ODAC Vote Split on Potential Approval of Adjuvant Sunitinib in High-Risk RCC

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 6-6 on the potential approval of sunitinib (Sutent) for use as an adjuvant therapy in patients with renal cell carcinoma (RCC) who have received nephrectomy and are at high risk of recurrence. The FDA will take this vote into consideration when determining its final approval decision, which is scheduled to be made by January 2018.

The panel was voting on the risk-benefit profile of sunitinib in this setting based on findings from the phase III S-TRAC trial, in which adjuvant sunitinib prolonged disease-free survival (DFS) by 1.2 years compared with placebo following nephrectomy for patients with high-risk clear cell RCC. Findings of the study were presented at the 2016 ESMO Congress and published in the New England Journal of Medicine.^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.

On June 1, 2017, the FDA granted a priority review to a supplemental new drug application for sunitinib in this setting. The agency will factor the ODAC panel discussion and vote into its final decision, which is scheduled to be made by January 2018.

“We are encouraged by today’s productive discussion and look forward to working with the FDA over the next few weeks as they incorporate today’s discussion into their review and decision regarding Sutent in this patient population,” Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development, said in a statement. “Sutent has long been a standard of care for the treatment of advanced RCC and we believe that this potential benefit can be extended into patients with high-risk of RCC recurrence, as demonstrated in the S-TRAC trial.”

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%).

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.