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Phase II Trial Indicates No Benefit of Sorafenib, Temsirolimus, or Bevacizumab Doublets vs Bevacizumab Alone in Advanced Renal Cell Carcinoma

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Key Points

  • There was no significant improvement in progression-free survival for doublets vs bevacizumab in patients with advanced renal cell carcinoma.
  • Response rates were higher with doublet combinations.

In a randomized phase II trial (BEST; ECOG-ACRIN E2804) reported in the Journal of Clinical Oncology, Flaherty et al found that adding the VEGFR inhibitor sorafenib (Nexavar) or the mTOR inhibitor temsirolimus (Torisel) to the VEGF inhibitor bevacizumab (Avastin) or using sorafenib-temsirolimus in combination did not improve progression-free survival vs bevacizumab alone in advanced renal cell carcinoma. It was hypothesized that since resistance to VEGF receptor inhibition may be due to hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from the different classes might improve outcomes compared with single-agent VEGF pathway inhibition.

Study Details

In the study, 331 evaluable patients with metastatic clear cell renal cell carcinoma were randomly assigned to receive bevacizumab 10 mg/kg intravenously every 2 weeks (n = 86); bevacizumab as above plus temsirolimus 25 mg intravenously every week (n = 80); bevacizumab 5 mg/kg intravenously every 2 weeks plus oral sorafenib 200 mg twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 (n = 83); or sorafenib 200 mg twice daily and temsirolimus 25 mg weekly as above (n = 84). Progression-free survival was the primary endpoint. Patients had a median age of 61 years and most were male (73%), white (94%), and had favorable or intermediate risk (72%).

No Significant Difference in Progression-Free Survival

Median progression-free survival was 7.5 months (90% confidence interval [CI] = 5.8–10.8 months) in the bevacizumab group, 7.6 months (90% CI = 6.7–9.2 months) for bevacizumab plus temsirolimus, 9.2 months (90% CI = 7.5–11.4 months) for bevacizumab plus sorafenib, and 7.4 months (90% CI = 5.6–7.9 months) for sorafenib plus temsirolimus. Hazard ratios vs bevacizumab alone were 1.01 (P = .95) for bevacizumab plus temsirolimus, 0.89 (P = .49) for bevacizumab plus sorafenib, and 1.07 (P = .68) for sorafenib plus temsirolimus.

Rates of 6-month progression-free survival were 55% vs 56%, 59%, and 54%. Median overall survival was 28.6 months vs 24.7, 27.5, and 24.3 months. Objective response rates were 13.2% vs 31.6% (P = .008), 30.4% (P = .009), and 20.2% (P = .30).

Adverse Events

Rates of grade ≥ 3 adverse events considered at least possibly related to treatment were 44% in the bevacizumab group, 77% in the bevacizumab-plus-temsirolimus group, 82% in the bevacizumab-plus-sorafenib group, and 84% in the sorafenib-plus-temsirolimus group. The most common were hypertension (20%) in the bevacizumab group, proteinuria (25%) and hypertension (17%) in the bevacizumab-temsirolimus group, hypertension (34%) and hand-foot reaction (22%) in the bevacizumab-sorafenib group, and hypophosphatemia (33%) and hyperglycemia (18%) in the sorafenib-temsirolimus group.

The investigators concluded: “The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy.”

Keith T. Flaherty, MD, of Massachusetts General Hospital Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.

The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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