A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer.
BACKGROUND
Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have been shown to have efficacy in renal cell cancer (RCC). This phase 2 study assessed the efficacy of daily oral dosing with everolimus in patients with RCC.


METHODS
Patients had confirmed predominantly clear cell RCC; had received <or=1 prior therapy; and had progressive, measurable metastatic disease. Everolimus was given at a dose of 10 mg daily orally without interruption (28-day cycle), with dose modifications for toxicity (graded according to National Cancer Institute Common Toxicity Criteria, version 3.0). Patients were evaluated every 2 cycles (8 weeks) using Response Evaluation Criteria in Solid Tumors (RECIST).


RESULTS
Of 41 enrolled patients, 39 were treated and evaluable for safety, 37 of whom were evaluable for response (2 patients withdrew after the first week of therapy). Approximately 78% of the patients were male, the median age was 60 years, 93% had a Zubrod performance status of 0 to 1, and 83% had received prior therapy. The median progression-free survival (PFS) was 11.2 months and the median overall survival was 22.1 months. Partial responses were observed in 5 (14%) patients, stable disease lasting >or=3 months was reported in 27 (73%) patients, and stable disease lasting >or=6 months was reported in 21 (57%) patients. Nausea (38% of patients), anorexia (38% of patients), diarrhea (31% of patients), stomatitis (31% of patients), pneumonitis (31% of patients), and rash (26% of patients) were common. 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).


CONCLUSIONS
In the current study, everolimus demonstrated encouraging antitumor activity against metastatic RCC as indicated by a PFS >or= 6 months for approximately 70% of patients.
Amato
Robert J
RJ
Department of Internal Medicine, Division of Oncology, The University of Texas Health Medical School, Memorial Hermann Cancer Center, Houston, Texas 77030, USA. robert.amato@uth.tmc.edu
Jac
Jaroslaw
J
Giessinger
Sarah
S
Saxena
Somyata
S
Willis
James P
JP
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D000068338:Everolimus; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011494:Protein Kinases / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus