Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature

Abstract

Introduction: While serine-threonine kinases (STK) are attractive therapeutic targets in epithelial ovarian cancer, clinical outcomes of STK inhibitors in the management of recurrent disease have not been completely described.

Areas covered: A systematic literature review of published clinical studies on STK inhibitors targeting mTOR, MAPK, and aurora kinase pathways in recurrent epithelial ovarian cancer was conducted, revealing 18 clinical trials (497 patients). Pooled analyses were performed to assess treatment response, survival time, and adverse events. Median progression-free survival was 3.4 months in STK inhibitor-based therapy, and the average response rate and clinical benefit rate were 13% and 67%, respectively. Among regimens comprised of only STK inhibitors (11 trials, 299 patients), median progression-free time was 2.7 months, response rate was 10%, and clinical benefit rate was 64%. Compared to single STK inhibitor monotherapy (52.5%), clinical benefit rates significantly improved when STK inhibitors were combined with a cytotoxic agent (71.4%), other class biological agent (74.2%), or an additional STK inhibitor (95.0%) (all, P ≤ 0.002).

Expert opinion: STK inhibitor-based therapy showed modest activity for recurrent epithelial ovarian cancer with reasonable clinical benefit rates, suggesting its potential utility for maintaining disease stability if supported by future studies. Efficacy appears greatly improved in appropriately selected patient populations, especially those with low-grade serous ovarian carcinoma, platinum-sensitive disease, cancers with somatic RAS or BRAF mutations, and when used in a combination regimen with a cytotoxic or biological agent.

Keywords: Aurora kinase inhibitor; MAPK inhibitor; MEK inhibitor; STK inhibitor; mTOR inhibitor; metformin; ovarian cancer; sorafenib.

Figure 1.

Selection schema. PubMed was searched on 9/24/2015. Abbreviation: STKi, serine-threonine kinase inhibitors.

Figure 2.

Treatment response based on study regimen and pathway. Response rates and clinical benefit rates broken down by (a) class of drug regimen and (b) STK pathway. mTOR inhibitors represent all STKi falling under the mTOR/AKT/PI3K pathway. Abbreviation: STKi, STK inhibitor.

Figure 3.

Treatment response per individual study regimen. Response rates and clinical benefit rates for each of 20 drug regimens represented in 18 clinical trials included in the analysis, listed in order of decreasing clinical benefit rates. Two trials randomized patients to different treatment regimens, which are listed separately in this table. *clinical benefit rate at least 53% based on best estimation among 51 cases. **SD and PD were not reported and clinical benefit rate is determined by the response rate.

Figure 4.

Correlation of treatment response with progression-free survival. Correlations of (a) response rate and (b) clinical benefit rate with PFS by individual drug regimen. Twelve studies with published PFS data were examined. Median PFS was 3.4 months demarcated horizontal lines. Median response rate was 8.1%, and median clinical benefit rate was 57.6% demarcated by vertical lines. Data points for drug regimens with both response rate and clinical benefit rate, and PFS above the median values for this analysis are labeled. Abbreviations: TC, paclitaxel and carboplatin; and PFS, progression-free survival.