Wong N Z H, Yap D W T, Ong R J M, Zhao J J, Chan Y H, Tey J C S, Sundar R, Lim J S J, Dawood S S
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Haematology-Oncology, National University Cancer Institute, National University Hospital, Singapore.
Ann Oncol. 2023 Oct 21. doi: 10.1016/j.annonc.2023.10.122.
Oral SERDs are a novel drug class that have been developed to counteract resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, with the FDA limiting approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. However, questions remain on whether patients with ESR1wt tumours stand to benefit from oral SERDs.
Manuscripts and conference presentations of Randomised Controlled Trials were extracted after a systematic search of Embase, PubMed and Cochrane from inception until January 21,2023. RCTs investigating the efficacy of oral SERDs versus endocrine therapy for ER positive, HER2 negative advanced breast cancer, and which reported the Kaplan Meier (KM) curves of PFS in the overall and ESR1 mutant (ESR1mt) population were selected. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM curves in all overall and ESR1mt cohorts. A bipartite matching algorithm, KMSubtraction, was used to derive survival data for unreported (ESR1wt) subgroups. An individual patient data (IPD) meta-analysis was then pursued, pooling data by ESR1 mutation status in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Guidelines for IPD.
The randomized clinical trials ACELERA, AMEERA-3, EMERALD and SERENA-2 were included, totalling 1290 patients. In the pooled analysis of the overall cohort, PFS benefit was observed with oral SERDs when compared with treatment of physicians choice (TPC) (HR 0.783, 95%CI 0.681-0.900, p<0.001). In the ESR1mt subgroup, oral SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared to TPC. In the ESR1wt subgroup, oral SERDs demonstrated no significant PFS benefit (HR 0.944, 95%CI 0.783-1.138, p=0.543) when compared to TPC.
The results of this IPD meta-analysis suggests that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup.
口服选择性雌激素受体降解剂（SERDs）是一类新型药物，旨在对抗因ESR1基因突变导致的耐药性。几种SERDs已从2期和3期试验中脱颖而出，尽管在总体人群中具有无进展生存期（PFS）获益，但美国食品药品监督管理局（FDA）仅批准将艾拉司群用于ESR1突变（ESR1mt）肿瘤患者。然而，ESR1野生型（ESR1wt）肿瘤患者是否能从口服SERDs中获益仍存在疑问。
对Embase、PubMed和Cochrane数据库从创建至2023年1月21日进行系统检索，提取随机对照试验的手稿和会议报告。选择研究口服SERDs与内分泌治疗对比用于雌激素受体（ER）阳性、人表皮生长因子受体2（HER2）阴性晚期乳腺癌疗效，且报告了总体人群和ESR1突变（ESR1mt）人群PFS的Kaplan-Meier（KM）曲线的随机对照试验。应用图形重建算法从所有总体和ESR1mt队列中报告的KM曲线估计事件发生时间结局。使用二分匹配算法KMSubtraction推导未报告的（ESR1wt）亚组的生存数据。然后根据系统评价和Meta分析的首选报告项目（PRISMA）和IPD的Cochrane指南，按ESR1突变状态汇总数据进行个体患者数据（IPD）Meta分析。
纳入随机临床试验ACELERA、AMEERA-3、EMERALD和SERENA-2，共1290例患者。在总体队列的汇总分析中，与医生选择的治疗（TPC）相比，口服SERDs观察到PFS获益（风险比[HR]0.783，95%置信区间[CI]0.681-0.900，p<0.001）。在ESR1mt亚组中，与TPC相比，口服SERDs显示PFS改善（HR 0.557，95%CI 0.440-0.705，p<0.001）。在ESR1wt亚组中，与TPC相比，口服SERDs未显示出显著的PFS获益（HR 0.944，95%CI 0.783-1.138，p=0.543）。
该IPD Meta分析结果表明，总体人群中的PFS获益主要由ESR1mt亚组驱动。
