Two angiogenesis inhibitors that are widely used in metastatic renal cell carcinoma did not improve survival compared with placebo when used as adjuvant treatment, a new study found.
Orlando, FL-Two angiogenesis inhibitors that are widely used in metastatic renal cell carcinoma (RCC) did not improve survival compared with placebo when used as adjuvant treatment, a new study found. The federally funded randomized trial studied the agents’ use in patients with locally advanced kidney cancer.
“Patients with locally advanced kidney cancer should not be treated with either adjuvant sorafenib or sunitinib,” stated lead author Naomi B. Haas, MD, associate professor of medicine at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, speaking at a pre-meeting press event for the Genitourinary Cancers Symposium in Orlando, FL.
Dr. HaasNo benefit was seen for adjuvant therapy with either sunitinib (Sutent) or sorafenib (Nexavar) compared to placebo. Treatment with either drug resulted in median disease-free survival (DFS) of 5.6 years; DFS was 5.7 years with placebo. The 40% rate of recurrence was also similar among the two treatment arms and placebo group.
These findings are of importance because both drugs have been used in the adjuvant setting off-label in about 45% of patients with locally advanced kidney cancer.
The phase III ASSURE (Adjuvant Sorafenib or Sunitinib in Unfavorable REnal cell carcinoma) trial was designed to test whether these agents would prove as effective in the adjuvant setting as they have for patients with advanced/metastatic RCC.
The randomized, double-blind, multicenter trial enrolled 1,943 patients with resected, intermediate, and very high-risk clear cell and non-clear cell RCC who had no prior systemic treatment. Patients were randomized to receive sorafenib, sunitinib, or placebo.
The trial was designed to detect a 25% reduction in the hazard ratio, which would equate to an improvement in estimated median DFS of 5.8 years with placebo to 7.7 years with the experimental agents. DFS was the primary endpoint; secondary endpoints were overall survival and tolerability.
Rates of adverse events and patient intolerance compelled lowering the original dosage of sorafenib, 400 mg twice daily to once daily, and of sunitinib, 50 mg once daily to 35 mg once daily. Discontinuation rates decreased from about 26% of patients on the original schedule to about 14% of patients who started on the lower dosages. The authors also found that discontinuation rates were reduced by dose titration.
Both drugs were associated with an increased incidence of hypertension (16% for active agents vs. 4% placebo). Compared to placebo, the sorafenib arm had higher rates of hand-foot syndrome and rash (15% vs. <1%) and diarrhea (9% vs. 0%). Patients in the sunitinib arm had higher rates of fatigue (18% vs. 3% placebo), hand-foot syndrome (33%), and diarrhea (10%).
With 62% of the study information available at an interim analysis, no evidence of any trend toward efficacy benefit, and significant high-grade toxicity seen with both sorafenib and sunitinib, the Data Safety Monitoring Committee recommended release of results even though no efficacy or futility boundaries had been reached.
The results of this study raise the question of whether anti-angiogenic agents have any role as treatment and prevention of recurrence in the adjuvant setting. If they do, how long should they be administered? Hopefully, the answers to these and other questions will emerge from further studies. Currently, ATLAS (NCT0599754) is looking at another anti-angiogenesis agent, axitinib (Inlyta), in very high-risk clear cell RCC patients; and SORCE (NCT00492258) is investigating sorafenib versus placebo for 1 or 3 years in resected patients with clear cell and non-clear cell RCC.
Dr. Haas has stock and other ownership interests in TetraLogic Pharmaceuticals, serves as a consultant/adviser for Bristol-Myers Squibb, GlaxoSmithKline, and Merck; and has provided expert testimony for Lilly. One of Dr. Haas’ co-authors is a consultant/adviser for Bayer and Pfizer and has received travel, accommodations, and expenses remuneration from Pfizer, and others have served as consultants/advisers to and/or have received honoraria from pharmaceutical companies.
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