2nd October 2009,
The phase III RECORD-1 study compared oral everolimus to placebo in 410 patients with metastatic renal cell carcinoma whose disease had progressed despite treatment. The trial was stopped early after a pre-specified interim analysis indicated a benefit in progression-free survival for everolimus.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Recent NICE guidance recommends the VEGF (vascular endothelial growth factor) inhibitor sunitinib as a first-line option for people with advanced and/or metastatic renal cell carcinoma (RCC) who are suitable for immunotherapy. As everolimus is licensed for use in patients with advanced cancer whose disease has progressed after treatment with VEGF inhibitors, the number of patients in this category is likely to be small initially. Results from the RECORD study have shown an extension in progression-free survival of two to three months over best standard care. NICE guidance on everolimus is anticipated in June 2010 and therefore, in the interim, local decision making bodies will need to identify the likely eligible patients for the drug and plan accordingly.
What is the background to this?
RCC is a highly vascular disease. Advanced or metastatic disease is known to be resistant to chemotherapy. Rates of response to chemotherapy alone are in the region of 5%. New drugs have been developed which target angiogenesis and tumour growth. These include sunitinib and sorafenib (VEGF receptor tyrosine kinase [TK] inhibitors); bevacizumab (a monoclonal antibody to VEGF) and temsirolimus which is directed at the mammalian target of rapamycin (mTOR) signal transduction pathway.
Everolimus is also an inhibitor of mTOR. Everolimus tablets (Afinitor®) were launched on 21st September 2009 for the treatment of patients with advanced RCC, whose disease has progressed on or after treatment with VEGF-targeted therapy. Further information can be found in the Summary of Product Characteristics. The cost for thirty days treatment with everolimus 10mg daily will be £2,970 (NHS List price).
What does this study claim?
Median progression free survival was 4.0 months (95% confidence interval [CI] 3.7 to 5.5) in the everolimus group and 1.9 months (1.8 to 1.9) for placebo patients.
How does this relate to other studies?
NICE guidance issued in March 2009 recommends sunitinib as a first-line option for people with advanced and/or metastatic RCC who are suitable for immunotherapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. However, more recently NICE has stated that bevacizumab, sorafenib and temsirolimus are not recommended as first-line treatment options for people with this condition. In addition, sorafenib and sunitinib are not recommended as second-line options.
A technology appraisal of everolimus for the second-line treatment of advanced and/or metastatic RCC is in progress and due to be published in June 2010.
RCC usually originates in the lining of the tubules of the kidney and accounts for approximately 3% of all adult cancers. Kidney cancer is becoming more common. In the UK, male kidney cancer incidence rates increased from 7.1 per 100,000 in 1975 to 13.9 per 100,000 in 2006. In women the rates more than doubled over the same period from 3.2 to 7.0 per 100,000. Some of the increase is believed to be due to wider use of diagnostic imaging techniques resulting in more kidney tumours being found by chance.
In England and Wales in 2004, there were 5,745 cases of newly diagnosed kidney cancer. The estimated overall 5-year survival rate for RCC is 44%, but this depends on the stage of disease at the time of diagnosis. The 5-year survival rate for metastatic RCC is approximately 10%.
Recent NICE guidance states that there are currently no interventions that reliably cure advanced and/or metastatic RCC. The primary objectives of treatment are relief of physical symptoms and maintenance of function. Advanced and/or metastatic RCC is usually treated with either interferon alfa-2a or interleukin-2 (aldesleukin), or a combination of the two. Approximately 14% of cases of metastatic RCC respond to interferon alfa when used alone. The median duration of response is six months. Interleukin-2 (aldesleukin) can result in a median duration of response of about 54 months, but it is not always tolerated.
Everolimus is in clinical trials for other types of cancer and for transplantation.
Motzer RJ, Escudier B, Oudard S et al for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372:449-56
Design: Randomised, double-blind, placebo-controlled, phase III trial.
Patients: Adults with metastatic RCC, with a clear-cell component, which had progressed on or within six months of stopping sunitinib or sorafenib, or both. Patients previously treated with interferon alfa, interleukin 2 (aldesleukin) or bevacizumab were also included, but patients previously on temsirolimus were excluded. Patients were stratified according to the Memorial Sloan-Kettering Cancer Center (MSKCC) score (favourable, intermediate and poor risk groups) and number of previous VEGF TK inhibitors.
Intervention and comparison: Oral everolimus 10mg once daily (n=272) or placebo (n=138) were combined with best supportive care. These were continued until death, disease progression, unacceptable toxicity or discontinuation for other reasons. Patients initially randomised to placebo could cross-over to open-label everolimus on disease progression.
Outcomes and results: Assessment of patient response was by blinded, independent review and reported as an intention to treat (ITT) analysis. The primary outcome was progression free survival, defined as time from randomisation to first documented sign of disease progression or death from any cause.
The trial was terminated early because the predefined stop criteria were met. The median duration of therapy was 95 days (range 12 to 315) in the everolimus group and 57 (21 to 237) in the placebo group. Compared to placebo, progression free survival was significantly prolonged in the everolimus group with 37% of events vs. 65% in the placebo group; hazard ratio [HR] 0.30, 95% CI 0.22 to 0.40, P<0.0001.
Median progression free survival was 4.0 months (95% CI 3.7 to 5.5) in the everolimus group and 1.9 (1.8 to 1.9) for placebo. Baseline MSKCC risk classification had no effect on the outcome (a pre-defined sub-group analysis). Adequate assessment of overall survival (a secondary endpoint) was not possible as placebo patients had been able to cross-over to everolimus treatment.
Adverse events were mainly classified according to the Common Terminology Criteria for Adverse Events as grade 1 or 2. The safety analysis involved all patients who had received at least one dose of study drug and were followed-up. The most common adverse events in the everolimus group (n=269) were stomatitis (40% of patients), rash, fatigue, asthenia and diarrhoea. 3% of the everolimus patients experienced grade 3 stomatitis compared to no patients in the placebo group (n=135). There were no cases of grade 3 or 4 infection in the placebo group compared to 2% and 1%, respectively, of patients in the everolimus group. Non-infectious pneumonitis was seen in 22 patients (8%) in the everolimus group, 8 of which were classified as grade 3 (6 of whom stopped therapy). There were statistically significant differences in the results of certain laboratory tests, such as hypercholesterolaemia and hyperglycaemia (more common in everolimus patients, probably as a result of the role of mTOR in glucose and lipid metabolism). Drug toxicity resulted in treatment being stopped in 10% of everolimus patients and 4% of the placebo group.
Sponsorship: Novartis Oncology
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