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The ECOG-ACRIN Cancer Research Group’s definitive phase III trial, E2805, shows no disease-free survival benefit with the use of either sorafenib or sunitinib as adjuvant treatment for locally advanced renal cell carcinoma
Philadelphia, March 8, 2016 –Final research results published online by The Lancet report no preventive benefit from the use of either Sutent® (sunitinib) or Nexavar® (sorafenib) following surgery in male and female adults with locally advanced kidney cancer, despite their widespread use in the metastatic setting. Each of these oral drugs is Food and Drug Administration (FDA) approved in the U.S. as a single agent for treating metastatic, or advanced, kidney cancer. However, their role in earlier stages of the disease has been unclear until now.
The research findings are based upon study E2805, a phase III trial designed and led by ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI). This is the first and largest trial reporting on the effectiveness of giving either sunitinib or sorafenib, both small molecule vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors, to patients after their surgery to remove the tumor.
“Unfortunately, the results of study E2805 lead us to conclude that there is a strong rationale against the use of sorafenib or sunitinib in the adjuvant setting,” said lead researcher Naomi B. Haas, MD, a medical oncologist at the University of Pennsylvania‘s Abramson Cancer Center in Philadelphia and a member of ECOG-ACRIN. “We found that neither sunitinib nor sorafenib reduced the incidence of recurrence as compared to standard care, which is observation.”
In this trial, 1943 patients in the U.S. and Canada who were considered at high risk of recurrence were enrolled between April 2006 and September 2010 and randomized equally to receive sunitinib (n=647) or sorafenib (n=649) or placebo (n=647) for one year.
The three groups of patients were selected using known or suspected risk factors for recurrence, including the stage and grade of kidney cancer, overall patient health, histology and type of surgery. The treatment regimens were either 54 weeks of sunitinib taken orally at 50 mg daily for 28 to 42 days per cycle, or sorafenib taken orally at 400 mg twice daily continuously, or the placebo.
The primary endpoint for this trial was disease-free survival. Secondary endpoints included overall survival and toxicity. There were no significant differences in disease-free survival or overall survival between either the patients taking a drug or the ones receiving the placebo, which was equal to standard care (observation). Median disease-free survival was 5.8 years for sunitinib, 6.16 years for sorafenib, and 6.6 years for the placebo.
Following a high rate of toxicity-related discontinuation after 1323 patients began treatment, each drug’s starting dose was reduced and then individually titrated. The most common adverse events (grade three or higher) on the sunitinib/sorafenib arms were hypertension (17%/16%), hand-foot reaction (15%/33%), rash (2%/15%), and fatigue (18%/7%) at the initial doses; the revised dosing strategy still resulted in high toxicity.
Researchers conclude that even if E2805 failed to establish a role for sorafenib or sunitinib in the adjuvant setting, its placebo-controlled design has provided a definitive answer that will likely prevent costs and toxicities associated with inappropriate use of these agents, considering the prevalence of the disease. The World Health Organization (WHO) estimates that 338,000 men and women worldwide were diagnosed with kidney cancer in 2012 and roughly 40 percent died from the disease.
The trial was conducted in association with all of the adult cancer research groups of the NCI-sponsored National Clinical Trials Network, these include the Alliance for Clinical Trials in Oncology, the Canadian Cancer Trials Group, ECOG-ACRIN, NRG Oncology and SWOG. Patients were enrolled through cancer centers and community hospitals in the U.S. and Canada that participate in the NCI’s National Clinical Trials Network.
Funding for trial E2805 was provided by the National Cancer Institute, ECOG-ACRIN Cancer Research Group, Pfizer and Bayer. Sunitinib and sorafenib were provided by Pfizer and Bayer, respectively, under Clinical Trials Agreements with NCI.
The original manuscript, “Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial,” is available online via subscription at http://dx.doi.org/10.1016/S0140-6736(16)00559-6.
The ECOG-ACRIN Cancer Research Group is a membership-based scientific organization that designs and conducts cancer research involving adults who have or are at risk of developing cancer. ECOG-ACRIN comprises nearly 1100 member institutions in the United States and around the world. Approximately 12,000 physicians, translational scientists, and associated research professionals from the member institutions are involved in Group research, which is organized into three scientific programs: Cancer Control and Outcomes, Therapeutic Studies, and Biomarker Sciences. ECOG-ACRIN is supported primarily through National Cancer Institute research grant funding, but also receives funding from private sector organizations through philanthropy and collaborations. It is headquartered in Philadelphia, Pa. For more information, visit www.ecog-acrin.org, call 215.789.3631, and follow the organization on Twitter: @eaonc.