Drugs targeting PI3K/AKT/mTOR pathway for locally-advanced, metastatic or recurrent endometrial cancer

What is the aim of this review?
To find out whether drugs that inhibit the PI3K/AKT/mTOR pathway (known as PI3K, AKT and mTOR inhibitors) can improve survival of women diagnosed with locally-advanced (cancer that has spread beyond the uterus/womb), metastatic or recurrent endometrial cancer.

Key messages
There is a low certainty of evidence from two clinical trials about the use of drugs targeting PI3K/AKT/mTOR pathway in women with locally-advanced, metastatic or recurrent endometrial cancer. Based on the small number of completed studies, women who have received prior treatment for advanced or recurrent endometrial cancer and received an mTOR inhibitor may have a lower risk of their cancer progressing compared to those who received chemotherapy/hormonal therapy alone. However, in women who received mTOR inhibitor-containing chemotherapy as part of their treatment when first diagnosed with advanced disease, mTOR inhibitor-containing treatment may result in their disease progressing more quickly and probably with increased complications compared to chemotherapy or hormonal therapy alone. Although mTOR inhibitors may change how long it takes for their cancer to progress, there may be little or no difference in how long women lived after treatment (known as overall survival). We await the publication of at least five studies examining the role of PI3K, AKT and mTOR inhibitors in advanced or recurrent endometrial cancer.

What was studied in the review?
Treatment for women with metastatic or recurrent endometrial cancer usually involves radiotherapy, chemotherapy, endocrine therapy or a combination of these to try to shrink or slow the growth of the cancer. The response of the cancer to these treatments is variable, but mostly modest. New treatments are needed to improve outcomes. The PI3K/AKT/mTOR pathway within an endometrial cancer cell is involved in the growth of endometrial cancer, and various drugs have been developed to target this pathway with the aim of reducing the growth of endometrial cancer cells. These are known as PI3K, AKT and mTOR inhibitors. We found relevant studies looking at mTOR inhibitors. mTOR inhibitors can be given alone or in combination with other cancer treatment drugs. They may be given along with chemotherapy or endocrine therapy. mTOR inhibitors act by blocking cancer cells from dividing and reproducing. Their adverse events can include ulcers along the digestive tract (known as mucositis), inflammation of lung tissues (known as pneumonitis) and low red blood cell counts (anaemia).

We include two studies that randomised 361 women. In one study, women received either an mTOR inhibitor (temsirolimus) in combination with other chemotherapy drugs, or the same chemotherapy drugs without the mTOR inhibitor and with a different targeted therapy (bevacizumab). This was given as part of their 'first-line' treatment after their initial diagnosis of advanced endometrial cancer. In the second study, women with recurrent disease or who had been treated with chemotherapy at least once before received an mTOR inhibitor (ridaforolimus) on its own, compared with a chemotherapy or hormonal therapy and no mTOR inhibitor.

What are the main results of the review?
For women who received mTOR inhibitor drugs as part of their first treatment, there may be a higher risk of disease worsening with an mTOR inhibitor than with conventional treatment and bevacizumab. However, for women with recurrent disease who had received chemotherapy previously, receiving an mTOR inhibitor drug may reduce the risk of the disease worsening compared to further chemotherapy or hormonal treatments. These results are based on one study only in each treatment setting.

There were side effects from mTOR inhibitors. Women may be more likely to experience ulcers within the digestive tract with mTOR inhibitors than women who received treatments without these drugs. There was probably little or no difference in the rates of inflammation of the lungs or anaemia between those who received mTOR inhibitors and those who did not, although we have only low certainty evidence about the result. None of the studies reported quality-of-life information.

There are five clinical trials currently recruiting women. We hope to have a clearer answer in the next update of this review, once data from these studies are available.

How up-to-date is this review?
We searched for studies that had been published up to January 2019.

