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Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III
Robert J Motzer1, Bernard Escudier, Stéphane Oudard
1Memorial Sloan-Kettering Cancer Center, New York, NY, USA. motzerr@mskcc.org
Background:
Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy.
Methods:
Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124.
Findings:
All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). 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%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity.
Interpretation:
Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.
Insights
Everolimus significantly improved progression-free survival in metastatic renal cell carcinoma patients who progressed on targeted therapies. This mTOR inhibitor offers a new treatment option, demonstrating superior efficacy over placebo.
Area of Science:
- Oncology
- Pharmacology
Background:
- Metastatic renal cell carcinoma (mRCC) is a complex cancer.
- Vascular endothelial growth factor-targeted therapies are standard treatments for mRCC.
- Resistance to targeted therapies necessitates alternative treatment strategies.
Purpose of the Study:
- To evaluate the efficacy of everolimus in patients with mRCC.
- To compare progression-free survival (PFS) between everolimus and placebo.
- To assess the safety profile of everolimus in this patient population.
Main Methods:
- A phase III, randomized, double-blind, placebo-controlled trial was conducted.
- Patients with mRCC progressing on sunitinib, sorafenib, or both were enrolled.
- Participants received either everolimus (10 mg daily) or placebo, plus best supportive care.
Main Results:
- Everolimus significantly prolonged PFS compared to placebo (median 4.0 vs. 1.9 months).
- The hazard ratio for progression was 0.30 (p<0.0001), indicating a substantial benefit.
- Common adverse events included stomatitis, rash, and fatigue; pneumonitis was observed in 8% of patients.
Conclusions:
- Everolimus is an effective treatment for patients with mRCC who have progressed on prior targeted therapies.
- The study demonstrates a significant improvement in PFS with everolimus.
- Everolimus offers a valuable therapeutic option for advanced renal cell carcinoma.
