Lau David, Kalaitzaki Eleftheria, Church David N, Pandha Hardev, Tomlinson Ian, Annels Nicola, Gerlinger Marco, Sclafani Francesco, Smith Gillian, Begum Ruwaida, Crux Richard, Gillbanks Angela, Wordsworth Sarah, Chau Ian, Starling Naureen, Cunningham David, Dhillon Tony
Royal Marsden Hospital NHS Foundation Trust, London, UK.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, UK.
ESMO Open. 2020 Feb;5(1). doi: 10.1136/esmoopen-2019-000638.
10%-15% of early-stage colon cancers harbour either deficient mismatch repair (dMMR), microsatellite instability high (MSI-H) or exonuclease domain mutations, and are characterised by high tumour mutational burden and increased lymphocytic infiltrate. Metastatic dMMR colon cancers are highly sensitive to immune checkpoint inhibition, and recent data show -mutant tumours are similarly responsive. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody avelumab following adjuvant chemotherapy improves disease-free survival (DFS) in patients with stage III dMMR/MSI-H or mutant colon cancer and is a cost-effective approach for the UK National Health Service (NHS).
We are recruiting patients with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H, locally or exonuclease domain mutation on central testing. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (capecitabine, oxaliplatin for 12 weeks or capecitabine for 24 weeks) or chemotherapy, followed by avelumab (10 mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR/MSI-H status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life and health resource use. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (ie, 87%). Target accrual is 402 patients, which provides 80% power to detect an HR of 0.48 for DFS at a two-sided alpha of 0.05. This national, multicentre phase III trial is sponsored by the Royal Marsden NHS Foundation Trust and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018.
NCT03827044.
10%-15%的早期结肠癌存在错配修复缺陷（dMMR）、微卫星高度不稳定（MSI-H）或外切酶结构域突变，其特征为肿瘤突变负荷高和淋巴细胞浸润增加。转移性dMMR结肠癌对免疫检查点抑制高度敏感，近期数据显示 -突变肿瘤也有类似反应。我们正在进行一项III期随机试验，以确定在辅助化疗后添加抗PD-L1抗体阿维鲁单抗是否能改善III期dMMR/MSI-H或 突变结肠癌患者的无病生存期（DFS），以及该方法对英国国家医疗服务体系（NHS）而言是否具有成本效益。
我们正在招募经中央检测确诊为dMMR/MSI-H、局部或外切酶结构域突变的III期结肠癌完全切除患者。符合条件的患者按1:1比例随机分为基于氟嘧啶的标准化疗组（卡培他滨、奥沙利铂治疗12周或卡培他滨治疗24周）或化疗后使用阿维鲁单抗组（10mg/kg，每2周一次，共24周）。分层因素为所接受的化疗和MMR/MSI-H状态。主要终点为DFS。次要终点包括总生存期、毒性、生活质量和卫生资源利用情况。预计对照组的3年DFS率约为75%。阿维鲁单抗预计将使3年DFS率提高12%（即87%）。目标入组患者为402例，这将提供80%的检验效能，在双侧α为0.05时检测出DFS的风险比为0.48。这项全国性、多中心III期试验由皇家马斯登国民保健服务信托基金赞助，预计英国约40个中心将参与。本研究于2018年8月开始招募患者。
NCT03827044。
