Background Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. Methods In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. Findings Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue (110 [18%] patients on sunitinib and 44 [7%] patients on sorafenib). There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. Interpretation Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. Funding US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.
|Number of pages||9|
|State||Published - May 14 2016|
Bibliographical noteFunding Information:
This study was funded by Public Health Service Grants to the ECOG-ACRIN Cancer Research Group (CA21115, CA66636, CA23318, CA180820, CA180794, CA15488, CA180867, CA27525, CA80775, CA21076, CA180799, CA14958, CA189859, CA17145, CA16116, CA180802, CA49883, CA49957, CA180847, CA13650, CA180790, CA107868, CA180821, CA31946, CA41287, CA32291, CA180836, CA11789, CA077202, CA180863, CA180888, CA180858, CA32102, CA105409, CA189953, CA20319). Support, including masked study drug, was also provided by Pfi zer and Bayer.
The E2805 double-blind, placebo-controlled, randomised, phase 3 trial was led by the Eastern Cooperative Oncology Group (ECOG-ACRIN) with participation from the Southwest Oncology Group (SWOG), Cancer and Leukemia Group B (Alliance), and the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). The study was done at 226 study centres in the USA and Canada. An independent data monitoring committee monitored the study. Approval for the study was granted by the institutional review board at each centre. The trial was supported by the Cancer Trials Evaluation Program (CTEP) of the National Cancer Institute. The study protocol is available online . Patients were recruited through ClinicalTrials.gov and through participating institutions. Potentially eligible patients presenting at participating sites were offered enrolment. We did not collect information about screening failures. Eligible patients had histologically proven, completely resected high-risk clear cell or non-clear cell renal-cell carcinoma within 12 weeks of removal of the primary tumour. The high-risk designation included the following criteria in accordance with the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 6th edition (2002): pT1b G3–4 N0 (or pNX where clinically N0) M0 to T(any) G(any) N + (fully resected) M0. Patients were required to have a left ventricular ejection fraction of 50% within 4 weeks before randomisation. Paraffin-embedded tumour samples were required for central review. Patients needed to be treatment-naive for kidney cancer, have good ECOG performance status (0 or 1), and normal liver and haematological function. The criterion for kidney function was a creatinine clearance of more than 30 mL per min. Exclusion criteria were uncontrolled hypertension, a pre-existing thyroid disorder, or known HIV infection. Patients with medullary kidney cancer and collecting duct kidney cancer were also excluded. Participants gave written informed consent.
© 2016 Elsevier Ltd.
ASJC Scopus subject areas
- Medicine (all)