A network meta-analysis of everolimus plus exemestane versus chemotherapy in the first- and second-line treatment of estrogen receptor-positive metastatic breast cancer

Abstract

The goal of this study was to compare the efficacy and toxicity of chemotherapy to exemestane plus everolimus (EXE/EVE) through a network meta-analysis (NMA) of randomized controlled trials. NMA methods extend standard pairwise meta-analysis to allow simultaneous comparison of multiple treatments while maintaining randomization of individual studies. The method enables "direct" evidence (i.e., evidence from studies directly comparing two interventions) and "indirect" evidence (i.e., evidence from studies that do not compare the two interventions directly) to be pooled under the assumption of evidence consistency. We used NMA to evaluate progression-free survival (PFS) and time to progression (TTP) curves in 34 studies, and response rate (RR) and the hazard ratios (HRs) of the PFS/TTP in 36 studies. A number needed to treat (NNT) analysis was also performed as well as descriptive comparison of reported toxicities. The NMA for PFS/TTP curves and for HR shows EXE/EVE is more efficacious than capecitabine plus sunitinib, CMF, megestrol acetate and tamoxifen, with an average of related-PFS/TTP difference ranging from about 10 months for capecitabine plus sunitinib to more than 6 months for tamoxifen. The NMA for overall RR shows that EXE/EVE provides a better RR than bevacizumab plus capecitabine, capecitabine, capecitabine plus sorafenib, capecitabine plus sunitinib, CMF, gemcitabine plus epirubicin plus paclitaxel, EVE plus tamoxifen, EXE, FEC, megestrol acetate, mitoxantrone, and tamoxifen. Finally, the NMA for NNT shows that EXE/EVE is more beneficial as compared to BMF, capecitabine, capecitabine plus sunitinib, CMF, FEC, megestrol acetate, mitoxantrone, and tamoxifen. The combination of EXE/EVE as first- or second-line therapy for ER+ve/HER2-ve metastatic breast cancer is more efficacious than several chemotherapy regimens that were reported in the literature. Toxicities also favored EXE/EVE in most instances.

Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis

“…20 Our data are consistent with previously published net work meta-analyses, although, to our knowledge, this analysis comprises the largest number of randomised controlled trials ever reported in hormone-receptor-positive, HER2-negative metastatic breast cancer and is the first comprehensive network meta-analysis to provide an indirect comparison of all CDK4/6 inhibitors plus aromatase inhibitors or fulvestrant and chemotherapybased regimens. [21][22][23][24] Moreover, this network metaanalysis is the first to include the BOLERO-6 trial, which, despite its small sample size, represents the only contemporary study directly comparing a hormone therapy plus targeted therapy (everolimus plus exemestane) versus chemo therapy (capecitabine), a regimen that is currently used in clinical practice (appendix p 18). 32 Results from the ongoing phase 3 PEARL trial are likely to provide additional evidence on this topic.…”

“…Some records were also retrieved via cross-references from published trials, the main international oncology guide lines, and most updated reviews or meta-analyses of therapeutic strategies in hormone-receptor-positive, HER2-negative metastatic breast cancer. [11][12][13][14][21][22][23][24] Phase 2 or 3 randomised controlled trials published in the form of full papers, or as abstracts if full papers were not available, were included in the analysis. No language restrictions were adopted for our search.…”

Enrichment of PI3K-AKT–mTOR Pathway Activation in Hepatic Metastases from Breast Cancer

“…PIK3CA is the second most commonly mutated gene in hormone receptor–positive breast cancer (5, 6). The inhibitor everolimus, a compound that specifically targets mTOR, a downstream member of the PI3K axis, is selected as an early therapeutic option for metastatic breast cancer patients presenting with well-defined molecular characteristics like ER expression (7–9). The therapeutic efficacy of a number of AKT, PI3K, and mTOR inhibitors is under extremely active clinical investigation for the treatment of breast cancer and many other cancers.…”

RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer

“…39 Although effective new targeted therapies for HER2- negative disease are emerging, they have lagged compared with treatments for HER2-positive disease. Two agents with different mechanisms of action approved to treat metastatic HER2-negative, hormone receptor-positive breast cancer are everolimus, a mammalian target of rapamyc inhibitor, 41,42 and palbociclib, an inhibitor of cyclin-dependent kinases 4 and 6. 7,8 Everolimus is administered with exemestane and palbociclib with letrozole, both aromatase inhibitors.…”