Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial.
Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial.
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DOI：
10.1016/s1470-2045(19)30825-3
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发表时间：
2020-03
期刊：
影响因子：
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通讯作者：
Blay JY
中科院分区：
文献类型：
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作者：
Italiano A;Mir O;Mathoulin-Pelissier S;Penel N;Piperno-Neumann S;Bompas E;Chevreau C;Duffaud F;Entz-Werlé N;Saada E;Ray-Coquard I;Lervat C;Gaspar N;Marec-Berard P;Pacquement H;Wright J;Toulmonde M;Bessede A;Crombe A;Kind M;Bellera C;Blay JY
复发和无法切除的尤文肉瘤和骨肉瘤的预后是令人沮丧的，在过去的几十年里没有变化。对患者的管理是基于各种细胞毒性方案的使用。然而，药物抑制甲硫氨酸信号和异常血管生成在尤文肉瘤和骨肉瘤的几个临床前模型中显示出有希望的结果。本研究旨在研究MET/VEGFR2抑制剂卡波赞替尼在晚期尤文和骨肉瘤患者中的活性。这是两个多中心单臂两阶段2期试验，评估卡波赞替尼对晚期尤文肉瘤或骨肉瘤患者的疗效和安全性。主要的资格标准包括：年龄≥12岁，脑电地形图表现状态≤1，转移的或不能切除的局部晚期疾病，以及有记录的疾病进展(根据RECISTV1.1)。以前的治疗路线的数量不受限制。患者每天服用卡波赞替尼(口服；成人：60毫克，儿童：40毫克/平方米)，直到疾病进展或不可接受的毒性。主要终点是尤文肉瘤的客观反应，以及基于6个月的客观反应和骨肉瘤无进展的双重终点。自2015年4月16日至2018年7月12日，共招募患者90例(尤文肉瘤45例；骨肉瘤45例)。尤文肉瘤和骨肉瘤的中位随访期分别为31.3个月(95%CI：[12.4-35.4])和31.1个月(95%CI：[24.4-31.7])。39例(86.7%)尤文肉瘤和42例(93.3%)骨肉瘤在组织学和放射学复查后可评估疗效。骨肉瘤部分缓解7例(16.7%)，病情稳定14例(33.3%)。尤文肉瘤部分缓解10例(25.6%)，稳定15例(38.4%)。14例骨肉瘤患者(33.3%)和10例尤文肉瘤患者(25.6%)在6个月内无进展。治疗耐受性良好，尽管1级或2级疲劳、腹泻、粘膜炎和肝脏转氨炎很常见。最常见的3~4级不良反应为低磷血症8例(8.9%)，天冬氨酸氨基转移酶升高5例(5.6%)，掌底综合征5例(5.6%)，气胸5例(5.6%)，中性粒细胞减少5例(5.6%)。61名患者(67.8%)至少报告了一次严重不良事件。临床试验登记：NCT02243605在这项研究中，卡波赞替尼在晚期尤文肉瘤和骨肉瘤患者中显示出显著的抗肿瘤活性，可能代表着这种情况下的一种新的治疗选择。
The prognosis of relapsed and unresectable Ewing sarcoma and osteosarcoma is dismal and unchanged over the last decades. Management of patients is based on the used of various cytotoxic regimens. However, pharmacologic inhibition of Met signaling and of aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. This study aims to investigate the activity of the MET/VEGFR2 inhibitor, cabozantinib in patients with advanced Ewing and osteosarcoma. These are two multi-centre single-arm two-stage phase 2 trials assessing the efficacy and safety of cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma. Main eligibility criteria included: age ≥ 12 years, ECOG Performance status ≤ 1, metastatic or unresectable locally advanced disease and documented disease progression (as per RECIST v1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (oral route; adults: 60 mg, children: 40 mg/m2), daily until progressive disease or unacceptable toxicity. The primary endpoint was objective response for Ewing sarcoma and a dual one based on a 6-month objective response and non-progression of osteosarcoma. From April 16 2015 to July 12 2018, 90 patients were recruited (Ewing sarcoma: 45; Osteosarcoma: 45). Median follow-up was 31.3 months (95%CI: [12.4–35.4]) and 31.1 months (95%CI: [24.4–31.7]), for Ewing sarcomas and osteosarcomas, respectively. Thirty-nine (86.7%) Ewing sarcoma and 42 (93.3%) osteosarcoma were assessable for efficacy after histological and radiological review. Seven patients with osteosarcoma (16.7%) had partial response and 14 (33.3%) had stable disease. Ten patients with Ewing sarcoma (25.6%) had partial response and 15 (38.4%) had stable disease. Fourteen osteosarcoma patients (33.3%) and 10 Ewing sarcoma patients (25.6%) were progression-free at six months. Therapy was well tolerated, although grade 1 or grade 2 fatigue, diarrhea, mucositis and liver transaminitis were common. The most common grade 3 or 4 adverse events were hypophosphatemia (n=8, 8.9%), aspartate aminotransferase increase (n=5,5.6%), palmo-plantar syndrome (n=5, 5.6%), pneumothorax (=5, 5.6%), neutropenia (n=5, 5.6%). At least one serious adverse event was reported in 61 patients (67.8%). Clinical Trial Registration: NCT02243605 In this study, cabozantinib showed marked antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and may represent a new therapeutic option in this setting.