cancer Res. 2019 Aug 15;25(16):4924-4932. doi: 10.1158/1078-0432.CCR-18-1189. Epub 2019 Apr 5.
Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib).
This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity.
Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg = 1, 800 mg = 1, and 1,000 mg = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks.
The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
异常激活 MET（肝细胞生长因子受体）信号参与了人类癌症的肿瘤发生。这项 I 期研究评估了强效和选择性 MET 抑制剂 savolitinib（AZD6094、HMPL-504、volitinib）的安全性、耐受性和最大耐受剂量（MTD）。
这项开放标签、多中心剂量递增和扩展研究评估了口服 savolitinib 治疗局部晚期或转移性实体瘤患者。采用 3+3 设计评估了每日重复给药（QD）和每日两次给药（BID）方案。剂量扩展阶段纳入了 12 例患者。主要目标是评估 savolitinib 的安全性、耐受性、MTD 和剂量限制性毒性（DLT）。次要和探索性目标包括药代动力学、生物标志物研究和抗肿瘤活性。
总体而言，共纳入 48 例患者。4 例患者在 QD savolitinib 后出现 DLT（600 mg=1，800 mg=1，和 1000 mg=2）；MTD 为 800 mg QD，BID 未达到。推荐的 II 期剂量（RP2D）为 600 mg QD。最常见的不良反应是恶心（30 例，63%）、呕吐（20 例，42%）、疲劳（20 例，42%）和外周水肿（15 例，31%）。在 600 mg QD 时，Cmax 为 2414.8ng/mL，AUC 为 17053.9 h·ng/mL，无明显药物蓄积。3 例具有乳头状肾细胞癌（PRCC）和 MET 异常的患者获得了部分缓解，缓解持续时间为 39 至 147 周。
savolitinib 的耐受性良好，RP2D 确立为 600 mg QD。初步抗肿瘤活性表明该药在 PRCC 患者中具有进一步研究的潜力。
