Segelov Eva, Waring Paul, Desai Jayesh, Wilson Kate, Gebski Val, Thavaneswaran Subotheni, Elez Elena, Underhill Craig, Pavlakis Nick, Chantrill Lorraine, Nott Louise, Jefford Michael, Khasraw Mustafa, Day Fiona, Wasan Harpreet, Ciardiello Fortunato, Karapetis Chris, Joubert Warren, van Hazel Guy, Haydon Andrew, Price Tim, Tejpar Sabine, Tebbutt Niall, Shapiro Jeremy
St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
University of Melbourne, Melbourne, Australia.
BMC Cancer. 2016 May 31;16:339. doi: 10.1186/s12885-016-2389-8.
Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are "wild type"). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a "quadruple wild type" tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent.
ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with "quadruple wild type" or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer.
This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the "quadruple wild type", which may 'superselect' for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups.
Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808 , registered 16 August 2012.
接受含奥沙利铂和伊立替康方案治疗后疾病进展的转移性结直肠癌患者，如果其KRAS基因未发生突变（即“野生型”），可能从表皮生长因子受体（EGFR）抑制性单克隆抗体中获益。目前尚不清楚这些抗体，如西妥昔单抗，在难治性转移性结直肠癌中作为单药治疗还是与伊立替康联合使用时疗效更佳。KRAS、BRAF和PIK3CA基因无突变预示着对EGFR抑制剂有反应。ICECREAM试验在两组患者中研究了单药治疗与化疗联合治疗的问题：一组为“四重野生型”肿瘤基因型（KRAS、NRAS、PI3KCA或BRAF基因均无突变），另一组为密码子G13D发生特定KRAS突变的患者，对于后者，EGFR抑制剂的疗效可能相当。
ICECREAM是一项随机、II期、开放标签、对照试验，比较西妥昔单抗单药或与伊立替康联合用于“四重野生型”或G13D突变型转移性结直肠癌患者的疗效，这些患者接受含奥沙利铂和氟嘧啶的化疗后疾病进展或不耐受该化疗。主要终点是治疗方案的6个月无进展生存获益。次要终点是缓解率、总生存期和生活质量。三级终点是用其他生物学标志物预测预后。国际合作促进了在这项前瞻性试验中招募这些在结直肠癌中不常见分子亚组的患者进行治疗。
这项独特的试验将提供关于西妥昔单抗疗效的前瞻性信息，以及在两组不同的转移性结直肠癌患者中化疗是否能进一步增强其疗效：“四重野生型”患者，这类患者可能“超选择”出对EGFR抑制敏感的肿瘤；以及罕见的KRAS G13D突变肿瘤，据推测这类肿瘤对该药物也敏感。专注于确定靶向治疗反应的阳性和阴性预测因素，旨在改善治疗结果、降低毒性并控制治疗成本。组织和血液将为分子研究提供资源。招募患者，特别是具有罕见G13D突变的患者，将证明国际合作在小的结直肠癌分子亚组中开展前瞻性试验的能力。
澳大利亚和新西兰临床试验注册中心：ACTRN12612000901808，于2012年8月16日注册。
