VEGF inhibitors show survival advantages in renal cell carcinoma

October 1, 2007

Survival advantages in metastatic renal cell carcinoma have emerged from clinical trials of two different vascular endothelial growth factor (VEGF) inhibitors.

Key Points

Progression-free and overall survival improved with the multitargeted receptor tyrosine kinase inhibitor sorafenib (Nexavar) in a large, multicenter, placebo-controlled trial of patients with advanced RCC. Sunitinib (Sutent), another multitargeted receptor tyrosine kinase inhibitor affecting the VEGF and platelet-derived growth factor signaling pathway, demonstrated superior progression-free survival compared to interferon-alfa (Intron A, Roferon-A) as first-line therapy for metastatic RCC.

"Sorafenib is an interesting agent that significantly increased progression-free survival compared to placebo in treatment-refractory patients," said Ronald Bukowski, MD, a urologic oncologist and professor of medicine at the Cleveland Clinic. "This led us to amend the protocol to allow crossover, and a large number of patients crossed over to sorafenib. The crossover, I believe, has confounded interpretation of the overall survival results, and the pre-planned secondary analysis censoring placebo data demonstrates the survival advantage for sorafenib therapy."

The pre-planned secondary analysis of overall survival censored placebo patients at crossover. Median survival in the placebo group decreased to 14.3 months, resulting in a statistically significant 22% difference favoring sorafenib (p=.0287).

Another objective of the study was to evaluate the prognostic value of biomarkers in RCC. Consistent with previous studies, the analysis showed that higher baseline VEGF levels predicted a significantly shorter progression-free survival. However, treatment with sorafenib resulted in significantly better progression-free survival compared to placebo in patients with low or high baseline VEGF levels.

"Sorafenib-associated changes in VEGF and soluble VEGF receptor are consistent with inhibition of VEGF signaling," Dr. Bukowski concluded.

Survival advantage maintained

Updated results of another trial confirmed a previously reported survival advantage for sunitinib versus interferon-alfa as first-line therapy for metastatic RCC. The new analysis also examined clinical features that might predict outcome with sunitinib, said Robert J. Motzer, MD, a member of the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center in New York.

The results showed that the initial survival advantage was largely maintained, as sunitinib patients had a median progression-free survival of 11 months compared to 5.1 months with interferon-alfa. The difference translated into a hazard ratio of 0.538 in favor of sunitinib (p<.000001).