Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan.
JAMA Netw Open. 2023 Aug 1;6(8):e2326834. doi: 10.1001/jamanetworkopen.2023.26834.
Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown.
To investigate time-dependent changes in the outcomes of bevacizumab therapy.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed.
Bevacizumab treatment vs placebo or no treatment.
Restricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups.
In the ICON7-A cohort (n = 745), restricted mean survival analysis showed that bevacizumab treatment (n = 384) had significantly better progression-free survival (PFS) than the control (n = 361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P < .001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P < .001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P < .001; after, 0.79; 95% CI, 0.63-0.98; P = .04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P < .001; after, 0.71; 95% CI, 0.56-0.90; P < .001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P < .001; after, 0.94; 95% CI, 0.78-1.15; P = .57). In Kaplan-Meier curve image-based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination-associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression.
In ovarian cancer, bevacizumab may reduce progression for approximately 1 year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome.
重要性：尽管贝伐珠单抗已被用于卵巢癌的治疗，但最佳使用方法尚不清楚。
目的：研究贝伐珠单抗治疗的结局随时间的变化。
设计、设置和参与者：本队列研究使用了 7 项之前发表的随机 3 期临床试验的数据（ICON7、GOG-0218、BOOST、GOG-0213、OCEANS、AURERIA 和 MITO16B），这些数据于 2023 年 1 月 10 日至 1 月 31 日从 Pubmed 上获取。从 ICON7 试验的 2 项辅助分析中获取了个体患者数据和肿瘤基因表达谱，生成了 ICON7-A 队列，其中包含 745 例病例。从其他研究中获取了已发表的 Kaplan-Meier 曲线并进行了图形分析。
暴露：贝伐珠单抗治疗与安慰剂或无治疗。
主要结果和测量：在 ICON7-A 队列（n=745）中，限制性平均生存时间和在特定时间点贝伐珠单抗治疗组与对照组之间的进展风险比。
结果：在 ICON7-A 队列（n=745）中，限制性平均生存分析显示，贝伐珠单抗治疗组（n=384）在贝伐珠单抗停药前的无进展生存期（PFS）显著长于对照组（n=361）（限制平均生存时间比值，1.08；95%CI，1.05-1.11；P<0.001），但在贝伐珠单抗停药后 PFS 显著缩短（0.79；95%CI，0.69-0.90；P<0.001），出现反弹。在事后分析中，同源重组缺陷（HRD）（前，1.05；95%CI，1.02-1.09；P<0.001；后，0.79；95%CI，0.63-0.98；P=0.04）和非 HRD 肿瘤（前，1.08；95%CI，1.03-1.15；P<0.001；后，0.71；95%CI，0.56-0.90；P<0.001）的浆液性亚型中同样观察到反弹，而非浆液性亚型则没有（前，1.11；95%CI，1.05-1.18；P<0.001；后，0.94；95%CI，0.78-1.15；P=0.57）。在 Kaplan-Meier 曲线图像分析中，在 ICON7 和 GOG-0218 队列及其按预后因素、同源重组相关突变和化疗敏感性分层的亚组中，均观察到反弹效应的趋势。相比之下，在 GOG-0213、OCEANS、AURERIA 和 MITO16B 研究中，没有观察到这种趋势，这些研究中经历复发的患者在进展前一直接受贝伐珠单抗治疗。
结论和相关性：在卵巢癌中，贝伐珠单抗在开始后约 1 年内可能降低进展风险，但停药后，无论 HRD 状态如何，浆液性亚型的后续进展可能增加。结果表明，在一线治疗中，贝伐珠单抗可能对预后较差、不太可能出现反弹结果的患者更有益。
