Bevacizumab combinations examined in advanced renal cell carcinoma

The results of two phase-3 studies examining the use of bevacizumab in combination with standard of care interferon alfa-2a and one phase-2 study of bevacizumab combined with everolimus to treat advanced renal cell carcinoma were recently published in the Journal of Clinical Oncology. The studies’ results indicate mixed success of the treatment regimens.

Phase-3 results from the AVOREN trial showed that the combination of bevacizumab (Avastin, Genentech) and interferon alfa-2a as first-line therapy in patients with metastatic renal cell carcinoma resulted in a nonsignificant improvement in OS.

These results, published by Bernard Escudier, MD, of the Institut Gustave Roussy, France, and colleagues, update findings presented at the 2007 and 2008 ASCO Annual Meetings detailing the safety of the combination and its beneficial effect on PFS.

From June 2004 to October 2005, researchers randomly assigned 649 previously untreated patients to bevacizumab plus interferon alfa-2a (n=327) or interferon alfa-2a plus placebo (n=322). The clinical cutoff for the final analysis of OS was September 2008, after 220 deaths had occurred in the combination arm and 224 deaths had occurred in the control arm.

Median follow-up was 23 months in the study arm and 21 months in the control arm. Median OS in the study arm was 23.3 months vs. 21.3 months in the control arm (HR=0.91; 95% CI, 0.76-1.1).

Stratified analysis by Memorial Sloan-Kettering Cancer Center risk and region showed improvement in OS in the study arm (HR=0.86; 95% CI, 0.72-1.04). Researchers observed a similar HR after they censored the 13 patients in the control arm who crossed over to bevacizumab plus interferon alfa-2a when the trial was unblinded (HR=0.84; 95% CI, 0.7-1.02).

A prespecified multiple Cox regression model indicated that several baseline prognostic factors, such as white blood cell count and Motzer score, were associated with survival independent of treatment. Adjustment for these baseline factors indicated a 22% reduction in the risk for death for patients in the combination arm compared with the control arm (HR=0.78; 95% CI, 0.63-0.96).

CALGB 90206

In addition to the AVOREN trial, CALGB 90206 was also undertaken to examine the combination treatment of bevacizumab plus interferon alfa-2a or interferon alfa-2a alone. OS results were similar between the two trials.

In this study, Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Institute, Ohio, and colleagues, randomly assigned patients bevacizumab plus interferon alfa-2a (n=363) or interferon alfa-2a alone (n=369).

Previously reported findings indicated that patients assigned combination treatment had improvements in PFS and overall response rates compared with patients on interferon alfa-2a alone.

Median OS for patients on combination treatment was 18.3 months vs. 17.4 months for patients on interferon alfa-2a alone (P=.097).

In addition, patients assigned the combination had significantly more grade-3 and grade-4 adverse events including hypertension, anorexia, fatigue and proteinuria.

Researchers from AVOREN and CALGB 90206 said confounding factors may be responsible for the lack of a statistically significant difference in OS between treatment arms.

Everolimus

John D. Hainsworth, MD, of the Sarah Cannon Research Institute, Nashville, Tenn., and colleagues reported the phase-2 results of a trial examining the use of bevacizumab 10 mg/kg plus everolimus 10 mg (Afinitor, Novartis) in patients with advanced renal cell carcinoma.

The researchers enrolled two small groups of patients onto this trial: previously untreated patients (n=50), and patients previously treated with sunitinib (Sutent, Pfizer) and/or sorafenib (Nexavar, Bayer; n=30).

Results showed that this combination treatment was active in both patient populations. Previously untreated patients had a PFS of 9.1 months, and those previously treated had a PFS of 7.1 months. The overall response rate was 30% in untreated patients and 23% in treated patients.

At the 2008 ASCO Annual Meeting, PFS data from this trial was reported as 12 months in previously untreated patients and 11 months in previously treated patients.

“Based on these promising preliminary data, two large studies were designed to test this regimen, one a first-line, large, randomized phase-2 study comparing this everolimus and bevacizumab regimen to the combination of bevacizumab and interferon, and one second-line phase-3 postsunitinib study, comparing the same regimen to everolimus plus placebo,” wrote Escudier, in an accompanying editorial.

“However, the final PFS reported herein are, respectively, 9.1 and 7.1 months in the untreated and TKI-pretreated groups, which are three and four months fewer than in the preliminary report. Knowing these final PFS data, the rationale for the two large, ongoing or planned studies described above is becoming much weaker, and the necessity to embark o these large studies becomes questionable,” he wrote.

Escudier said readers should always be sure that the data presented at major meetings is confirmed in the final results of a study.

Escudier B. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.7849.

Escudier B. J Clin Oncol. 2010;doi:10.1200/JCO.2009.27.4951.

Hainsworth JD. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.3152.

Rini BI. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.5561.