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
• metformin
• mTOR inhibitor
• ovarian cancer
• sorafenib
• STK inhibitor

Article highlights

• Clinical outcomes of serine-threonine kinase inhibitors targeting mTOR, MAPK, and aurora kinase pathways for recurrent ovarian cancer were examined in 18 clinical trials.

• Median progression-free survival was 3.4 months for STK inhibitor-based therapy with response rate being 13% in largely platinum-resistant study population.

• The main benefit of STK inhibitor-based therapy seems to be its ability to maintain disease stability in ovarian cancer recurrence as the majority of patients undergoing this treatment (67%) attained clinical benefit; however, additional research is needed to support this idea.

• Treatment responses improved when STK inhibitors were combined with other class biological agents or with cytotoxic agents. This was most notable in a single study of multiple STK inhibitors, where both agents may act together to overcome drug resistance. Randomized controlled trials are needed to directly compare the effects of STK inhibitors to cytotoxic chemotherapy.

• Treatment response was significantly improved in selected patient populations with somatic mutations affecting STK inhibitor pathways, with platinum-sensitive disease, and with low-grade serous ovarian carcinoma, indicating the importance of appropriate patient selection when using these drugs.

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Acknowledgements

The authors thank Stephen B Gruber for his scientific advice in the preparation of this study.

Declaration of interest

MA Ciccone is supported by the ARCS Foundation Inc and the Los Angeles founder chapter-Margaret Kersten Ponty Postdoctoral Fellowship. Furthermore, K Matsuo is supported by the Ensign Endowment for Gynecologic Cancer Research. Additionally, A Maoz is supported by the Marita and Gary Robb Postdoctoral Fellowship in Oncology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.