徐瑞华，中山大学肿瘤防治中心主任、院长、所长，国家新药（抗肿瘤药物）临床试验中心主任。教授，博士生导师、结直肠癌内科首席专家。

《柳叶刀肿瘤分册》2018年3月16日在线先发

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext

作为二线治疗方案治疗转移性结直肠癌联合或不联合贝伐单抗的XELIRI改良方案（卡培他滨联合伊立替康）对比FOLFIRI（亚叶酸、氟尿嘧啶、伊立替康）方案（AXEPT试验）：一项多中心、开放标签、随机化、非劣效3期临床试验

背景

对XELIRI改良方案（mXELIRI方案，卡培他滨联合伊立替康）的研究表明，该方案在一线治疗和二线治疗中疗效佳、耐受性好。因此，我们旨在对mXELIRI方案与标准的FOLFIRI（亚叶酸、氟尿嘧啶、伊立替康）方案作为二线治疗方案治疗转移性结直肠癌的疗效和安全性进行了比较，两种方案均联合或不联合贝伐单抗。

方法

我们进行了一项多中心、开放标签、随机化、非劣效性3期临床试验。我们从日本、中国、韩国的98家医院入组了患者，患者年龄≥20岁、组织学证实且不能手术切除的结直肠腺癌，并且已撤出针对转移性结直肠癌的一线化疗。我们通过一个集中的电子系统，随机将患者（1：1）分组，一组接受mXELIRI方案并联合或不联合贝伐单抗（第1天，静滴伊立替康200mg/m2，联合第1-14天每日两次口服卡培他滨800mg/m2，21天一重复，第1天联合或不联合静滴贝伐单抗7.5mg/kg）,另一组接受FOLFIRI方案联合或不联合贝伐单抗（第1天，静滴伊立替康180mg/m2、亚叶酸钙200mg/m2、氟尿嘧啶400mg/m2、并连续46小时静脉输注氟尿嘧啶[2400mg/m2]，每14天一重复，联合或不联合第1天静滴贝伐单抗5mg/kg）。我们采用最小化方法，根据国家、ECOG体能状况、转移部位数、既往奥沙利铂治疗情况、同步贝伐单抗治疗情况进行随机化亚组分层。患者和医生知晓治疗分组情况。主要终点为总生存，在意向性治疗原则的基础上进行分析，风险比（HR）的非劣效上边界为1.30。本研究已在ClinicalTrials.gov网站注册，研究仍在进行，但不再招募患者。

结果

2013年12月2日至2015年8月13日，我们入组并随机化分配了650名患者，一组接受mXELIRI方案并联合或不联合贝伐单抗治疗（n=326），另一组接受FOLFIRI方案并联合或不联合贝伐单抗治疗（n=324）。中位随访15.8个月（IQR，8.7–24.9）后，共计490名患者死亡（mXELIRI方案联合或不联合贝伐单抗组242名、FOLFIRI方案联合或不联合贝伐单抗组248名），mXELIRI方案组的中位总生存期为16.8个月（95%CI，15.3-19.1），FOLFIRI组则为15.4个月（13.0-17.7）（HR，0.85；95%CI，0.71-1.02；非劣效性检验p<0.0001）。在符合试验方案的安全性分析人群中，最常见的3-4级不良反应为中性粒细胞减少症（影响了mXELIRI组310名患者中的52名[17%]、FOLFIRI组310名患者中的133名[43%]）。mXELIRI组3-4级腹泻的发生率（22[7%]）高于FOLFIRI组（10[3%]）。mXELIRI组310名患者中46名（15%）报告有严重不良反应，FOLFIRI组310名患者中则有63名（20%）。mXELIRI组中观察到有2名治疗相关性死亡（1名局限性肺炎、1名肺部感染），FOLFIRI组1名治疗相关性死亡（肺部感染）。

