A pilot study of antiangiogenic therapy with bevacizumab and thalidomide in patients with metastatic renal cell carcinoma

Abstract

The use of antiangiogenic agents represents a promising strategy for the treatment of patients with metastatic renal cell carcinoma. Objective responses to single-agent thalidomide have been described, and a randomized study showed that bevacizumab (a neutralizing antibody against vascular endothelial growth factor) delayed time to progression of metastatic renal cancer. A pilot study combining these two agents was performed. Sequential cohorts of 10 and 12 patients (crossing over from placebo therapy in the aforementioned randomized bevacizuamab trial) were treated with low-dose bevacizumab alone or bevacizumab plus the maximum tolerated dose of thalidomide as determined by intrapatient escalation. Toxicity, objective responses, and time to progression were the endpoints of this study. Patients tolerated thalidomide and bevacizumab well, with more than 50% of patients escalating to at least 500 mg/d thalidomide. Grades 1 and 2 sensory neuropathy limited thalidomide dose escalation in 3 of 12 patients. The incidence of grades 3 and 4 toxicity was not different between patients treated with bevacizumab alone versus bevacizumab plus thalidomide. There were no objective responses and no difference in progression-free survival between the groups (2.4 months for bevacizumab alone, 3.0 months for bevacizumab plus thalidomide). Combination antiangiogenic therapy with bevacizumab plus thalidomide in patients with renal cell carcinoma is associated with similar toxicity and progression-free survival compared with bevacizumab alone. This study illustrates a clinical trial design for rapidly testing the feasibility and safety of combining antiangiogenic agents, an approach that will be necessary for rapidly evaluating the many potential combinations of antiangiogenic agents.

FIGURE 1

Progression-free survival of patients treated with bevacizumab alone or bevacizumab plus thalidomide on the crossover arm of a randomized phase 2 trial comparing high-dose bevacizumab, low-dose bevacizumab, and placebo. Each cohort was compared with patients who had been randomly assigned to the low-dose bevacizumab arm of the original phase 2 trial. There was no difference in time to progression between any of the groups (all P > 0.40).

FIGURE 2

Changes in total tumor burden (expressed as a percentage of baseline tumor burden) over time in patients treated on the original randomized phase 2 trial and those treated with low-dose bevacizumab alone or bevacizumab plus thalidomide on the crossover arm of the trial. High-dose bevacizumab was associated with a statistically significant reduction in change in tumor burden (as assessed at 5 and 13 weeks) compared with either low-dose bevacizumab alone or placebo (P < 0.0001, Jonckheere test for trend). Combination therapy with thalidomide was not significantly different from either group who received low-dose bevacizumab alone.