FDA Grants Adjuvant Sunitinib Priority Review in High-Risk RCC

Mace Rothenberg, MD

The FDA has granted a priority review designation to sunitinib (Sutent) for use as an adjuvant therapy in patients with renal cell carcinoma (RCC) who have received nephrectomy and are high risk for recurrence.

The supplemental new drug application for sunitinib is based on findings from the phase III S-TRAC trial, which were presented at the 2016 ESMO Congress and published in the New England Journal of Medicine.^1,2 In the study, adjuvant sunitinib prolonged disease-free survival (DFS) by 1.2 years compared with placebo following nephrectomy for patients with high-risk clear cell RCC.

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.

The FDA is scheduled to make its final decision by January 2018.

“There is currently no approved therapy for patients with kidney cancer post-surgery, and we know that some patients are at risk of their cancer returning,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, the manufacturer of sunitinib, said in a statement. “Given our experience with Sutent in patients with advanced or metastatic kidney cancer, we set out to determine whether Sutent could reduce the risk of recurrence in high-risk patients.”

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).

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).

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%).

Pfizer also reported in a press release that the European Medicines Agency validated for review a type II variation application for sunitinib for use in the same setting as the FDA application.

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.