Barcelona, Spain (UroToday.com) Overall, 16% of all patients diagnosed with renal cell carcinoma (RCC) have loco-regional disease at diagnosis, and 40% of these patients relapse after a radical nephrectomy with metastasis. In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional RCC at high risk of recurrence after nephrectomy (HR 0.76, 95% CI 0.59-0.98, p = 0.03).1 Subsequently, Ravaud et al. previously applied the 16-gene Recurrence Score and confirmed its prognostic value.2 At the ESMO 2019 poster discussion, Dr. Ravaud and colleagues reported the results of their retrospective exploratory genomic and transcriptomic analyses using nephrectomy biospecimens from the S-TRAC trial.
For this study, formalin-fixed paraffin-embedded tumor tissue blocks from patients who provided informed consent were used for whole exome (WES) and whole transcriptome (RNAseq) sequencing to examine somatic mutations and analyze relevant gene expression signatures in relation to clinical outcome. Gene expression signature analyses included published signatures [effector T-cell (Teff), angiogenesis, myeloid inflammation (Minf)] among others. Cox proportional analyses of DFS were performed for each genotype or signature in sunitinib versus placebo groups and between genotypes or signatures within each treatment group.
Overall, there were 171 patients (sunitinib, n = 91; placebo, n = 80) were genotyped and 133 (sunitinib, n = 72; placebo, n = 61) were included in the gene expression signature analyses. Differences in DFS were observed relative to wildtype when mutations in genes such as ARID1A, MTOR, or ROBO3 were present. The presence or absence of mutation in BAP1, SETD2 or PBRM1, however, did not distinguish patients with respect to DFS. Low tumor mutational burden was associated with longer DFS in placebo as compared to high tumor mutational burden (HR 0.253; 95% CI 0.119-0.541), but not in sunitinib. 
Low-angiogenesis gene expression signature showed a modest association with shorter DFS vs high- angiogenesis gene expression signature in placebo (HR 1.912; 95% CI 0.829-4.409) but did not differentiate DFS in sunitinib. Patients with low-Minf gene expression signature in sunitinib had longer DFS vs those with high-Minf gene expression signature (HR 0.304; 95% CI 0.132-0.702). Using the new JAVELIN Renal 101 signature, high expression of the signature showed a modest association with prolonged DFS vs low expression in the placebo (HR 0.42; 95% CI 0.18-0.98) and in the sunitinib arm (HR 0.51; 95% CI 0.24-1.08).
Dr. Ravaud concluded this analysis of S-TRAC with the following conclusions:
- Whole transcriptome profiling analyses showed distinct biological associations with DFS benefit and adjuvant sunitinib
- Mutations in specific genes (WDFY4, CSPG4) were associated with worse outcomes in the placebo arm, but not in the sunitinib arm
- Together, these findings suggest that the genomic analysis of high-risk RCC can help identify patients who may benefit from adjuvant sunitinib
- Independent validation studies are needed to confirm these findings
Clinical trial identification NCT00375674
Presented by: Alain Ravaud, M.D., Ph.D., Hôpital Saint André, CHU de Bordeaux, France
Co-Authors: J.-F. Martini 2, K. Ching 2, M. Staehler 3, A. Magheli 4, B. Escudier 5, X.J. Mu 2, O. Valota 6, X. Lin 2, R. Motzer 7
2. Pfizer, La Jolla, US3. University of Munich, Munich, DE
4. Charité Universitaetsmedizin Berlin, Berlin, DE
5. Gustave Roussy - Cancer Campus, Villejuif, FR
6. Pfizer S.r.L, Milan, IT
7. Memorial Sloan-Kettering Cancer Center, New York, US
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain
References:
- Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375(23):2246-2254.
- Rini BI, Escudier B, Martini J, 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. Clin Cancer Res 2018 Sep 15;24(18):4407-4415.
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ESMO 2019: Invited Discussant: (904PD, 905PD, 906PD) NABUCCO (mUC), FGFR3 Alteration as a Predictor of Non-Response to Neoadjuvant Pembrolizumab (mUC), and Adjuvant Sunitinib in Patients with High-Risk (RCC)