Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial

Abstract

Purpose: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence.

Patients and methods: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo.

Results: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib.

Conclusion: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.

Trial registration: ClinicalTrials.gov NCT00492258.

FIG 1.

CONSORT diagram. DFS, disease-free survival; OS, overall survival.

FIG 2.

Disease-free survival in patients randomly assigned to (A) 3 years of sorafenib versus placebo and (B) 1 year of sorafenib versus placebo.

FIG 3.

Overall survival in patients randomly assigned to (A) 3 years of sorafenib versus placebo and (B) 1 year of sorafenib versus placebo. The figures have been truncated at 11 years.

FIG A1.

Kaplan-Meier curves of the prespecified and prepowered disease-free survival analyses in Leibovich high-risk patients.

FIG A2.

Kaplan-Meier curves of the prespecified and prepowered disease-free survival analyses in patients with clear cell renal cell carcinoma.

FIG A3.

Kaplan-Meier curves for metastasis-free survival.

FIG A4.

Kaplan-Meier curves for renal cell carcinoma (RCC)–specific survival.

FIG A5.

Time to discontinuation or end of treatment by arm, (A) overall and by starting dose: (B) full dose and (C) reduced dose.

FIG A6.

Months on treatment versus total pill count taken per participant in each of the arms. For patients who reached 36 months on treatment, total pill count varied significantly.