Use of adjuvant sorafenib and sunitinib failed to extend disease-free survival (DFS) in patients with locally advanced kidney cancer at high risk of recurrence, according to initial results from the ASSURE study presented at the 2015 Genitourinary Cancers Symposium. ASSURE is the first and largest study of adjuvant vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors in kidney cancer.
Both sorafenib and sunitinib are widely effective in metastatic kidney cancer, and the investigators of ASSURE hoped that the drugs would also provide benefit in the adjuvant setting. However, the findings of this randomized trial suggest that close observation should remain the standard of care, they said.
“No one could be more disappointed in these results than me, except for patients with kidney cancer. Even though these drugs provide benefit in the metastatic setting, they did not reduce disease recurrence in the adjuvant setting, while they did increase side effects,” said lead author Naomi B. Haas, MD, Abramson Cancer Center of the University of Pennsylvania, Philadelphia.
Haas said analysis of tumor specimens collected during the trial may provide some clues to whether specific subsets of patients might derive a treatment benefit from adjuvant sorafenib or sunitinib.
ASSURE enrolled 1943 patients who underwent complete resection and were categorized as intermediate risk or high risk for recurrence according to tumor size and grade and lymph node involvement. Treatment arms were well balanced for type of kidney cancer, type of surgery, performance status, and risk of recurrence.
Patients were randomized in a 1:1:1 ratio to receive sorafenib (n=649), sunitinib (n=647), or placebo (n=647) for 1 year. After 1322 patients were accrued, the starting doses of active drugs were lowered and titrated according to side effects, which reduced the rates of discontinuation in the experimental arms from about 26% for patients initiated at full doses to 14% for those started on reduced doses. Haas said that the dosing adjustments could have relevance for reducing discontinuation of these drugs in other settings.
Interim analysis revealed similar rates of recurrence in all 3 groups (around 40%) and of DFS (5.6-5.7 years), the primary end point of the trial. Five-year DFS rates were 53.8% for sunitinib and 52.8% for sorafenib, which were similar to the 55.8% seen in the placebo arm. Overall survival was not significantly different between treatment arms and ranged from 77% to 81%.
Based on these interim findings, the Data Safety and Monitoring Committee recommended release of the results.
Both active drugs had side effects. The most common grade ≥3 side effects were hypertension (16% for both sorafenib and sunitinib, and 4% for placebo), hand-foot reaction (sorafenib 33%, sunitinib 14%, and placebo 1%), rash (15%, 2%, and 1%, respectively), and fatigue (7%, 17%, and 3%, respectively).
Final analysis of recurrence and survival will be presented in the future.
“The findings suggest that patients with locally advanced kidney cancer treated with surgery should not receive adjuvant sorafenib or sunitinib,” Haas noted.
All patients in the trial exceeded the 4.6-year DFS projected in the null hypothesis when the trial was designed, she added.
Other adjuvant trials are ongoing in kidney cancer. These include a study of axitinib (a VEGF receptor inhibitor) and a study of everolimus (mTOR inhibitor), both of which are accruing patients. Adjuvant trials of immunotherapy and other targeted approaches are being considered.
During a question-and-answer session following Haas’ presentation at a premeeting presscast, moderator Charles Ryan, MD, professor, University of California San Francisco School of Medicine, noted that some oncologists are using adjuvant VEGF therapy with no supportive evidence. In his view, the interim results of ASSURE provide convincing evidence against this practice.
“The fact that this is a negative trial in no way diminishes its importance. Tyrosine kinase inhibitors may not be as effective as chemotherapy in the adjuvant treatment of solid tumors,” Ryan stated. “This study supports my current practice of not using these drugs in the adjuvant setting.”
Haas NB, Manola J, Uzzo RG, et al. Initial results from ASSURE (E2805): adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol. 2015;33(suppl 7):abstract 403. Presented at: 2015 Genitourinary Cancers Symposium; February 26-28, 2015; Orlando, FL.