Abstract：
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.
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.
We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I2 = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAFv600 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%, I2 = 0%) and 27% (95%-CI 10-48%, I2 = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients.
MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAFv600 mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.
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.
We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I2 = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAFv600 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%, I2 = 0%) and 27% (95%-CI 10-48%, I2 = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients.
MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAFv600 mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.
摘要：
背景：RAS/RAF/MEK/ERK（MAPK）通路在卵巢癌的发生中起作用。低级别浆液性卵巢癌（LGSOC）经常携带激活MAPK突变。MAPK抑制剂已用于卵巢癌（OC）患者的小亚群，以控制肿瘤的生长。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.我们的目的是确定临床获益率(CBR)，具有最佳CBR和总体反应率（ORR）的MAPK抑制剂亚组，和最常见的不良事件。
方法：我们在PubMed中进行了搜索，Embase通过Ovid,Cochrane文库和clinicaltrials.gov关于评估用MAPK途径抑制剂对OC患者单MAPK途径抑制的有效性的研究。我们的主要结果包括CBR，由疾病稳定(SD)患者的比例定义，完全缓解（CR）和部分缓解（PR）。次要结果包括ORR（包括PR和CR）以及3级和4级不良事件。采用随机效应模型进行Meta分析。
结果：我们纳入了9项研究，共319名OC患者，为此，我们确定了63%的合并CBR(95%-CI39-84%，I2=92%)。在BRAFv600突变的LGSOC（n=6）中，Raf-和MEK抑制剂的联合治疗具有最大的疗效，CBR为100％，ORR为83％。MEK抑制剂作为单一药剂具有最好的功效。通过肿瘤组织学亚组分析显示，LGSOC患者的CBR和ORR明显更高，合并的CBR和ORR为87%(95%-CI81-92%，I2=0%)和27%(95%-CI10-48%，I2=77%)。经常报告3级或更高的不良事件：167例患者中有123例。
结论：MEK抑制剂是（LGS）OC中最有前途的单一药物。然而,BRAFv600突变患者应考虑双重MAPK通路抑制，或未突变的OC，由于具有更高的疗效和可耐受的毒性谱的适应症，因此具有耗尽的治疗选择。
方法：我们在PubMed中进行了搜索，
结果：我们纳入了9项研究，共319名OC患者，
结论：MEK抑制剂是（LGS）OC中最有前途的单一药物。
