Hybrid-control arm construction using historical trial data for an early-phase, randomized controlled trial in metastatic colorectal cancer.
Hybrid-control arm construction using historical trial data for an early-phase, randomized controlled trial in metastatic colorectal cancer.
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DOI：
10.1038/s43856-022-00155-y
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发表时间：
2022
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二线以上转移性结直肠癌患者的治疗仍然具有挑战性，突出了对在既往二线治疗期间或之后发生疾病进展的患者进行联合治疗的早期试验的必要性。在这些试验中利用混合对照设计可以保留随机化的益处，同时通过整合历史试验数据来加强证据。已经建立了一些例子来评估这种设计在支持早期转移性结直肠癌试验中的适用性。MORPHEUS-CRC是一项伞形、多中心、开放标签、Ib/II期、随机、对照试验（NCT 03555149），活性试验组正在进行中。入选的患者被分配到对照组（瑞格非尼，15例患者随机化，13例分析）或多个实验组，用于基于免疫疗法的治疗组合。完成了一个实验组（atezolizumab + isatuximab，15例患者接受随机化和分析），并将其纳入混合对照研究，其中混合对照组通过整合IMblaze 370 III期试验（NCT 02788279）的数据构建。为了估计治疗疗效，在具有标准化死亡率加权的频率论框架或具有相称先验的贝叶斯框架中使用考克斯和逻辑回归模型。主要终点是客观缓解率，而疾病控制率、无进展生存期和总生存期是混合对照研究中评估的结局。在MORPHEUS-CRC试验中，实验组未显示有效性信号，但安全性特征耐受良好。混合对照设计中估计的治疗效果与使用频率论或贝叶斯模型的MORPHEUS-CRC试验中的治疗效果相当。混合控制提供了可比的治疗效果估计与一般提高精度，因此可以告知转移性结直肠癌的早期临床开发的价值。转移性结直肠癌患者的治疗-这意味着它已经扩散到身体的其他部位-是困难的，当标准疗法停止工作时，患者需要新的疗法。我们在一项临床试验中比较了转移性结直肠癌患者的药物组合与标准治疗，其中患者被随机分配到组合或对照（标准）治疗。我们发现，虽然这种组合是安全的，但它并不有效。然而，我们也表明，我们可以将我们的对照组和以前试验的对照组的数据联合收割机结合起来，以更精确地估计治疗效果。诸如此类的统计方法将试验数据联合收割机组合起来，可能意味着在未来的试验中必须招募更少的患者进入对照组，以改善获得潜在有效的新治疗方法的机会。Li et al.报告了在转移性结直肠癌患者中开展的Ib/II期MORPHEUS-CRC试验的atezolizumab/isatuximab组的结局。此外，作者利用III期IMblaze 370研究的历史对照数据提供更精确的治疗效果估计。
Treatment for metastatic colorectal cancer patients beyond the second line remains challenging, highlighting the need for early phase trials of combination therapies for patients who had disease progression during or following two prior lines of therapy. Leveraging hybrid control design in these trials may preserve the benefits of randomization while strengthening evidence by integrating historical trial data. Few examples have been established to assess the applicability of such design in supporting early phase metastatic colorectal cancer trials. MORPHEUS-CRC is an umbrella, multicenter, open-label, phase Ib/II, randomized, controlled trial (NCT03555149), with active experimental arms ongoing. Patients enrolled were assigned to a control arm (regorafenib, 15 patients randomized and 13 analysed) or multiple experimental arms for immunotherapy-based treatment combinations. One experimental arm (atezolizumab + isatuximab, 15 patients randomized and analysed) was completed and included in the hybrid-control study, where the hybrid-control arm was constructed by integrating data from the IMblaze370 phase 3 trial (NCT02788279). To estimate treatment efficacy, Cox and logistic regression models were used in a frequentist framework with standardized mortality ratio weighting or in a Bayesian framework with commensurate priors. The primary endpoint is objective response rate, while disease control rate, progression-free survival, and overall survival were the outcomes assessed in the hybrid-control study. The experimental arm showed no efficacy signal, yet a well-tolerated safety profile in the MORPHEUS-CRC trial. Treatment effects estimated in hybrid control design were comparable to those in the MORPHEUS-CRC trial using either frequentist or Bayesian models. Hybrid control provides comparable treatment-effect estimates with generally improved precision, and thus can be of value to inform early-phase clinical development in metastatic colorectal cancer. Treatment of patients with metastatic colorectal cancer – meaning that it has spread to other parts of the body – is difficult, and new therapies are needed for patients when standard therapies stop working. We compare a combination of drugs with a standard treatment for patients with metastatic colorectal cancer in a clinical trial, in which patients are randomly allocated to either the combination or the control (standard) treatment. We find that while the combination is safe, it isn’t effective. We also show, however, that we can combine data from our control group and the control group of a previous trial to more precisely estimate treatment effects. Statistical approaches such as this to combine data from trials may mean that fewer patients have to be recruited to control groups in future trials, to improve access to potentially effective new treatments. Li et al. report outcomes from the atezolizumab/isatuximab arm of the phase Ib/II MORPHEUS-CRC trial in patients with metastatic colorectal cancer. In addition, the authors leverage historical control data from the phase III IMblaze370 study to provide more precise treatment effect estimates.
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