Bevcizumab Plus Interferon Alfa 2a for Metastatic Renal Carcinoma

Abstract & Commentary

By William B. Ershler, MD, Editor

Synopsis: In a European multicenter trial of interferon alfa with or without bevacizumab for treatment of metastatic renal carcinoma, response rate and progression free survival was superior for those receiving the combination. Future trials, particularly those intending to measure long-term survival will need to also include the newly available tyrosine kinase inhibitors.

Source: Escudier B, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double blind phase III trial. Lancet. 2007;370:2103-2111.

Renal cell carcinoma is refractory to standard chemotherapeutic approaches and survival for those with metastatic disease is limited.1,2 Approximately one-third of patients present with metastatic disease and almost another third will relapse with metastatic disease after initial curative-intent nephrectomy.3

Until recently, the standard systemic therapy has been with either interferon or interleukin-2. However, response rates had remained disappointing (around 20%) and there was substantial toxicity. Interferon was shown to modestly enhance median overall survival to 13 months4 and high dose interleukin-2 resulted in apparently curative outcomes in a small percentage (5-10%).5

A typically vascular tumor, renal carcinoma has been associated with mutations of the von Hippel-Lindau tumor suppressor gene and associated over expression of vascular endothelial growth factor (VEGF).6 Currently, various strategies are being explored to inhibit angiogenesis, and one involves treatment with the humanized anti-VEGF monoclonal antibody bevacizumab. In phase II studies in previously untreated patients with metastatic renal cell carcinoma, bevacizumab monotherapy resulted in a median progression-free survival of 8.5 months7 and some had durable responses lasting as long as 3-5 years.8

Escudier and colleagues report the findings from a European multicenter, double blind, phase III trial in which 649 patients with previously untreated metastatic renal cell carcinoma received interferon alfa-2a (9 MIU subcutaneously three times weekly) and either bevacizumab (10 mg/kg) or placebo every two weeks.

At the time of unblinding, 230 progression events and 114 deaths had occurred among the 325 patients who had been randomized to the bevacizumab/interferon alfa arm compared with 275 events and 137 deaths among the 316 in the placebo/interferon arm.

Median duration of progression-free survival was significantly longer in the bevacizumab/interferon alfa group than it was in the control group (10.2 months vs 5.4 months; hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.52-0.75; p = 0.0001). Improved progression-free survival was observed with bevacizumab/interferon alfa for all risk categories. Deaths due to adverse events occurred in 8 patients (2%) who received one or more doses of bevacizumab and 7 (2%) of those who did not receive the drug. Three deaths among the bevacizumab-treated patients were considered by the investigators to be possibly related to the drug. The most commonly reported grade 3 or worse adverse events were fatigue and asthenia, and these occurred with comparable frequencies in the two arms.

Commentary

As originally written, this large multicenter trial was designed to address the effect on overall survival of bevacizumab added to interferon in patients with metastatic renal cancer. However, during the trial promising new therapies were shown to have significant activity in this clinical setting and it became apparent that their introduction as second line therapy would likely confound analysis of overall survival. Among these new agents are the tyrosine kinase inhibitors sunitinib9 and sorefenib.10 Accordingly, the investigators in consultation with regulatory agencies amended the protocol to define primary results in terms of progression-free survival (PFS) at this time, and report overall survival at a later date.

In this regard, it is also quite apparent that bevacizumab is an active agent against renal cancer; a welcome finding for a disease with a history of failed therapies. Now, however, the addition of the tyrosine kinase inhibitors provides GU oncologists with a whole new set of questions and a calling to provide rational clinical trials to address optimal treatment for a cadre of heretofore unresponsive patients. Topics such as the need for the moderately toxic interferon and the appropriate sequencing or combination of bevacizumab and TK inhibitor will be prime questions to address in well constructed clinical trials.

References

1. Motzer RJ, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;22(3):454-463.

2. Motzer RJ, et al. Renal-cell carcinoma. N Engl J Med. 1996;335(12):865-875.

3. Rouviere O, et al. Nonmetastatic renal-cell carcinoma: is it really possible to define rational guidelines for post-treatment follow-up? Nat Clin Pract Oncol. 2006;3(4):200-213.

4. Coppin C, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005(1):CD001425.

5. Parton M, et al. Role of cytokine therapy in 2006 and beyond for metastatic renal cell cancer. J Clin Oncol. 2006;24(35):5584-5592.

6. Brieger J, et al. Inverse regulation of vascular endothelial growth factor and VHL tumor suppressor gene in sporadic renal cell carcinomas is correlated with vascular growth: an in vivo study on 29 tumors. J Mol Med. 1999;77(6):505-510.

7. Yang JC, et al. N Engl J Med. 2003;349(5):427-434.

8. Yang JC. Bevacizumab for patients with metastatic renal cancer: an update. Clin Cancer Res. 2004;10(18 Pt 2):6367S-70S.

9. Motzer RJ, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295(21):2516-2524.

10. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125-134. Erratum in N Engl J Med. 2007 12;357(2):203.