Identification of prognostic genomic biomarkers in metastatic clear cell renal cell carcinoma (mccRCC): An analysis of the large retrospective real world clinico-genomic data from Flatiron Health (FH)-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB).

4553 Background: Despite a number of therapeutic improvements, mccRCC still has a poor prognosis, with limited prognostic predictors for clinical practice. The aim of this study was to evaluate the prognostic value of three clusters of co-occurring genes in mccRCC. Methods: We conducted a retrospective analysis of adult patients with mccRCC who were profiled by performing FMI genomic tests using tissue biopsies or blood samples. Data were from the nationwide (US-based) de-identified FH-FMI CGDB, originating from approximately 280 US cancer clinics (~800 sites of care). Patients diagnosed from January 01, 2011 to June 30, 2022 were followed until death or the last available observation (within December 31, 2022). Overall Survival (OS) was estimated using the Kaplan-Meier methods, while Cox proportional hazard model with risk set adjustment was used to assess the prognostic role of three pre-specified clusters of co-occurring genes; cluster 1 (C1) included VHL, SETD2, PBRM1, KDM5C, MTOR, and NFE2L2, cluster 2 (C2) included TP53, TSC1, and TERT, while cluster 3 (C3) included CDKN2A, CDKN2B, BAP1, NF2, MTAP, and ARID1A. Patients were considered cluster-positive (+) if they exhibited mutations in at least one gene within the cluster, and none in the other clusters. Results: 789 mccRCC patients were included median age: 61 years, male: 71.1%, white race: 71.2%. Among the 720 (91.3%) treated patients, 516 (71.7%) and 59 (8.2%) were classified per IMDC score as poor/intermediate and favorable risk, respectively (145 missing). Overall, almost half (45.5%; 359) were profiled after the diagnosis of metastasis (median gap time of 7.9 months) and 29 (3.7%) underwent multiple profile assessments, resulting in a total of 818 specimens analyzed. 332 (42.1%), 27 (3.4%), and 32 (4.1%) patients were C1+, C2+, and C3+, respectively. Median OS was 37 months (95% CI: 34-42). C1+ patients had higher OS compared to C1- (median OS: 50 vs. 30 months; HR: 0.57, p<0.001), while C3+ was associated with worse OS (median OS: 38 vs. 20 months; HR: 1.94, p=0.004). No association was found between C2 and OS (HR: 1.27; p=0.4). C1+ patients were more frequently classified as favorable risk compared to C1- (10.2% C1+ vs. 6.8% C1-, p=0.046) and they had longer duration of first-line (L1) treatment (median DoT: 9 vs. 7 months, p = 0.02). No significant differences between C2+ and C2-, C3+ and C3- patients were observed in L1 duration and IMDC distribution. Conclusions: This large-scale study identified two independent prognostic gene clusters in mccRCC. Further analyses will focus on the validation of the predictive role of these biomarkers with the ultimate aim of helping us develop tailored treatment strategies.