National Cancer Center Hospital, Tokyo, Japan.
The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Clin Lung Cancer. 2019 May;20(3):e317-e328. doi: 10.1016/j.cllc.2018.12.018. Epub 2018 Dec 31.
Cabozantinib inhibits tyrosine kinases including MET, AXL, VEGFR2, RET, KIT, and ROS1 and has demonstrated antitumor activity in multiple tumor types. The primary objective of this phase 1 study (NCT01553656) was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of cabozantinib in Japanese patients.
Patients with advanced solid tumors were enrolled at 2 sites in Japan. After determining the MTD and RP2D, an expansion in non-small-cell lung cancer (NSCLC) consisting of 3 molecularly defined cohorts (EGFR mutation; KRAS mutation; ALK, RET, or ROS1 fusion) was initiated. The study was registered with ClinicalTrials.gov (NCT01553656).
Forty-three Japanese patients were enrolled (dose escalation, n = 23; NSCLC expansion, n = 20). The MTD of cabozantinib capsules was 60 mg daily, and the RP2D of cabozantinib tablets was 60 mg daily. Dose-limiting toxicities were hypertension, proteinuria, and venous embolism. Safety and pharmacokinetics in Japanese patients were consistent with those in non-Japanese patients. Common adverse events included palmar-plantar erythrodysesthesia, hypertension, and diarrhea. Reduction in tumor lesion size was observed in multiple tumor types in the dose-escalation cohorts, with partial responses observed in 4 of 9 patients with NSCLC (EGFR mutation, n = 1; ALK fusion, n = 2; and RET fusion, n = 1). In the NSCLC expansion, 4 patients with EGFR-mutant NSCLC had partial responses; the remaining 16 (EGFR mutation, n = 11; KRAS mutation, n = 2; ALK fusion, n = 1; and RET fusion, n = 2) had stable disease as best response.
Cabozantinib had a manageable safety profile in Japanese patients with solid tumors. Responses were observed in diverse molecular subtypes of NSCLC.
卡博替尼抑制包括 MET、AXL、VEGFR2、RET、KIT 和 ROS1 的酪氨酸激酶，在多种肿瘤类型中显示出抗肿瘤活性。这项 1 期研究（NCT01553656）的主要目的是确定卡博替尼在日本患者中的最大耐受剂量（MTD）和推荐的 2 期剂量（RP2D）。
在日本的 2 个地点招募了患有晚期实体瘤的患者。在确定 MTD 和 RP2D 后，开始对非小细胞肺癌（NSCLC）进行扩展，包括 3 个分子定义的队列（EGFR 突变；KRAS 突变；ALK、RET 或 ROS1 融合）。该研究在 ClinicalTrials.gov 上注册（NCT01553656）。
共招募了 43 名日本患者（剂量递增组 n=23；NSCLC 扩展组 n=20）。卡博替尼胶囊的 MTD 为每日 60mg，卡博替尼片剂的 RP2D 为每日 60mg。剂量限制毒性为高血压、蛋白尿和静脉栓塞。日本患者的安全性和药代动力学与非日本患者一致。常见的不良反应包括掌跖红斑感觉迟钝、高血压和腹泻。在剂量递增队列中观察到多种肿瘤类型的肿瘤病变大小缩小，在 9 名 NSCLC 患者中有 4 名观察到部分缓解（EGFR 突变，n=1；ALK 融合，n=2；RET 融合，n=1）。在 NSCLC 扩展中，4 名 EGFR 突变型 NSCLC 患者有部分缓解；其余 16 名（EGFR 突变，n=11；KRAS 突变，n=2；ALK 融合，n=1；RET 融合，n=2）的最佳反应为疾病稳定。
卡博替尼在日本实体瘤患者中的安全性可控。在 NSCLC 的多种分子亚型中观察到反应。
