ESMO 2019: Phase 3 Trial of Adjuvant Sunitinib in Patients with High-risk Renal Cell Carcinoma: Comprehensive Tumor Genomic and Transcriptomic Analyses

Barcelona, Spain (UroToday.com) Surgical resection is the treatment of choice for Stage 1-3 renal cell carcinoma. As of 2016, SEER data suggests that 16% of patients are diagnosed with the locoregional disease at the time of presentation, and up to 40% of these patients recur with metastatic disease. Multiple studies have looked at the role of adjuvant therapy with various tyrosine kinase inhibitors. The S-TRAC study1 showed a statistically significant benefit for median disease-free survival (DFS) with sunitinib in high-risk patients with locoregional disease relative to placebo (6.8 years versus 5.6 year, HR 0.76, P = 0.03). The S-TRAC investigators previously applied the Rini recurrence score to samples from this trial and confirmed its prognostic utility but was unable to predict differential benefit from adjuvant therapy2.

In this poster, Dr. Ravaud and colleagues present the results of a retrospective genomic and transcriptomic analysis of patient nephrectomy specimens from the S-TRAC trial to further explore potential biomarkers of response to adjuvant therapy. In total, 171 patients were genotyped with whole-exome sequencing (91 treated with sunitinib and 80 placebo), and 133 patient samples were subjected to transcriptomic analysis.

With regards to mutational status, mutations in ARID1A were associated with decreased DFS relative to wild-type in the sunitinib treated arm. Lower tumor mutational burden was associated with improved DFS in the placebo arm (HR 0.253, 95% CI: 0.119-0.541, P = 0.0052), but not in patients treated with sunitinib. Mutations in CSPG4 and WDFY4 trended towards better outcomes in sunitinib treated patients, but not placebo treated patients. Of the gene expression signatures tested, only the Myeloid Inflammation Signature was associated with DFS in sunitinib treated patients. Patients with low expression of this signature did better (HR 0.304, 95% CI: 0.132-0.702, P = 0.0023).

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In summary, genomic analysis may be able to distinguish which patients with high-risk locoregional renal cell carcinoma are likely to recur, specifically patients who receive no adjuvant therapy and have higher tumor mutational burden or sunitinib treated patients with wild-type ARID1A or mutations in CSPG4 and WDFY4. Application of the myeloid inflammation signature may also identify patients who would benefit from adjuvant sunitinib therapy. These findings require validation in a larger prospective cohort before they can influence clinical decision making. 



Presented by: Alain Ravaud, M.D., Ph.D., Medical Oncologist at the Hôpital Saint André, CHU de Bordeaux, France 

Written by: Alok Tewari, MD, Ph.D., Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain

References: 
1. Ravaud A. et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. The New England Journal of Medicine. 2016; 375:2246-2254 DOI: 10.1056/NEJMoa1611406.
2. Rini B. et al. Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib. Clinical Cancer Research. 2018 Sept DOI: 10.1158/1078-0432.CCR-18-0323.

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