Improved endpoints for cancer immunotherapy trials.
Improved endpoints for cancer immunotherapy trials.
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DOI：
10.1093/jnci/djq310
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发表时间：
2010-09-22
期刊：
影响因子：
--
通讯作者：
Wolchok J
中科院分区：
文献类型：
--
作者：
Hoos A;Eggermont AM;Janetzki S;Hodi FS;Ibrahim R;Anderson A;Humphrey R;Blumenstein B;Old L;Wolchok J
与直接作用于肿瘤的化疗不同，癌症免疫疗法对免疫系统产生影响，并表现出新的动力学，涉及建立细胞免疫应答，随后改变肿瘤负荷或患者生存率。因此，一些免疫治疗临床试验的充分设计和评价需要一个新的开发范式，包括重新考虑既定的终点。在2004年至2009年期间，由癌症研究所癌症免疫治疗联盟和合作伙伴组织推动的几项倡议系统地评估了以免疫治疗为中心的临床开发范式，并制定了重新定义试验终点的原则。在此基础上，生成了一系列支持三个新终点建议的临床和实验室数据。首先，细胞免疫应答测定产生高度可变的结果。多中心试验中的测定协调可以最大限度地减少变异性，并有助于将细胞免疫应答建立为可重复的生物标志物，从而允许研究其与临床结局的关系。其次，免疫疗法可能诱导实体瘤疗效评价标准或世界卫生组织标准未捕获的新型抗肿瘤应答模式。定义了新的免疫相关应答标准，以更全面地捕获所有应答模式。第三，随机免疫治疗试验中Kaplan-Meier曲线的延迟分离会影响结果。改变统计模型，描述风险比作为时间的函数，并认识到曲线分离前后的差异，可以改善III期试验的规划。这些建议可能会改善我们的癌症免疫治疗试验工具，并可能为临床研究提供更现实和有用的模型。
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
8.4
作者：
Copier, J.;Dalgleish, A. G.;Hakansson, L.
通讯作者：
Hakansson, L.
影响因子：
3.9
作者：
Hobeika, AC;Morse, MA;Clay, TM
通讯作者：
Clay, TM
影响因子：
5.8
作者：
Janetzki, S.;Janetzki, S.;Hoos, A.
通讯作者：
Hoos, A.