Authors' conclusions: 

Two RCTs have been reported to date, with low certainty of evidence. In a recurrent disease setting, mTOR inhibitors may result in improved progression-free survival, but we found no clear benefit in overall survival or tumour response rate. We await the publication of at least five ongoing studies investigating the role of PI3K/AKT/mTOR inhibitors in advanced or recurrent endometrial cancer before any conclusions can be drawn on their use.

Read the full abstract...
Background: 

Endometrial cancer is one of the most common gynaecological cancers in developed countries. Treatment of advanced endometrial cancer usually involves radiotherapy, chemotherapy, endocrine therapy or a combination of these. However, survival outcomes are poor in advanced or metastatic disease. Better systemic treatment options are needed to improve survival and safety outcomes for these women. The PI3K/AKT/mTOR pathway is a frequently altered signalling pathway in endometrial cancer. Single-arm studies have reported some encouraging results of the PI3K/AKT/mTOR inhibition in advanced or recurrent endometrial cancer.

Objectives: 

To assess the efficacy and safety of PI3K/AKT/mTOR inhibitor-containing regimens in women with locally-advanced, metastatic or recurrent endometrial cancer.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase to 16 January 2019; and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov in July 2018. We also reviewed reference lists from included studies and endometrial cancer guidelines.

Selection criteria: 

We included randomised controlled trials (RCTs) comparing a regimen with a PI3K/AKT/mTOR inhibitor (either alone or in combination with other treatments, such as chemotherapy or hormonal therapy) versus a comparator regimen without a PI3K/AKT/mTOR inhibitor. There were no restrictions on which comparator(s) were included.

Data collection and analysis: 

We extracted data independently, and assessed risks of bias and the certainty of the evidence. The primary outcome measures were progression-free survival and toxicity (grade 3/4 where available). We derived hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes. Secondary outcomes included overall survival, objective tumour response rate, quality of life and treatment-related death. We used GRADEproGDT to assess the certainty of the evidence for the most important outcomes (by first-line and second/third-line therapy for progression-free survival and overall survival).

Main results: 

We included two RCTs involving 361 women. One study assessed the effects of the mTOR inhibitor temsirolimus, in combination with carboplatin/paclitaxel versus carboplatin/paclitaxel and bevacizumab in treatment-naïve women with advanced or recurrent endometrial cancer. The second study compared the mTOR inhibitor ridaforolimus alone versus progestin or investigator choice of chemotherapy in women who had received prior treatment for metastatic or recurrent endometrial cancer. We identified five ongoing studies on the effects of PI3K and AKT inhibitors, metformin and dual mTOR inhibitors.

For first-line therapy, an mTOR inhibitor-containing regimen may worsen progression-free survival (HR 1.43, 95% CI 1.06 to 1.93; 1 study, 231 participants; low-certainty evidence), while for second/third-line therapy, an mTOR inhibitor probably improves progression-free survival compared to chemotherapy or endocrine therapy (HR 0.53, 95% CI 0.31 to 0.91; 1 study, 95 participants; moderate-certainty evidence). Data on toxicity were available from both studies: administering an mTOR inhibitor regimen may increase the risk of grade 3/4 mucositis (RR 10.42, 95% CI 1.34 to 80.74; 2 studies, 357 participants; low-certainty evidence), but may result in little to no difference in risk of anaemia or interstitial pneumonitis (low-certainty evidence for both toxicities). Overall, event rates were low. For first-line therapy, an mTOR inhibitor-containing regimen may result in little to no difference in overall survival compared to chemotherapy (HR 1.32, 95% CI 0.98 to 1.781 study, 231 participants; low-certainty evidence). The finding was similar for second/third-line therapy (HR 1.06, 95% CI 0.70 to 1.61; 1 study, 130 participants; low-certainty evidence). Administering mTOR inhibitor-containing regimens may result in little to no difference in tumour response compared to chemotherapy or hormonal therapy in first-line or second/third-line therapy (first line: RR 0.93, 95% CI 0.75 to 1.17; 1 study, 231 participants; second/third line: RR 0.22, 95% CI 0.01 to 4.40; 1 study, 61 participants; low-certainty evidence).

Neither study collected or reported quality-of-life data.

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