Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial

Summary

Background

Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted.

Methods

In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com, number BO17705E.

Findings

325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10·2 months vs 5·4 months; HR 0·63, 95% CI 0·52–0·75; p=0·0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]).

Interpretation

The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.

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.