Afinitor (everolimus) has been approved by the FDA for patients with advanced renal cell carcinoma after failure of treatment with sunitinib (Sutent) or sorafenib(Drug information on sorafenib) (Nexavar).
FDA regulatory filing for Afinitor was based on data from RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily), a phase III clinical trial that studied the effects of an oral mTOR inhibitor in advanced RCC patients whose cancer progressed despite prior treatment.
The international, multicenter, randomized, double-blind trial involved 416 patients with advanced RCC whose cancer progressed despite prior treatment with sunitinib, sorafenib, or both sequentially.
In addition, prior therapy with bevacizumab(Drug information on bevacizumab), interferon alfa, and interleukin-2 was allowed. Patients were randomized to receive everolimus (10 mg) daily or placebo, in conjunction with best supportive care.
The primary endpoint of the study was progression-free survival, which was assessed via a blinded independent, central radiological review (ESMO 2008 abstract 720; See “Novel Agents May Overcome Resistance to Trastuzumab(Drug information on trastuzumab),” July 2008, page 1). According to the results, improvement in progression-free survival was seen for all subgroups. Median PFS was four months for everolimus group vs 1.9 months for placebo.
Ten percent of the patients had adverse events, including stomatitis, infections, asthenia, fatigue, cough and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia.
The lead author of RECORD-1 was Bernard Escudier, MD, from Institut Gustave Roussy in Villejuif, France.
In another phase II study, everolimus was assessed for daily oral dosing in patients with RCC. In this research, conducted at Houston’s Memorial Hermann Cancer Center at the University of Texas Health Medical School, enrolled patients had confirmed predominantly clear cell RCC; had received at least one 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. Patients were evaluated every two cycles (eight weeks) using RECIST.
Of 41 enrolled patients, 39 were treated and evaluable for safety, 37 of whom were evaluable for response, wrote Robert J. Amato, DO, and colleagues in Cancer online (March 20, 2009). Dr. Amato’s group reported that the median PFS was 11.2 months and the median overall survival was 22.1 months. Partial responses were observed in 14% of the patients and stable disease lasting at least three months was reported in 73%. Stable disease lasting at least 10 months was reported in 57% patients. Adverse effects included nausea and diarrhea.