Hendrikse C S E, Theelen P M M, van der Ploeg P, Westgeest H M, Boere I A, Thijs A M J, Ottevanger P B, van de Stolpe A, Lambrechts S, Bekkers R L M, Piek J M J
Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands; GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands.
Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands.
Gynecol Oncol. 2023 Apr;171:83-94. doi: 10.1016/j.ygyno.2023.01.038. Epub 2023 Feb 24.
BACKGROUND: The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events. METHODS: We conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model. RESULTS: We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAF mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81-92%, I = 0%) and 27% (95%-CI 10-48%, I = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients. CONCLUSIONS: MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAF mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.
背景:RAS/RAF/MEK/ERK(MAPK)通路在卵巢癌发生过程中发挥作用。低级别浆液性卵巢癌(LGSOC)常存在激活的MAPK突变。MAPK抑制剂已用于一小部分卵巢癌(OC)患者以控制肿瘤生长。因此,我们进行了一项荟萃分析以评估MAPK抑制剂在OC患者中的有效性。我们旨在确定临床获益率(CBR)、CBR和总缓解率(ORR)最佳的MAPK抑制剂亚组以及最常见的不良事件。 方法:我们在PubMed、通过Ovid检索的Embase、Cochrane图书馆和clinicaltrials.gov上搜索评估MAPK通路抑制剂单药抑制MAPK通路在OC患者中疗效的研究。我们的主要结局包括CBR,其定义为疾病稳定(SD)、完全缓解(CR)和部分缓解(PR)的患者比例。次要结局包括ORR(包括PR和CR)以及3级和4级不良事件。使用随机效应模型进行荟萃分析。 结果:我们纳入了9项研究,共319例OC患者,我们确定其合并CBR为63%(95%置信区间39 - 84%,I = 92%)。在BRAF突变的LGSOC患者(n = 6)中联合使用Raf和MEK抑制剂疗效最佳,CBR为100%,ORR为83%。MEK抑制剂作为单药疗效最佳。按肿瘤组织学进行的亚组分析显示,LGSOC患者的CBR和ORR显著更高,合并CBR和ORR分别为87%(95%置信区间81 - 92%,I = 0%)和27%(95%置信区间10 - 48%,I = 77%)。经常报告3级或更高等级的不良事件:167例患者中有123例。 结论:MEK抑制剂是(LGS)OC中最有前景的单药。然而,对于BRAF突变患者或因疗效较高且毒性可耐受而治疗选择有限的非突变OC患者,应考虑双重MAPK通路抑制。
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