Department of Medical Oncology, Dana-Farber Cancer Institute, Wayland, MA, USA.
AstraZeneca, Gaithersburg, MD, USA.
Clin Ther. 2020 Oct;42(10):1955-1974.e15. doi: 10.1016/j.clinthera.2020.08.017. Epub 2020 Oct 6.
The goal of this study was to estimate the relative efficacy of acalabrutinib (monotherapy and in combination with obinutuzumab) compared with standard frontline treatments for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, through a network meta-analysis (NMA).
The efficacy of acalabrutinib from ELEVATE-TN (study of Obinutuzumab + Chlorambucil, Acalabrutinib [ACP-196] + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL) was compared to bendamustine + rituximab, chlorambucil-based therapy, alemtuzumab, ibrutinib mono/combination therapy and venetoclax + obinutuzumab using data from eight randomized controlled trials (RCTs). Relevant RCTs were identified using a systematic literature review. Two evidence networks were constructed: Network A, composed solely of RCTs that met the inclusion criteria; and Network B, composed of 7 RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil + obinutuzumab from iLLUMINATE. Bayesian NMAs were conducted on progression-free survival (PFS) and overall survival (OS) endpoints; results were reported by using hazard ratios (HRs) and 95% credible intervals (CrIs). HRs were considered significant if their CrIs did not cross 1. Treatments were ranked by using the surface under the cumulative ranking area (SUCRA) values. Expert opinion from 2 hematologists was sought to validate results.
Both networks showed a significant improvement in PFS for acalabrutinib + obinutuzumab over all comparators. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B. Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax + obinutuzumab in Network B but not Network A. Although OS HRs all favored acalabrutinib, most were not significant and were characterized by wide CrIs, indicating a high level of uncertainty. Acalabrutinib + obinutuzumab ranked highest in terms of PFS improvement (SUCRA values, 98% and 100%) and OS improvement (SUCRA values, 92% and 94%), followed by acalabrutinib monotherapy (SUCRA values for PFS, 88% and 90%; OS, 83% and 87%) in Networks A and B, respectively.
Acalabrutinib was associated with favorable PFS and OS compared with frontline CLL therapies and ranked highest in treatment efficacy over the other comparators. The NMA was limited by heterogeneity in patient baseline characteristics across trials, variable treatment regimens, and short study follow-up times. Despite these limitations, the NMA provides insights into the relative efficacy of acalabrutinib compared with frontline CLL therapies in the absence of head-to-head clinical trials.
本研究旨在通过网络荟萃分析（NMA），评估阿卡鲁胺（单药治疗和与奥滨尤妥珠单抗联合治疗）在氟达拉滨不耐受的慢性淋巴细胞白血病（CLL）患者中的相对疗效，与标准一线治疗相比。
ELEVATE-TN 研究（奥滨尤妥珠单抗联合苯丁酸氮芥、阿卡鲁胺联合奥滨尤妥珠单抗和阿卡鲁胺治疗未经治疗的 CLL 患者）中阿卡鲁胺的疗效与苯达莫司汀+利妥昔单抗、氯苯丁酸氮芥为基础的治疗、阿仑珠单抗、伊布替尼单药/联合治疗和 Venetoclax+奥滨尤妥珠单抗进行比较，使用了来自八项随机对照试验（RCT）的数据。通过系统文献回顾确定了相关 RCT。构建了两个证据网络：网络 A，仅由符合纳入标准的 RCT 组成；网络 B，由 7 项 RCT 和一项来自 RESONATE-2 的伊布替尼与氯苯丁酸氮芥+奥滨尤妥珠单抗的交叉试验比较的已发表内容组成。对无进展生存期（PFS）和总生存期（OS）终点进行贝叶斯 NMA；结果以风险比（HR）和 95%可信区间（CrI）报告。如果 CrI 不跨越 1，则认为 HR 有意义。使用累积排序区域（SUCRA）值对治疗进行排名。寻求了两位血液学家的专家意见以验证结果。
两个网络均显示阿卡鲁胺联合奥滨尤妥珠单抗与所有比较药物相比，PFS 有显著改善。两个网络还显示阿卡鲁胺单药治疗与大多数比较药物相比，PFS 有显著改善，在网络 A 中发现与伊布替尼单药治疗有显著差异，但在网络 B 中没有。相反，在网络 B 中，阿卡鲁胺单药治疗与 Venetoclax+奥滨尤妥珠单抗相比，PFS 有显著差异，但在网络 A 中没有。尽管 OS HR 均有利于阿卡鲁胺，但大多数均无统计学意义，且 CrI 较宽，表明存在高度不确定性。阿卡鲁胺联合奥滨尤妥珠单抗在 PFS 改善方面（SUCRA 值，98%和 100%）和 OS 改善方面（SUCRA 值，92%和 94%）均排名最高，其次是阿卡鲁胺单药治疗（网络 A 和 B 中 PFS 的 SUCRA 值分别为 88%和 90%；OS 为 83%和 87%）。
阿卡鲁胺与 CLL 一线治疗相比，PFS 和 OS 均有改善，在与其他比较药物的疗效比较中排名最高。NMA 受到试验间患者基线特征的异质性、不同的治疗方案和较短的研究随访时间的限制。尽管存在这些限制，但 NMA 提供了关于阿卡鲁胺与 CLL 一线治疗相比的相对疗效的见解，而无需头对头的临床试验。
