Adjuvant Sunitinib Extends DFS in High-Risk RCC

Alain Ravaud, MD, PhD

Adjuvant sunitinib (Sutent) prolonged disease-free survival (DFS) by 1.2 years compared with placebo following nephrectomy for patients with high-risk clear cell renal cell carcinoma (RCC), according to findings from the phase III S-TRAC trial presented at the 2016 ESMO Congress and published in the New England Journal of Medicine (NEJM).^1,2

After a median follow-up duration of 5.4 years, the median DFS was 6.8 years in the sunitinib arm compared with 5.6 years with placebo (HR, 0.76; 95% CI, 0.59-0.98; P = .03). In higher risk patients, the median DFS was 6.2 versus 4.0 years for sunitinib and placebo, respectively (HR, 0.74; 95% CI, 0.55-0.99; P = .04). Grade 3/4 adverse events (AEs) were experienced by 63.4% of patients in the sunitinib group compared with 21.7% in the placebo arm.

“Sunitinib is a potential new option for adjuvant therapy in renal cell carcinoma, given the increase in disease-free survival and the manageable safety profile," lead investigator Alain Ravaud, MD, PhD, head of medical oncology, University Hospital of Bordeaux, France, said in a statement. "The results of this trial could change practice because there is currently no standard treatment in this setting.”

The study randomized 615 patients with clear cell RCC to receive sunitinib (n = 309) or placebo (n = 306). Patient characteristics were well balanced between the arms. The median age of patients in the sunitinib arm was 57 years, and most were males (71.8%). Most patients had an ECOG performance score of 0 (73.8%).

Overall, 90.6% of those in the sunitinib arm had a stage 3 tumor, with no nodal involvement and no metastasis. Of these patients, 37.2% were considered low-risk (any Fuhrman grade and ECOG score of 0 or Fuhrman grade 1 and ECOG score of ≥1) and 53.4% were high-risk (Fuhrman grade ≥2 and ECOG score of ≥1).

Sunitinib was administered at 50 mg daily for 4 weeks followed by 2 weeks without treatment. One dose reduction was allowed in the study, to 37.5 mg per day. Overall, more than half of patients (54.2%) were able to maintain treatment with the starting dose of 50 mg per day. The median daily dose was 45.9 mg.

After 3 years, 64.9% of those in the sunitinib group were alive and remained disease-free compared with 59.5% in the placebo arm. At 5 years, the DFS rate was 59.3% with sunitinib versus 51.3% for placebo. Median overall survival findings were not yet mature at the time of the analysis; however, the hazard ratio between the two arms for survival was 1.01 (95% CI, 0.72-1.44; P = .94).

Treatment-emergent AEs were experienced by 99.7% of patients treated with sunitinib versus 88.5% in the placebo arm. Treatment-emergent AEs by investigator assessment occurred in 98.4% of those treated with sunitinib versus 75.7% with placebo. AEs led to discontinuation for 28.1% of patients in the sunitinib arm versus 5.6% of those in the placebo group.

The most common AEs in the sunitinib arm were diarrhea (56.9%), palmar—plantar erythrodysesthesia (50.3%), hypertension (36.9%), fatigue (36.9%), and nausea (34.3%). The most common grade 3/4 AEs were palmar–plantar erythrodysesthesia (16%), neutropenia (8.5%), hypertension (7.8%), and thrombocytopenia (6.2%). The rate of serious adverse events AEs was similar for sunitinib (21.9%) versus placebo (17.1%).

“We hope sunitinib will be approved by regulators for adjuvant therapy in renal cell carcinoma. Clinicians should then use the drug according to the trial. In other words, in patients with predominant clear cell renal cell carcinoma without metastases and at high risk of recurrence, at a starting dose of 50 mg and a minimum dose of 37.5 mg per day and with the same dosing schedule," said Ravaud. "This is particularly important since sunitinib was not beneficial in another trial using a different methodology.”

In the phase III ASSURE trial³ neither sunitinib nor sorafenib (Nexavar) improved outcomes when administered after surgery to patients with locally advanced RCC. The trial enrolled patients with non-clear cell histology (21%), those at intermediate risk (50%), and patients with less than stage 3 disease (34%). Additionally, the daily dose of sunitinib was modified from 50 mg per day to 35 mg.

The median DFS was 5.8 years in both the sorafenib and sunitinib arms and 6.0 years in the placebo arm. The 5-year DFS rate was 52.8% in the sorafenib arm, 53.8% in the sunitinib arm, and 55.8% in the placebo arm. In those with clear cell carcinoma, the DFS was 5.6 years with sunitinib, 5.1 years with sorafenib, and 5.7 years with placebo. The 5-year survival rate was 76.9% with sunitinib, 80.7% with sorafenib, and 78.7% with placebo.

“Disease-free survival is a useful surrogate endpoint, but the results from different studies have been contradictory. It does not necessarily translate to overall survival, which is the gold standard," Thomas Powles, MBBS, professor of urology cancer, Barts Cancer Institute, London, UK, commented in a statement from ESMO.. "Preliminary results in this setting do not point towards a survival benefit. There are a number of other trials ongoing in this area and I would like to see one of these being positive to tip the balance towards benefit.”

The phase III ATLAS trial is currently assessing adjuvant therapy with axitinib (Inlyta) for patients with high-risk, clear cell RCC. This study enrolled 700 patients (NCT01599754). Additionally, the phase III PROTECT study is looking at adjuvant pazopanib (Votrient) in patients with intermediate or high-risk, clear cell RCC. This large study included 1540 patients (NCT01235962).

References:

1. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy [published online October 10, 2016]. N Engl J Med. DOI: 10.1056/NEJMoa1611406.
2. Ravaud A, Motzer RJ, Pandha HS, et al. Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract for LBA11.
3. Haas NB, Manola J, Uzzo RG, et al. Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol. 2015;33 (suppl 7; abstr 403)

Results from these studies will provide further evidence for adjuvant therapy in RCC; however, until they report their results, Powles could not make a recommendation regarding whether adjuvant therapy is warranted. “Without a consistently positive disease-free survival signal it would be premature for me to recommend sunitinib as adjuvant therapy for my patients, particularly when one considers the toxicity," he said. "A positive survival signal, or meta-analysis for disease-free survival, would be needed. Other studies in this area are awaited.”

The investigator assessed median DFS in the sunitinib arm was 6.5 years compared with 4.5 years with placebo (HR, 0.81; 95% CI, 0.64-1.02; P = .08). In higher risk patients, the median DFS by investigator assessment was 5.9 versus 3.9 years for sunitinib and placebo, respectively (HR, 0.76; 95% CI, 0.58-1.01; P = .06).