Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events.

— Alain Ravaud, MD, PhD, and colleagues

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In the phase III S-TRAC trial reported at the recent European Society for Medical Oncology meeting and in The New England Journal of Medicine by Alain Ravaud, MD, PhD, of Bordeaux University Hospital, and colleagues, adjuvant sunitinib (Sutent) significantly prolonged disease-free survival vs placebo in patients with high-risk renal cell carcinoma after nephrectomy.¹

Study Details

In this double-blind trial, 615 patients with locoregional clear cell renal cell carcinoma at high risk of recurrence after nephrectomy from 99 sites in 21 countries were randomly assigned between September 2007 and April 2011 to receive sunitinib at 50 mg/d (n = 309) or placebo (n = 306). Treatment was given on a 4-week-on/2-week-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary endpoint was disease-free survival on blinded independent central review in the intent-to-treat population.

Patients had a median age of 57 to 58 years (25%–27% ≥ 65 years), 72% to 75% were male, and 82% to 86% were white. The median interval from diagnosis was 10.7 weeks, 99% had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 91% had UCLA Integrated Staging System stage T3 tumors, with 53% to 54% of these considered higher risk. (Higher risk was defined as stage T3, no or undetermined nodal involvement, no metastasis, Fuhrman grade 2 or higher, and performance status of 1 or higher or a stage T4 tumor, local nodal involvement, or both.) From 48% to 53% of patients had disease of the right kidney.

Disease-Free Survival Outcomes

Median duration of follow-up was 5.4 years in both the sunitinib group and placebo group. Data cutoff was in April 2016. On central review, median disease-free survival was 6.8 years (95% confidence interval [CI] = 5.8 years to not reached) in the sunitinib group vs 5.6 years (95% CI = 3.8 to 6.6 years) in the placebo group (hazard ratio [HR] = 0.76, P =.03). Disease-free survival rates were 64.9% vs 59.5% at 3 years and 59.3% vs 51.3% at 5 years.

Among higher-risk patients, median disease-free survival was 6.2 vs 4.0 years (HR = 0.74, P = .04). On investigator assessment, median disease-free survival was 6.5 vs 4.5 years (HR = 0.81, P = .08) among all patients and 5.9 vs 3.9 years (HR = 0.76, P = .06) among higher-risk patients.

Data on overall survival were not mature. At data cutoff, death had occurred in 20.7% of patients in the sunitinib group and 20.9% in the placebo group (HR = 1.01, P = .94). Median overall survival was not reached in either group.

Adverse Events

The most common adverse events of any grade in the sunitinib group were diarrhea (57% vs 21%), palmar-plantar erythrodysesthesia (50% vs 10%), hypertension (37% vs 12%), fatigue (37% vs 24%), and nausea (34% vs 14%). Grade 3 (48% vs 16%) or 4 (12% vs 4%) adverse events were more common in the sunitinib group, with the most common being palmar-plantar erythrodysesthesia (16% vs < 1%), hypertension (8% vs 1%), and neutropenia (8% vs 0%).

Adverse events led to dose reduction in 34% vs 2%, dose interruption in 46% vs 13%, and discontinuation in 28% vs 6%. Serious adverse events occurred in 22% vs 17%. No deaths were attributed to study drug toxicity.

Patients in the sunitinib group had lower scores on most European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30 module (EORTC QLQ-C30) subscales during treatment, with a minimally important difference (10 points) exceeded for diarrhea and loss of appetite (P < .001 for both comparisons with placebo).

The investigators concluded: “Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events.” ■

Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Ravaud A, Motzer RJ, Pandha HS, et al: Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. October 9, 2016 (early release online).