LAUSR

4568 Background: hERV levels positively correlate with tumor immune infiltrate and were recently shown to be associated with clinical benefit to PD-1/PD-L1 blockade in two small cohorts of patients (pts) with mccRCC (Smith C.C. et al and Panda A. et al; 2018). We tested whether hERV levels correlate with efficacy of nivolumab in a prospective phase II study of pts with mccRCC (Checkmate 010). Methods: Reverse transcribed RNA extracted from 99 FFPE pretreatment tumors were analyzed by RT-qPCR to assess levels of pan- ERVE4, pan- ERV3.2, hERV4700 GAG or ENV, and the reference genes 18S and HPRT1. Normalized hERV levels were transformed as categorical value (high or low) using population quartiles as cutoffs. For each cutoff, samples with non-quantifiable hERV levels for which the limit of quantification was above the tested cutoff could not be categorized and were excluded from analysis. Log rank test was used to test the association of hERV levels with PFS/irPFS (RECISTv1.1/irRECIST) at each cutoff using Holm-Bonferroni correction for Type I error control; adjusted P-values are reported. Fisher’s exact test was then used to explore the association with ORR/irORR (RECISTv1.1/irRECIST). Results: Among the hERV studied, only hERV4700 ENV was significantly associated with PFS/irPFS. At the 25th percentile cutoff, 45 pts had high levels of hERV4700 ENV and 24 pts had low levels of hERV4700 ENV. Median PFS and irPFS were significantly longer in the high- hERV4700 ENV group [7.0 (95% CI: 2.2 - 10.2) and 8.5 (95% CI: 4.2 - 14.1) months, respectively] versus the low- hERV4700 ENV group [2.6 (95% CI: 1.4 - 5.4) and 2.9 (95% CI: 1.4 - 5.7) months, respectively] ( P = 0.010 for PFS and P = 0.028 for irPFS). At the same cutoff, ORR and irORR rates were significantly higher in the high- hERV4700 ENV group [35.6 (95% CI: 21.9 - 51.2) % for both ORR/irORR] versus the low- hERV4700 ENV group [12.5 (95% CI: 2.7 - 32.4) and 8.3 (95% CI: 1.0 - 27.0) %, respectively] ( P = 0.036 for ORR and P = 0.012 for irORR). Conclusions: hERV4700 ENV levels may predict outcome on nivolumab in mccRCC. Validation of our results and correlation of hERV levels with immune markers in a controlled phase III trial (CheckMate 025) is ongoing.