BERKELEY, CA (UroToday.com) - Mammalian target of rapamycin (mTOR) is a molecule that controls a variety of signaling pathways that regulate many facets of cell growth and metabolism.
Everolimus is a synthetic, orally available analogue of rapamycin that works to effectively inhibit mTOR activation thus blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. In the absence of activated mTOR, S6K1 is not phosphorylated, and eIF-4E remains associated with its binding protein, limiting its availability to form eIF-4F complexes. This diminishes translation of certain mTOR-controlled mRNAs and decreases transcription of important genes that regulate cell proliferation and modulate cell death.
Renal cell carcinoma (RCC) is an attractive clinical target for everolimus therapy because of the dysregulated signaling through mTOR, the highly vasculized nature of renal causing RCC to possess a higher concentration of angiogenic factors, the well distribution of TSC, loss of function of the VHL gene in 60% of clear cell RCCs, and the overexpression of TDF-α, which causes RCC growth.
A phase II study treated 37 patients with clear cell RCC with everolimus 10 mg daily orally without interruption (28-day cycle), with dose modifications for toxicity.1 Median progression-free survival (PFS) was 11.2 months, and median overall survival was 22.1 months. Five patients (14%) achieved partial response, 27 patients (73%) achieved stable disease lasting ≥3 months, and 21 patients (57%) achieved stable disease lasting ≥6 months. Grade 3 of 4 adverse events included pneumonitis (18% of patients); transaminase elevations (10% of patients); thrombocytopenia, hyperglycemia, and alkaline phosphatase elevations (8% each of patients); and hyperlipidemia (5% of patients). The study demonstrated encouraging antitumor activity as evidenced by a PFS ≥6 months. Responses to everolimus were noted in several metastatic sites, including lungs, lymph nodes, liver, and bone.
This instigated a pivotal trial of second-line everolimus for advanced clear cell RCC. The phase III study was randomized, double-blind, placebo-controlled and enrolled patients (treatment, n=272; placebo, n=138) with progressive disease that was refractory to sunitinib, sorafenib, or both agents.2 The treatment group received everolimus 10 mg daily. The results indicated a significant difference between both arms of the trial. Those in the treatment group had a PFS of 4 months (vs. 1.9 months in the control group). Eight patients in the treatment group experienced grade 3 pneumonitis, and commonly reported adverse events of mild or moderate severity included stomatitis (107 [40%] patients in the everolimus group vs. 11 [8%] in the placebo group), rash (66 [25%] vs. six [4%]), and fatigue (53 [20%] vs. 22 [16%]). The researchers concluded that everolimus prolonged PFS relative to the placebo in patients with metastatic RCC that had progressed on other targeted therapies. The efficacy and safety results of these trials led to the FDA approval of everolimus 10 mg/day in advanced clear cell RCC in patients who failed treatment with sunitinib or sorafenib.
A number of phase I and phase II clinical trials are currently investigating the optimal use of everolimus in combination therapy as well as for monotherapy. A randomized phase II trial in Europe is using everolimus to treat previously untreated metastatic clear cell RCC to better define the roles of targeted and biological therapies in advanced disease. A phase I trial of everolimus plus sorafenib in 15 patients with clear cell RCC established a maximum tolerated dose of everolimus 10 mg and twice daily sorafenib 400 mg as safe and effective for treating progressive metastatic RCC. The number of adverse events actually decreased as the dose level increased. A phase II study evaluated everolimus and bevacizumab using 48 patients with metastatic clear cell RCC. Partial or minor (10-30% tumor reduction) was observed in 66% of previously untreated patients and 39% of patients who were previously treated with sorafenib and/or sunitinib. A phase I trial is evaluating the combination of everolimus with sorafenib 400 mg twice daily. The toxicity profile was favorable.
Everolimus provides a significant benefit to patients with renal cell carcinoma and has the potential for greater potency when used in combination therapy.
- O’Donnell A, Faivre S, Burris H, et al. Phase I pharmacokinetic and pharmacodynamics study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008;26:1588-95.
- Motzer R, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase III trial. Lancet 2008;372:449-56.
Robert J. Amato, DOa and Mika Stepankiw, MSb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
- Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston (Medical School), Memorial Hermann Cancer Center
- University of Texas Health Science Center at Houston
Robert J. Amato, D.O.
The University of Texas
Memorial Hermann Cancer Center
6410 Fannin St., Suite 830
Houston, TX 77030