Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial.
Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial.
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DOI：
10.1016/s1470-2045(13)70163-3
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Quirke P
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文献类型：
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作者：
Seymour MT;Brown SR;Middleton G;Maughan T;Richman S;Gwyther S;Lowe C;Seligmann JF;Wadsley J;Maisey N;Chau I;Hill M;Dawson L;Falk S;O'Callaghan A;Benstead K;Chambers P;Oliver A;Marshall H;Napp V;Quirke P
针对EGFR的治疗性抗体在晚期结直肠癌中具有活性，但临床试验的结果不一致，而且受益最大的人群也不确定。我们的目的是评估在伊立替康的基础上加用帕尼图单抗治疗晚期结直肠癌。在这项开放的随机试验中，我们从英国的60个中心招募了使用或不使用奥沙利铂的氟嘧啶治疗后进展的晚期结直肠癌患者。从2006年12月到2008年6月，分子未选择的患者被招募为三臂设计，包括伊立替康(对照组)、伊立替康+环孢素组和伊立替康+帕尼图单抗(IRPAN)组。从2008年6月10日起，为了回应新的数据，该试验被修改为前瞻性分层设计，将Panitumumab随机分配给患有KRAS野生型肿瘤的患者；报告了Irinotcan组和Irpan组之间的比较结果。我们使用计算机生成的随机序列(按既往EGFR靶向治疗分层，然后按中心、WHO表现状态、既往奥沙利铂、既往贝伐单抗、既往剂量修改和最佳既往反应)随机将患者分配给伊立替康或伊尔潘。两组患者均接受伊立替康350 mg/m2静脉滴注，每3周一次(如果≥年龄70岁或功能状态2岁，则静脉滴注300 mg/m2)；伊尔潘组同时每3周静脉滴注帕尼单抗9 mg/kg。主要终点是未接受过EGFR靶向治疗的KRAS野生型患者的总存活率，按治疗意向进行分析。对肿瘤DNA进行了KRASC.146、BRAF、NRAS和PIK3CA突变的焦解测序，并分析了预定义的分子亚群与Panitumab效应的相互作用。本研究已注册，编号为ISRCTN93248876。2006年12月4日至2010年8月31日期间，共有1198名患者入选，其中460人为KRAS.12-13患者中的原发人群，61人为野生型肿瘤，以前未接受过EGFR靶向治疗。230例患者随机分为伊立替康组和伊尔潘组各230例。两组总生存期无差异(HR 1·01，95%CI为0·83-1·23；P=0·91)，但IRPAN组的无进展生存期(0·78，0·-0·95；P=0·015)和有效数(79例[34%]对27例[12%]；P<；0·0001)均高于伊立替康组。与伊立替康组相比，伊立替康组更常见的是3级或更严重的腹泻(219例患者中[29%]对218例患者中39[18%])、皮肤毒性(41[19%]对无)、嗜睡(45[21]%对24[11%])、感染(42[19%]对22[10%])和血液毒性(48[22%]对27[12%])。我们记录了5例与治疗相关的死亡，其中2例发生在伊尔潘组，3例发生在伊立替康组。在伊立替康中加入帕尼图单抗并不能改善野生型KRAS肿瘤患者的总体存活率。需要进一步改进分子选择，才能从EGFR靶向剂中获得实质性的好处。英国安进癌症研究公司。
Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks (300 mg/m2 if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12–13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83–1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64–0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. Cancer Research UK, Amgen Inc.