解释

就总生存期而言，mXELIRI方案联合或不联合贝伐单抗耐受性好，非劣效于FOLFIRI方案联合或不联合贝伐单抗。FOLFIRI方案是针对转移性结直肠癌的标准二线基础治疗方案，mXELIRI方案至少对于亚洲患者可以是一种替代方案。

《壹篇》南南和北北

Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial

Background

Studies of a modified XELIRI (mXELIRI; capecitabine plus irinotecan) regimen suggest promising efficacy and tolerability profiles in the first-line and second-line settings. Therefore, we aimed to compare the efficacy and safety of the mXELIRI regimen with that of standard FOLFIRI (leucovorin, fluorouracil, and irinotecan), with or without bevacizumab in both regimens, as a second-line therapy for metastatic colorectal cancer.

Methods

We did a multicentre, open-label, randomised, non-inferiority, phase 3 trial. We enrolled patients from 98 hospitals in Japan, China, and South Korea who were aged 20 years or older with histologically confirmed and unresectable colorectal adenocarcinoma, and who had withdrawn from first-line chemotherapy for metastatic colorectal cancer. We randomly assigned patients (1:1) to receive either mXELIRI with or without bevacizumab (irinotecan 200 mg/m2 intravenously on day 1 plus oral capecitabine 800 mg/m2 twice daily on days 1–14, repeated every 21 days, with or without bevacizumab 7·5 mg/kg intravenously on day 1) or FOLFIRI with or without bevacizumab (irinotecan 180 mg/m2 intravenously on day 1, leucovorin 200 mg/m2 intravenously on day 1, fluorouracil 400 mg/m2 intravenously on day 1, and a 46-h continuous intravenous infusion of fluorouracil [2400 mg/m2], repeated every 14 days, with or without the addition of bevacizumab 5 mg/kg intravenously on day 1) via a centralised electronic system. We used the minimisation method to stratify randomisation by country, Eastern Cooperative Oncology Group performance status, number of metastatic sites, previous oxaliplatin treatment, and concomitant bevacizumab treatment. Patients and clinicians were not masked to the allocated treatment. The primary endpoint was overall survival analysed on an intention-to-treat basis with a non-inferiority upper margin of 1·30 for the hazard ratio (HR). This study is registered with ClinicalTrials.gov, number NCT01996306, and is ongoing but no longer recruiting participants.

Findings

Between Dec 2, 2013, and Aug 13, 2015, 650 patients were enrolled and randomly assigned to receive mXELIRI with or without bevacizumab (n=326) or FOLFIRI with or without bevacizumab (n=324). After a median follow-up of 15·8 months (IQR 8·7–24·9), a total of 490 patients had died (242 in the mXELIRI with or without bevacizumab group and 248 in the FOLFIRI with or without bevacizumab group) and the median overall survival was 16·8 months (95% CI 15·3–19·1) in the mXELIRI group and 15·4 months (13·0–17·7) in the FOLFIRI group (HR 0·85, 95% CI 0·71–1·02; pnon-inferiority<0·0001). In the per-protocol safety population, the most common grade 3–4 adverse event was neutropenia (affecting 52 [17%] of 310 patients in the mXELIRI group and 133 [43%] of 310 in the FOLFIRI group). Incidences of grade 3–4 diarrhoea were higher in the mXELIRI group (22 [7%]) than in the FOLFIRI group (ten [3%]). Serious adverse events were reported in 46 (15%) of 310 patients in the mXELIRI group and 63 (20%) of 310 in the FOLFIRI group. Two treatment-related deaths (one pneumonitis and one lung infection) were observed in the mXELIRI group and there was one treatment-related death (lung infection) in the FOLFIRI group.

Interpretation

mXELIRI with or without bevacizumab is well tolerated and non-inferior to FOLFIRI with or without bevacizumab in terms of overall survival. mXELIRI could be an alternative to FOLFIRI as a standard second-line backbone treatment for metastatic colorectal cancer, at least for Asian patient populations.

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