Adjuvant treatment with the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors sorafenib or sunitinib are no more effective than a placebo in preventing recurrence in patients with advanced kidney cancer following surgery, according to a multi-institutional study.1

The randomized, double-blind phase 3 trial, known as the ASSURE study, demonstrated no difference in median years of disease-free survival (DFS) in the adjuvant setting.

The study included 1943 patients who were treated in the United States and Canada with 1 year of sorafenib, sunitinib, or a placebo following resection.

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The researchers found that the median years of DFS were 5.8 years for sunitinib, 6.1 years for sorafenib, and 6.6 years for placebo patients. The findings closely mirror those of adjuvant trials in other tumors, such as breast and metastatic colorectal cancers, in which the benefits of bevacizumab in metastatic disease were not seen in the adjuvant setting.

“I was very disappointed. We were really excited. This study was designed almost at the same time that the drugs were given approval in the metastatic setting,” said study author Naomi Haas, MD, who is an associate professor in the Division of Hematology/Oncology at the Perelman School of Medicine and director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

In this study, 647 patients were assigned to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6-week cycle; 649 patients were assigned sorafenib 400 mg twice per day orally throughout each cycle and 647 were assigned to placebo.

The authors noted that this cohort included a histologically representative and diverse population. Sunitinib and sorafenib are both tyrosine kinase inhibitors and both have been shown to be effective in treating metastatic disease. However, the researchers found a duration of therapy greater than 6 months did not differ from 3 to 6 months or less than 3 months of therapy in terms of DFS.

Dr Haas said that there are other ongoing adjuvant trials investigating different lengths of therapy with sunitinib and sorafenib, as well as different kinase inhibitors. There are also plans for a perioperative trial with an immune checkpoint inhibitor set to open in the next 3 to 5 months.

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“We are already designing a clinical trial with the checkpoint inhibitor nivolumab and that trial will hopefully enroll patients this summer. This will be an adjuvant study,” Dr Haas said in an interview with Cancer Therapy Advisor.

In the early years of the trial, about a third of patients stopped treatment because they found the side effects, such as hypertension and fatigue, were too difficult to tolerate.

“The agents have significant side effects. They can cause high blood pressure and tiredness and if the patients aren’t monitored closely, they can get sores on their hands and feet. There is a learning curve with giving these drugs,” said Dr Haas.

The most common grade 3 or worse adverse event was hypertension (17% for patients who received sunitinib and 16% for patients who received sorafenib). The second-most common grade 3 or worse adverse event was hand-foot syndrome (15% for patients who received sunitinib and 33% for patients who received sorafenib).

Philippe Spiess, MD, who is a genitourinary oncologist at Moffitt Cancer Center and an associate professor of oncology and urology at the University of South Florida Morsani College of Medicine in Tampa, said the results of the present study raised the question: “what, if anything, can be offered to patients exhibiting adverse pathological features following kidney cancer surgical resection in the absence of suspected metastatic disease?” He said a fundamental question becomes whether patients are bound for disease recurrence and progression regardless of whether adjuvant systemic agents are employed. Dr Spiess said it may be that the presently tested targeted agents are not sufficiently effective to alter the natural history of the disease.

“Unfortunately…we don’t have these highly clinically relevant answers,” Dr Spiess told Cancer Therapy Advisor. “I similarly think we need to conceive our adjuvant trials differently by personalizing our ‘high risk designation’ of patients with non-metastatic kidney cancer based on their clinical, pathological, and unique molecular profiles and subsequent risk of progression.”


  1. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial [published online ahead of print March 8, 2016]. Lancet. doi: 10.1016/S0140-6736(16)00559-6.