Daud Adil, Kluger Harriet M, Kurzrock Razelle, Schimmoller Frauke, Weitzman Aaron L, Samuel Thomas A, Moussa Ali H, Gordon Michael S, Shapiro Geoffrey I
University of California, San Francisco Medical Center at Parnassus, 1600 Divisadero Street, MZ Bldg A, San Francisco, CA 94115, USA.
Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, PO Box 208028, New Haven, CT 06520-8028, USA.
Br J Cancer. 2017 Feb 14;116(4):432-440. doi: 10.1038/bjc.2016.419. Epub 2017 Jan 19.
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.
一项II期随机停药试验评估了卡博替尼（XL184）在一组转移性黑色素瘤患者中的疗效，卡博替尼是一种口服生物可利用的酪氨酸激酶抑制剂，可抑制包括血管内皮生长因子（VEGF）受体、间质-上皮转化因子（MET）和AXL在内的多种激酶。
患者在为期12周的导入期内每日接受100mg卡博替尼治疗。根据实体瘤疗效评价标准（RECIST），第12周病情稳定（SD）的患者被随机分为卡博替尼组或安慰剂组。主要终点为第12周时的客观缓解率（ORR）和随机分组后的无进展生存期（PFS）。
共纳入77例患者（62%为皮肤型、30%为葡萄膜型、8%为黏膜型）。第12周时，ORR为5%；39%的患者病情稳定。在导入期，总体可评估患者中有55%的患者靶病灶较基线缩小，葡萄膜黑色素瘤患者中这一比例为59%。随机分组后，卡博替尼组的中位PFS为4.1个月，安慰剂组为2.8个月（风险比为0.59；P=0.284）。从研究第1天起的中位PFS为3.8个月，6个月PFS率为33%，中位总生存期为9.4个月。最常见的3/4级不良事件为疲劳（14%）、高血压（10%）和腹痛（8%）。有1例与治疗相关的死亡报告，死因是憩室穿孔导致的腹膜炎。
卡博替尼对转移性黑色素瘤患者，包括葡萄膜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。
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