Date Published: February 6, 2018
Publisher: Public Library of Science
Author(s): Xuan Li, Danian Dai, Bo Chen, Hailin Tang, Xiaoming Xie, Weidong Wei, Marco Falasca.
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 meta-analysis to assess the clinical effect of using PI3K/AKT/mTOR pathway inhibitors on advanced solid tumours.
All 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.
In 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).
Our 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.
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. Three classes of PI3K enzymes (Class I, II, III PI3K) are expressed in human cells, and the lipid product of class I PI3Ks activates the downstream kinase AKT (AKT1, AKT2, AKT3). The mTOR protein has two cellular complexes (mTORC1 and mTORC2), one of which (mTORC1) is a key node in cell growth that can be activated by PI3K/AKT signals or signals from other pathways[3, 4]. Activating mutations in the PI3K pathway are commonly found in solid cancers; in advanced cancers, this mutation rate can increase by 30% -60% in different tumour types, such as breast cancer, gastric cancer and colorectal cancer[5–8].
This study found 3579 potentially relevant articles, but 559 studies were excluded because they were duplicate reports. After a carefully review of the remaining studies, the full texts of 46 RCT studies were included in the final analysis (Fig 1). All included studies focused on advanced or metastatic solid tumours. Twelve studies focused on breast cancer[17–28], 13 on renal cancer[29–41], 4 on lung cancer[42–45], 4 on neuroendocrine tumors[46–49], 3 on gastrointestinal cancer[50–52], 3 on head and neck squamous cell cancer[53–55], 2 on sarcomas[56, 57], 1 on liver cancer, 1 on pancreatic cancer, 1 on endometrial cancer, 1 on glioblastoma and 1 on melanoma.The basic characteristics of the studies are outlined in Table 1. A total of 15511 cases were included in the meta-analysis, namely, 8478 cases in the experimental groups and 7033 cases in the control groups. Nineteen phase III RCT studies and 27 phase II RCT studies were analysed. A total of 32 studies reported mTOR inhibitors, 9 reported PI3K inhibitors, 4 reported AKT inhibitors and 1 reported PI3K/AKT/mTOR pathway inhibitors. The Egger’ s test results were P > |t| = 0.230 for PFS and P > |t| = 0.957 for OS showing no significant publication bias in this analysis. The Jadad score of the studies included in the meta-analysis ranged from 4 to 5. Thus, all studies were of good quality (Table 1 and S2 Table).
This systematic review and meta-analysis, which included 46 randomized controlled trials with a total of 15511 patients and more than 100 arms, was conducted to fully assess the effect of PI3K pathway inhibitors on solid tumours. Our analysis showed that the addition of PI3K pathway inhibitors significantly improves the PFS of subjects with in advanced solid cancers, although their efficacy differed among tumour types. We found that most trials focused on breast cancer, renal cancer, lung cancer, gastrointestinal cancer, head and neck squamous cell cancer and neuroendocrine tumours. Our analysis results suggest that the PI3K/AKT/mTOR inhibitors added to the therapy regimen significantly improved the PFS especially among patients with breast cancer and neuroendocrine tumours. Patients with mutations in the PI3K pathway may benefit more from treatment with PI3K pathway inhibitors than patients without mutations based on the PFS. The pooled results showed no improvement in OS inhibitors or in ORR as a result of the treatment of advanced solid tumours with PI3K pathway inhibitors.
Our meta-analysis results suggest that the addition of PI3K pathway inhibitors to the therapy regimens for advanced solid tumours significantly improved the PFS, especially among patients with breast cancer and neuroendocrine tumours and those with PI3K mutations. However, this study was unable to observe improvements in the OS and ORR as a result of PI3K pathway inhibitors. Considering the side effects of PI3K pathway inhibitors when these drugs are used, the risk-benefit analysis must be carefully performed. In the future, more studies that are focused on selected types of cancers will be required to identify suitable patients who will benefit the most from therapies with PI3K pathway inhibitors.