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