No Disease-Free Survival Benefit of Adjuvant Sunitinib or Sorafenib in High-Risk Nonmetastatic Renal Cell Carcinoma


Key Points

  • Neither sunitinib nor sorafenib improved disease-free survival vs placebo.
  • Both agents were associated with high rates of treatment discontinuation due to adverse events.   

In a phase III trial (ECOG-ACRIN E2805) reported in The Lancet by Haas et al, no benefit of adjuvant VEGFR (vascular endothelial growth factor receptor) inhibitor treatment with sunitinib or sorafenib (Nexavar) was observed vs placebo in patients with completely resected high-risk nonmetastatic renal cell carcinoma.

Study Details

In the double-blind trial, 1,943 patients with pathologic stage high-grade T1b or greater disease and complete resection from the National Clinical Trials Network at 226 sites in the United States and Canada were randomly assigned between April 2006 and September 2010 to receive sunitinib (n = 647), sorafenib (n = 649), or placebo (n = 647) for 54 weeks. After high rates of toxicity-related treatment discontinuation were observed among the first 1,323 patients enrolled (44% of 438 sunitinib patients, 45% of 441 sorafenib patients; 11% of placebo patients), the starting dose of each drug was reduced and then individually titrated up to the original doses. Initial treatment was sunitinib at 50 mg/d for the first 28 days of each 6-week cycle or sorafenib at 400 mg twice per day in all cycles; the starting dose was reduced to 37.5 mg of sunitinib or 400 mg/d of sorafenib for the first one or two cycles of therapy. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population.

No Disease-Free Survival Differences

Due to the low conditional power for the primary endpoint, in October 2014, the Data Safety Monitoring Committee recommended that blinded follow-up be stopped and study results released. Median follow-up was 5.8 years.

The primary analysis showed no significant differences in disease-free survival, with a median duration of 5.8 years (interquartile range [IQR] = 1.6–8.2 years) for sunitinib (hazard ratio [HR] = 1.02, P = .8038, vs placebo), 6.1 years (IQR = 1.7 years to not estimable) for sorafenib (HR = 0.97, P = .7184, vs placebo), and 6.6 years (IQR = 1.5 years to not estimable) for placebo. Five-year disease-free survival was 54.3%, 54.0%, and 56.4%, respectively.

Among patients with clear cell histology (79% to 80% across groups), no differences in disease-free survival were observed with sunitinib (HR = 1.02, P = .8931) or sorafenib (HR = 0.99, P = .8734) vs placebo. Although the hazard ratios and interactions were not significant, the hazard ratios were higher for women (1.29) than for men (0.95) and for white patients (1.09) than for members of other races/ethnicities (0.74; n = 164) among patients receiving sunitinib; similar outcomes were observed for women (1.30) and men (0.89) as well as white patients (1.06) vs those of other races/ethnicities (0.49; n = 180) receiving sorafenib.   

Overall Survival

Median overall survival had not been reached in any group. No significant difference was observed for the sunitinib group (HR = 1.17, P = .1762) or sorafenib group (HR = 0.98, P = .8577) vs placebo. Five-year overall survival was 77.9%, 80.5%, and 80.3%, respectively.  

Adverse Events

Grade ≥ 3 adverse events occurred in 63% of sunitinib patients, 72% of sorafenib patients, and 25% of placebo patients; after reduction of the starting dose, grade ≥ 3 adverse events still occurred in > 55% of patients in the sunitinib and sorafenib groups. The most common grade ≥ 3 adverse events were hypertension (17% of sunitinib patients, 16% of sorafenib patients), hand-foot syndrome (15% and 33%), rash (2% and 15%), and fatigue (17% and 7%). Among patients starting at reduced doses, adverse events led to discontinuation of treatment in 34% of sunitinib patients, 30% of sorafenib patients, and 10% of placebo patients.  

The investigators concluded: “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.”

The study was funded by the National Cancer Institute, the ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.

Naomi B. Haas, MD, of Abramson Cancer Center, University of Pennsylvania, is the corresponding author of The Lancet article. 
