Orlando, FL—Surprisingly, the use of adjuvant sorafenib (Nexavar) and sunitinib (Sutent) failed to extend disease-free survival (DFS) in patients with locally advanced kidney cancer who are at high risk for recurrence, according to initial results of the ASSURE study. The ASSURE trial is the first and largest study investigating the use of adjuvant tyrosine kinase inhibitors/vascular endothelial growth factor (VEGF) inhibitors in kidney cancer.
The results surprised the lead investigator, Naomi B. Haas, MD, Cancer Therapeutics Program Co-Leader, Abramson Cancer Center, University of Pennsylvania, Philadelphia. She discussed the results at the 2015 Genitourinary Cancers Symposium.
Sorafenib and sunitinib are both widely effective in metastatic kidney cancer, and the investigators of ASSURE hoped that these drugs would also provide benefits for patients in the adjuvant setting. However, the findings of this randomized, placebo-controlled trial suggest that close observation should remain the standard of care, Dr Haas 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 Dr Haas.
She added that analysis of tumor specimens collected during the trial may provide some clues as to whether specific subsets of patients may derive a treatment benefit from adjuvant therapy with sorafenib or sunitinib.
ASSURE enrolled 1943 patients who underwent complete resection and were categorized as having intermediate- or high-risk for disease recurrence according to tumor size and grade, and lymph node involvement. The treatment arms were well-balanced for the type of kidney cancer, type of surgery, performance status, and risk for disease recurrence.
Patients were randomized in a 1:1:1 ratio to receive sorafenib, sunitinib, or placebo for 1 year. After 1322 patients were accrued, the starting doses of the active drugs were lowered and titrated according to the side effects, which reduced the rates of discontinuation in the experimental arms from approximately 26% for patients starting with full doses to 14% for those starting with reduced doses.
Dr Haas said that the dosing adjustments could have relevance for reducing discontinuation of these drugs in other settings.
Interim analysis revealed similar rates (approximately 40%) of recurrence in all 3 groups and similar rates (5.6-5.7 years) of DFS, the primary end point of the trial.
The 5-year recurrence-free survival rates were 53.8% with sunitinib and 52.8% with sorafenib, which was similar to the 55.8% in the placebo arm. Overall survival was not significantly different between arms, ranging from 77% to 81%.
Based on these interim findings, the Data Safety and Monitoring Committee recommended release of the results.
The most common side effects with the 2 active drugs included grade ≥3 hypertension (16% each for sorafenib and sunitinib vs 4% for placebo), hand-foot reaction (sorafenib, 33%; sunitinib, 14%; placebo, 1%), rash (15%, 2%, and 1%, respectively), and fatigue (7%, 17%, and 3%, respectively).
Final analysis of disease 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,” Dr Haas said.
All patients in the trial exceeded the 4.6-year DFS projected in the null hypothesis when the trial was designed, she added.
At a question and answer session after Dr Haas’ presentation for the press, Charles Ryan, MD, of the University of California, San Francisco, who moderated the discussion, 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 [VEGF inhibitors] may not be as effective as chemotherapy in the adjuvant treatment of solid tumors,” Dr Ryan stated. “This study supports my current practice of not using these drugs in the adjuvant setting.”
Other Adjuvant Trials
Other adjuvant trials are ongoing in kidney cancer. These include a study of the tyrosine kinase/VEGF inhibitor axitinib (Inlyta), and a study of the mTOR inhibitor everolimus (Afinitor); both trials are currently accruing patients. Adjuvant trials of immunotherapy and other targeted approaches are being considered.