Abstract
BackgroundThe phosphatidylinositol-3- kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) plays a key role in cancer. We performed this meta-analysis to assess the clinical effect of using PI3K/AKT/mTOR pathway inhibitors on advanced solid tumours.MethodsAll the randomised controlled trials (RCT) that compared the therapy with PI3K/AKT/mTOR pathway inhibitors with other therapies were included. The main end-point was progression-free survival (PFS); other end-points included overall survival (OS) and objective response rate (ORR). A subgroup analysis was performed mainly for PFS.ResultsIn total, 46 eligible RCT were included. The pooled results showed that PI3K/AKT/mTOR pathway inhibitor-based regimens significantly improved the PFS of patients with advanced solid tumours (hazard ratios (HR) = 0.79; 95% confidence intervals (CI): 0.71–0.88) and PI3K pathway mutations (HR = 0.69; 95% CI: 0.56–0.85). All single PI3K/AKT/mTOR pathway inhibitor therapies were compared with other targeted therapies (HR = 0.99; 95% CI: 0.93–1.06) and dual targeted therapies, including PI3K/AKT/mTOR pathway inhibitors and other targeted therapies (HR = 1.04; 95% CI: 0.62–1.74), which showed no significant differences in the PFS. Additional PI3K/AKT/mTOR pathway inhibitors showed no advantage with respect to the OS (HR = 0.98; 95% CI: 0.90–1.07) or ORR (risk ratio (RR) = 1.02; 95% CI: 0.87–1.20).ConclusionOur meta-analysis results suggest that the addition of the PI3K pathway inhibitors to the therapy regiment for advanced solid tumours significantly improves PFS. The way that patients are selected to receive the PI3K pathway inhibitors might be more meaningful in the future.
Highlights
The phosphatidylinositol-3- kinase (PI3K)/AKT/mTOR pathway plays a key role in the promotion of cell survival and proliferation in cancers[1, 2], and elevated PI3K pathway signalling seems to be a hallmark of cancer
The pooled results showed that PI3K/AKT/mTOR pathway inhibitor-based regimens significantly improved the progressionfree survival (PFS) of patients with advanced solid tumours (hazard ratios (HR) = 0.79; 95% confidence intervals (CI): 0.71–0.88) and PI3K pathway mutations (HR = 0.69; 95% CI: 0.56–0.85)
All single PI3K/AKT/mTOR pathway inhibitor therapies were compared with other targeted therapies (HR = 0.99; 95% CI: 0.93–1.06) and dual targeted therapies, including PI3K/AKT/mTOR pathway inhibitors and other targeted therapies (HR = 1.04; 95% CI: 0.62–1.74), which showed no significant differences in the PFS
Summary
The PI3K/AKT/mTOR pathway plays a key role in the promotion of cell survival and proliferation in cancers[1, 2], and elevated PI3K pathway signalling seems to be a hallmark of cancer. Many phase I trials of PI3K pathway inhibitors have assessed their anti-tumour activity alone or combined with other therapies, but the dose-limited toxicities have still halted some trials early and have prevented further testing[13,14,15]. Those phase II and III trials that have tested the anti-tumour effects of PI3K pathway inhibitors are disputed, and some actual clinical results are apparently lower than expected. The phosphatidylinositol-3- kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) plays a key role in cancer We performed this metaanalysis to assess the clinical effect of using PI3K/AKT/mTOR pathway inhibitors on advanced solid tumours
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