Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study.
Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study.
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DOI：
10.1080/2162402x.2018.1474319
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Ghiringhelli F
中科院分区：
文献类型：
--
作者：
Isambert N;Hervieu A;Rébé C;Hennequin A;Borg C;Zanetta S;Chevriaux A;Richard C;Derangère V;Limagne E;Blanc J;Bertaut A;Ghiringhelli F
在临床前模型中，IL-1β抑制可增强氟尿嘧啶（5-FU）的疗效。在这项II期研究中，我们评估了5-FU联合贝伐珠单抗和阿那白滞素（一种IL-1β和α抑制剂）在化疗和抗血管生成治疗难治性转移性结直肠癌（mCRC）患者中的活性和安全性。符合条件的患者患有不可切除的mCRC;对氟尿嘧啶、伊立替康、奥沙利铂、抗VEGF治疗和抗EGFR治疗（对于野生型KRAS肿瘤）难治或不耐受。患者接受简化的酸性亚叶酸加5-FU方案和贝伐珠单抗（5 mg/kg）治疗，均通过静脉输注30 min，每2周一次。阿那白滞素（100 mg）每天皮下注射一次。主要终点是根据CHOI标准确定的2个月缓解率。32例转移性结直肠癌患者入组。5例患者表现出缓解（Choi标准），22例患者的疾病稳定为最佳2个月总体缓解。中位无进展生存期和总生存期分别为5.4个月（95% CI，3.6-6.6）和14.5个月（95% CI，9-20.6）。20例患者出现3级毒性。未发生与治疗相关的4级或5级毒性。最常见的3级不良事件是8例（25%）患者的中性粒细胞减少症，7例（21.9%）患者的消化道副作用和6例（18.75%）患者的高血压。没有报告与治疗相关的死亡或严重不良事件。5-FU加贝伐珠单抗和阿那白滞素具有良好的活性和可管理的安全性，表明这种组合可能成为难治性mCRC患者的潜在治疗选择。
In preclinical models, IL-1β inhibition could enhance the efficacy of fluorouracil (5-FU). In this phase 2 study, we assessed the activity and safety of 5-FU plus bevacizumab and anakinra (an IL-1β and α inhibitor) in patients with metastatic colorectal (mCRC) refractory to chemotherapy and anti-angiogenic therapy. Eligible patients had unresectable mCRC; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were treated with a simplified acid folinic plus 5-FU regimen and bevacizumab (5 mg/kg) both administered by intravenous infusion for 30 min every 2 weeks. Anakinra (100 mg) was injected subcutaneously once daily. The primary endpoint was the 2-month response rate determined upon CHOI criteria. Thirty two patients with metastatic colorectal cancer were enrolled. Five patients demonstrated response (Choi criteria) and 22 patients had stable disease as the best 2-month overall response. Median progression-free and overall survival were 5.4 (95% CI, 3.6–6.6) and 14.5 months (95% CI, 9–20.6) respectively. Twenty patients experienced grade 3 toxicity. No grade 4 or 5 toxicity related to therapy occurred. The most common grade 3 adverse events were neutropenia in 8 (25%) patients, digestive side effects in 7 (21.9%) patients and hypertension in 6 (18.75%) patients. No treatment-related deaths or serious adverse events were reported.5-FU plus bevacizumab and anakinra has promising activity and a manageable safety profile, suggesting that this combination might become a potential treatment option for patients with refractory mCRC.