The Validity of Surrogate Endpoints in Sub Groups of Metastatic Colorectal Cancer Patients Defined by Treatment Class and KRAS Status.
The Validity of Surrogate Endpoints in Sub Groups of Metastatic Colorectal Cancer Patients Defined by Treatment Class and KRAS Status.
复制标题
DOI：
10.3390/cancers14215391
复制
发表时间：
2022-11-01
期刊：
影响因子：
5.2
通讯作者：
Bujkiewicz, Sylwia
中科院分区：
文献类型：
--
作者：
Poad, Heather;Khan, Sam;Wheaton, Lorna;Thomas, Anne;Sweeting, Michael;Bujkiewicz, Sylwia
关键词：
在临床试验中评估新的癌症疗法时，可能需要很长时间才能估计其对总体生存率的有效性，这通常是监管决策者主要感兴趣的结果。为了加快患者获得新疗法的速度，监管机构通常根据替代结果衡量的治疗效果做出决定；例如，研究治疗对延缓癌症复发的影响，这可以更早地测量。为了使此类决策稳健，替代终点必须是总生存期的有效预测因子。验证可能很复杂，之前对晚期结直肠癌的研究表明，替代终点的有效性可能取决于治疗类别。我们对此进行了调查，结果表明，与忽略治疗类别时相比，某些治疗类别中替代终点的有效性更强。替代品的有效性需要仔细考虑，以确保做出适当的监管决策。背景和目的：文献研究结果表明，转移性结直肠癌 (mCRC) 替代终点的有效性可能取决于治疗的作用机制。我们探讨了这一点以及克尔斯滕大鼠肉瘤 (KRAS) 状态对转移性结直肠癌代孕模式的影响。方法：进行系统评价以确定转移性结直肠癌药物治疗的随机对照试验 (RCT)。用于替代终点评估的贝叶斯荟萃分析方法用于根据 KRAS 状态和治疗类别评估所有随机对照试验中的替代关系。探索的替代终点包括无进展生存期 (PFS) 作为总生存期 (OS) 的替代终点，以及肿瘤反应 (TR) 作为 PFS 和 OS 的替代终点。结果：系统评价中确定了 66 项随机对照试验。在所有数据和按 KRAS 状态划分的亚组中，PFS 与 OS 均显示出很强的替代关系。与整体分析相比，个体治疗类别中的相关性似乎更强。研究发现，TR-PFS 和 TR-OS 关系总体较弱，但在表皮生长因子受体 + 化疗（EGFR + 化疗）治疗类别中较强；总体上和野生型 (WT) 患者中的 TR-PFS 均如此，但在数据有限的突变 (MT) KRAS 状态患者中则不然。结论：PFS 似乎是 OS 的良好替代终点。对于 EGFR + 化疗治疗类别，TR 显示与 PFS 和 OS 存在中等替代关系。有一些证据表明作用机制对转移性结直肠癌替代模式的强度有影响，但几乎没有证据表明 KRAS 状态对替代终点有效性的影响。
When evaluating new cancer therapies in clinical trials, it may take a long time to estimate their effectiveness on overall survival, an outcome typically of main interest to regulatory decision-makers. To expedite access to new therapies for patients, regulatory agencies often make their decisions based on treatment effectiveness measured on surrogate outcomes; for example looking at the impact of treatment on delaying cancer recurrence, which can be measured earlier. For such decisions to be robust, a surrogate endpoint needs to be a valid predictor of overall survival. The validation can be complex and previous research in advanced colorectal cancer has suggested that the validity of a surrogate endpoint may depend on treatment class. We have investigated this and our results indicated that the validity of surrogate endpoints is stronger within some treatment classes compared to when ignoring the treatment class. Surrogate’s validity needs careful consideration to ensure appropriate regulatory decisions. Background and Aim: Findings from the literature suggest that the validity of surrogate endpoints in metastatic colorectal cancer (mCRC) may depend on a treatments’ mechanism of action. We explore this and the impact of Kirsten rat sarcoma (KRAS) status on surrogacy patterns in mCRC. Methods: A systematic review was undertaken to identify randomized controlled trials (RCTs) for pharmacological therapies in mCRC. Bayesian meta-analytic methods for surrogate endpoint evaluation were used to evaluate surrogate relationships across all RCTs, by KRAS status and treatment class. Surrogate endpoints explored were progression free survival (PFS) as a surrogate endpoint for overall survival (OS), and tumour response (TR) as a surrogate for PFS and OS. Results: 66 RCTs were identified from the systematic review. PFS showed a strong surrogate relationship with OS across all data and in subgroups by KRAS status. The relationship appeared stronger within individual treatment classes compared to the overall analysis. The TR-PFS and TR-OS relationships were found to be weak overall but stronger within the Epidermal Growth Factor Receptor + Chemotherapy (EGFR + Chemo) treatment class; both overall and in the wild type (WT) patients for TR-PFS, but not in patients with the mutant (MT) KRAS status where data were limited. Conclusions: PFS appeared to be a good surrogate endpoint for OS. TR showed a moderate surrogate relationship with PFS and OS for the EGFR + Chemo treatment class. There was some evidence of impact of the mechanism of action on the strength of the surrogacy patterns in mCRC, but little evidence of the impact of KRAS status on the validity of surrogate endpoints.
登录
查看更多内容
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：
3.8
作者：
Reinacher-Schick A;Schulmann K;Modest DP;Bruns N;Graeven U;Jaworska M;Greil R;Porschen R;Arnold D;Schmiegel W;Tannapfel A
通讯作者：
Tannapfel A
影响因子：
50.5
作者：
Douillard, J. Y.;Siena, S.;Sidhu, R.
通讯作者：
Sidhu, R.
影响因子：
45.3
作者：
Buyse, Marc;Burzykowski, Tomasz;Piedbois, Pascal
通讯作者：
Piedbois, Pascal
影响因子：
4
作者：
Cicero G;De Luca R;Dieli F
通讯作者：
Dieli F