Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial

Abstract

Summary 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 [17%] patients on sunitinib and 44 [7%] patients on sorafenib). There were five deaths related to treatment or occurring within 30 days...

What Survival Benefits are Needed to Make Adjuvant Sorafenib Worthwhile After Resection of Intermediate- or High-Risk Renal Cell Carcinoma? Clinical Investigators’ Preferences in the SORCE Trial

“…The S-TRAC trial (one year of sunitinib versus placebo, n = 615) showed an improvement in its primary endpoint of DFS (medians 5.6 years versus 6.8 years, HR 0.76; p = 0.03), but there was no difference in OS after a median follow-up of 5.4 years, with additional follow-up required for the final analysis of OS [3]. The ASSURE trial (one year of sunitinib versus one year of sorafenib versus placebo, n = 1943) showed no differences in either its primary endpoint of DFS (for sunitinib versus placebo the HR was 1.02; p = 0.80, for sorafenib versus placebo the HR was 0.97; p = 0.72), or in OS [19]. The PROTECT trial (one year of pazopanib versus placebo, n = 1538) did not show a statistically significant improvement in its primary endpoint of DFS (HR 0.86; p = 0.17) [20].…”

“…Significant treatment toxicity was reported in all of the three trials with published data, with more than 60% of participants on active treatment in S-TRAC and ASSURE experiencing a grade three or four toxicity, and more than a quarter discontinuing study drug because of adverse events [3,19]. Toxicity also occurred in PROTECT, leading to a reduction in the starting dose of pazopanib from 800 mg to 600 mg daily [20].…”

Management of advanced kidney cancer: Canadian Kidney Cancer Forum (CKCF) consensus update 2017

“…14 The phase 3 S-TRAC two-arm randomized, placebo-controlled trial of one year of sunitinib or placebo in patients at high risk of recurrence showed an improvement in the primary endpoint of DFS with adjuvant sunitinib comparable to the time on therapy. 15 Data for OS, a secondary endpoint, was not mature at the time of publication.…”

Stellungnahme zur adjuvanten Therapie des fortgeschrittenen Nierenzellkarzinoms

“…Allerdings zeigte die Analyse der Subgruppen in ASSU-RE den gleichen Trend der Gesamtstudie. Sowohl für Tumorgröße (T1-2 vs. T3-4), Stadium (AJCC I-II vs. III-IV), Histologie (klarzellig vs. andere) als auch für das Grading (G1-2, G3, G4) konnte kein Vorteil durch eine TKI Behandlung gezeigt werden [1].…”