ArticlesBevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial
Introduction
Renal cell carcinoma is diagnosed in more than 120 000 patients in Europe and the USA every year, and causes about 60 000 deaths.1 Most of these cases are clear-cell carcinomas.2 The 5-year survival rate for patients with stage IV renal cell carcinoma is 10–20%, and a third of patients have stage IV disease at presentation.3, 4 A further 20–30% of patients with initially localised disease relapse after nephrectomy.5
Most patients with clear-cell renal cell carcinoma have mutations of the von Hippel–Lindau tumour suppressor gene, leading to increased transcription of several hypoxia-inducible genes.6 One of these factors is the vascular endothelial growth factor (VEGF), a potent proangiogenic molecule that inhibits dendritic cell maturation and tumour cell apoptosis, as well as stimulating tumour angiogenesis.7, 8, 9 These findings stimulated the clinical assessment of strategies that inhibit the activity of VEGF.
Metastatic renal cell carcinoma is highly resistant to conventional treatment.4 Until recently, the standard systemic treatment for metastatic renal cell carcinoma was immunotherapy with either interleukin 2 or interferon, both of which produce modest overall response rates (<20%) along with substantial toxicities, although occasional, durable complete responses are seen. Randomised trials have shown that interferon results in a median overall survival of 13 months10 and high-dose interleukin 2 can achieve curative outcomes in 5–10% of patients.11, 12 The tyrosine kinase inhibitors sorafenib and sunitinib have also been approved for the treatment of advanced renal cell carcinoma. In patients who have failed interferon or interleukin 2, sorafenib doubles progression-free survival compared with placebo13, 14 and sunitinib results in an overall response rate of 42%.15, 16 More recently, sunitinib has been shown to significantly increase progression-free survival compared with interferon (11 months vs 5 months; p<0·001) in previously untreated patients.17 Despite this progress in the management of metastatic renal cell carcinoma over the past 2 years, only the mammalian target of rapamycin (mTOR) inhibitor temsirolimus has been shown to improve overall survival compared with interferon alone, in patients with poor prognosis and previously untreated non-clear-cell tumours.18
Bevacizumab is a humanised monoclonal antibody that inhibits VEGF. The drug has shown a clinical benefit in phase II studies of metastatic renal cell carcinoma: bevacizumab monotherapy resulted in a median progression-free survival of 8·5 months in previously untreated patients; monotherapy increased the median time to disease progression compared with placebo (4·8 months vs 2·5 months; hazard ratio [HR] 0·39, p<0·001) in patients with previously treated disease.19, 20 A number of patients have had durable responses lasting 3–5 years with continued bevacizumab therapy.21 The efficacy and safety profiles of bevacizumab when administered in combination with a wide range of chemotherapeutic and targeted agents in several other tumour types are well defined.20, 22, 23, 24, 25, 26
These data, together with the long-established role of immunotherapy as the first-line standard of care for metastatic renal cell carcinoma, formed a strong rationale to examine bevacizumab in combination with interferon. The aim of this study was to determine whether first-line bevacizumab plus interferon improves efficacy compared with interferon alone.
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Patients
Patients were eligible for enrolment if they were aged 18 years or older, with measurable or non-measurable tumour (according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria27), had predominantly (>50%) clear-cell renal cell carcinoma (based on routine assessment of tumour histopathology by local pathologists with the American Joint Committee on Cancer/International Union Against Cancer [AJCC/UICC] classification28), and had undergone nephrectomy or partial nephrectomy (if
Results
821 patients were screened, of whom 649 were randomised to one of the two treatment groups between June, 2004, and October, 2005 (figure 1). Two (0·6%) patients in the bevacizumab plus interferon alfa group and six (2%) in the placebo plus interferon alfa group withdrew before treatment. All remaining patients (n=641) received at least one dose of study treatment. The arms were balanced with regard to baseline disease and demographic characteristics (table 1).
At the time of clinical data cutoff
Discussion
This multicentre, randomised, double-blind phase III study suggests that the combination of bevacizumab with interferon alfa in patients with metastatic clear-cell renal cell carcinoma produces significant and clinically meaningful improvements in progression-free survival and overall response rates compared with placebo plus interferon alfa. Since this report is based on the results of an interim analysis of overall survival and final analysis of progression-free survival, overall survival
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