ORLANDO – Adjuvant therapy with targeted vascular endothelial growth factor (VEGF) inhibitors did not prolong disease-free survival or overall survival of patients with locally advanced kidney cancers, results of a randomized, controlled trial show.
Among more than 1,900 patients with advanced kidney cancer assigned to receive adjuvant therapy with the VEGF inhibitor sunitinib (Sutent), sorafenib (Nexavar) or placebo, there were no significant differences by treatment group in either disease-free survival (DFS), overall survival, or time to disease recurrence, reported Dr. Naomi B. Haas of the Abramson Cancer, University of Pennsylvania, Philadelphia.
“The findings from this study suggest that patients with locally advanced kidney cancer completely resected should not be treated with either adjuvant sorafenib or sunitinib,” she said in a media briefing prior to her presentation of the data in an oral abstract at the 2015 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.
Approximately one-third of patients with kidney cancer may go on to develop metastatic disease, Dr. Haas noted. Because of the relative success of tyrosine kinase inhibitors (TKI) targeted to VEGF in other forms of cancer, the investigators designed a trial (ASSURE; ECOG E2805) to test two such agents in adjuvant therapy for patients with completely resected, locally advanced, nonmetastatic kidney cancer.
Following surgery, the patients were stratified by TNM stage and grade into intermediate-risk or high-risk categories, with further stratification by histologic subtype (clear cell or non–clear cell), performance status, and surgery type (open vs. laparoscopic). The patients were then randomized evenly to receive a 1-year course of either sunitinib daily 4 out of 6 weeks for 9 cycles (647 patients), sorafenib twice daily for 9 cycles (649), or placebo (647) daily.
On the advice of the data safety-monitoring committee, the starting dose of each TKI was reduced after 1,322 patients had been accrued. Too many patients were dropping out of the study due to treatment intolerance, prompting investigators to lower the starting dose of sunitinib from 50 mg to 37.5 mg daily, and the starting dose of sorafenib from 400 mg twice daily to 400 mg once daily.
Median disease-free survival, the primary endpoint, was 5.6 years in each active drug arm, compared with 5.7 years with placebo. The hazard ratios for sunitinib and sorafenib were 1.01 and 0.98, respectively, and neither was statistically significantly different from placebo.
“Patients on all three arms of the trial did better than our null hypothesis, which was approximately 4.9 years [DFS],” Dr. Haas said.
Five-year overall survival was 76.9% in the patients who had taken sunitinib, 80.7% in those who had taken sorafenib, and 78.7% in the placebo group. Again, these differences were not significant.
The most common grade 3 adverse events, all occurring in greater frequency in the TKI arms, compared with placebo, were hypertension, hand-foot reactions, rash, and fatigue.
Dr. Charles J. Ryan, who moderated the briefing but was not involved in the study commented that ECOG E2805 was “an important study, the first adjuvant study using tyrosine kinase inhibitors in kidney cancer, and the fact that it is a negative study I think in no way diminishes from the importance of it.”
“It’s important to point out that TKIs are not chemotherapy; they act in a different manner and therefore may not be as effective against micrometastatic disease as chemotherapy is in other solid tumors.”
Dr. Ryan is an ASCO Expert and professor of medicine and urology at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.