Simeone D’Ambrosio , Fabio Salomone , Filippo Vitale , Annarita Avanzo , Angela Viggiano , Luigi Liguori , Roberto Ferrara , Antonio Nuccio , Giuseppe Viscardi , Fabiana Napolitano , Antonio Santaniello , Luigi Formisano , Roberto Bianco , Alberto Servetto
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For each RCT, we collected PFS results by BICR and by local IA. We calculated the discrepancy index (DI) as the ratio of BICR and IA Hazard Ratios (HR<sub>BICR</sub>/HR<sub>IA</sub>) for PFS. An overall DI and relative confidence interval (CI) were calculated using a fixed-effect model weighted for the inverse of variance.</div></div><div><h3>Findings</h3><div>Only 32/140 (22.9 %) RCTs reported both BICR and local IA PFS data, including 17,054 patients. PFS was the sole primary endpoint in 19/32 (59.4 %) and a co-primary endpoint 9/32 (28.2 %) trials. The study design was open label or double-blind in 17/32 (53.1 %) and 15/32 (46.9 %) RCTs, respectively. The overall DI was 1.07 (95 % CI 1.01–1.13; I<sup>2</sup> =0, p = 0.02), revealing a more optimistic analysis of results in favor of local IA. In the 17 open-label trials, the overall DI was 1.09 (95 % CI 1.02–1.17, I2 =0, p = 0.02), revealing a more favorable interpretation of PFS results by local investigators.</div></div><div><h3>Interpretation</h3><div>We found a statistically significant difference between BICR and local IA of PFS in trials of IO in cancer. 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引用次数: 0
摘要
背景：在采用开放标签设计的随机对照试验（RCT）中，研究者对无进展生存期（PFS）事件的评估可能不准确。我们探讨了在晚期癌症免疫疗法（IO）试验中，通过盲法独立中央审查（BICR）或当地研究者评估（IA）对无进展生存期进行评估的差异：我们系统回顾了截至2023年12月发表在PubMed索引期刊上的研究晚期肿瘤IO的RCT文章。对于每项 RCT，我们都收集了 BICR 和当地 IA 的 PFS 结果。我们计算了差异指数（DI），即 BICR 和 IA 的 PFS 危险比（HRBICR/HRIA）。采用方差倒数加权的固定效应模型计算了总体差异指数和相对置信区间（CI）：只有 32/140 项（22.9%）研究同时报告了 BICR 和局部 IA PFS 数据，包括 17,054 名患者。PFS是19/32（59.4%）项试验的唯一主要终点，也是9/32（28.2%）项试验的共同主要终点。17/32（53.1%）和15/32（46.9%）项RCT的研究设计分别为开放标签或双盲。总体DI为1.07 (95 % CI 1.01-1.13; I2 =0, p = 0.02)，显示出更乐观的结果分析有利于局部IA。在17项开放标签试验中，总的DI为1.09（95 % CI 1.02-1.17，I2 =0，P = 0.02），显示当地研究者对PFS结果的解释更为有利：我们发现，在癌症 IO 试验中，BICR 和当地 IA 对 PFS 的判定在统计学上存在显著差异。这些结果表明，在进行IO试验的RCT中，尤其是在开放标签试验中，建议进行双重评估：这项工作得到了 MFAG27826-2022 基金（Alberto Servetto 博士）的支持。
Blinded independent central review versus local investigator assessment of PFS in RCTs of immunotherapy in advanced cancers: A systematic review and meta-analysis
Background
Assessment of Progression-free survival (PFS) events by investigators might be inaccurate in randomized controlled trials (RCTs) with open-label design. We explored differences in PFS evaluated by blinded independent central review (BICR) or local investigator assessment (IA) in trials testing immunotherapy (IO) in advanced cancers.
Methods
We systematically reviewed articles of RCTs investigating IO in advanced tumors, published in PubMed-indexed journals up to December 2023. For each RCT, we collected PFS results by BICR and by local IA. We calculated the discrepancy index (DI) as the ratio of BICR and IA Hazard Ratios (HRBICR/HRIA) for PFS. An overall DI and relative confidence interval (CI) were calculated using a fixed-effect model weighted for the inverse of variance.
Findings
Only 32/140 (22.9 %) RCTs reported both BICR and local IA PFS data, including 17,054 patients. PFS was the sole primary endpoint in 19/32 (59.4 %) and a co-primary endpoint 9/32 (28.2 %) trials. The study design was open label or double-blind in 17/32 (53.1 %) and 15/32 (46.9 %) RCTs, respectively. The overall DI was 1.07 (95 % CI 1.01–1.13; I2 =0, p = 0.02), revealing a more optimistic analysis of results in favor of local IA. In the 17 open-label trials, the overall DI was 1.09 (95 % CI 1.02–1.17, I2 =0, p = 0.02), revealing a more favorable interpretation of PFS results by local investigators.
Interpretation
We found a statistically significant difference between BICR and local IA of PFS in trials of IO in cancer. These results suggest that the double assessment is recommended in RCTs testing IO, especially in open-label trials.
Funding
This work was supported by the MFAG27826–2022 grant (Dr. Alberto Servetto).
期刊介绍：
The European Journal of Cancer (EJC) serves as a comprehensive platform integrating preclinical, digital, translational, and clinical research across the spectrum of cancer. From epidemiology, carcinogenesis, and biology to groundbreaking innovations in cancer treatment and patient care, the journal covers a wide array of topics. We publish original research, reviews, previews, editorial comments, and correspondence, fostering dialogue and advancement in the fight against cancer. Join us in our mission to drive progress and improve outcomes in cancer research and patient care.
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