Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma.
Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma.
复制标题
DOI：
10.1038/bjc.2016.419
复制
发表时间：
2017-02-14
影响因子：
8.8
通讯作者：
Shapiro GI
中科院分区：
文献类型：
--
作者：
Daud A;Kluger HM;Kurzrock R;Schimmoller F;Weitzman AL;Samuel TA;Moussa AH;Gordon MS;Shapiro GI
一项II期随机停用试验在一组转移性黑色素瘤患者中评估了Cabozantinib(XL184)，这是一种口服生物可用的酪氨酸激酶抑制剂，包括血管内皮生长因子受体、MET和Axl。患者在12周的入门治疗中每天服用卡波赞替尼100 mg。12周时，根据实体肿瘤反应评估标准(RECIST)，病情稳定(SD)的患者随机接受卡波赞替尼或安慰剂治疗。主要终点是第12周的客观反应率(ORR)和术后无进展生存率(PFS)。77名患者入选(62%是皮肤，30%是葡萄膜，8%是粘膜)。在12周时，ORR为5%，39%的患者有SD。在引入阶段，55%的可评估患者和59%的可评估葡萄膜黑色素瘤患者的靶点皮损比基线有所减少。随机分组后，服用卡波赞替尼的中位PFS为4.1月，服用安慰剂的中位PFS为2.8月(风险比为0.59P=0.284)。研究第1天开始的中位PFS为3.8个月，6个月PFS为33%，中位总生存期为9.4个月。最常见的3/4级不良事件是乏力(14%)、高血压(10%)和腹痛(8%)。据报道，1例因憩室穿孔引起的腹膜炎与治疗有关。卡波赞替尼对包括葡萄膜黑色素瘤在内的转移性黑色素瘤患者具有临床活性。有必要进行进一步的临床研究。
A phase II randomised discontinuation trial assessed cabozantinib (XL184), an orally bioavailable inhibitor of tyrosine kinases including VEGF receptors, MET, and AXL, in a cohort of patients with metastatic melanoma. Patients received cabozantinib 100 mg daily during a 12-week lead-in. Patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumours (RECIST) at week 12 were randomised to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and postrandomisation progression-free survival (PFS). Seventy-seven patients were enroled (62% cutaneous, 30% uveal, and 8% mucosal). At week 12, the ORR was 5% 39% of patients had SD. During the lead-in phase, reduction in target lesions from baseline was seen in 55% of evaluable patients overall and in 59% of evaluable patients with uveal melanoma. Median PFS after randomisation was 4.1 months with cabozantinib and 2.8 months with placebo (hazard ratio of 0.59; P=0.284). Median PFS from study day 1 was 3.8 months, 6-month PFS was 33%, and median overall survival was 9.4 months. The most common grade 3/4 adverse events were fatigue (14%), hypertension (10%), and abdominal pain (8%). One treatment-related death was reported from peritonitis due to diverticular perforation. Cabozantinib has clinical activity in patients with metastatic melanoma, including uveal melanoma. Further clinical investigation is warranted.