Evaluating the combined role of HHLA2 and PD-L1 as biomarkers in first-line nivolumab therapy in advanced clear cell renal cell carcinoma.

598 Background: PD-1 directed immune checkpoint inhibitors are effective in many tumor types, including kidney cancers. HHLA2 is a negative immune checkpoint, generally expressed on PD-L1 negative clear cell renal cell carcinomas (ccRCC) (Bhatt, et al. 2021). Therapeutics targeting either HHLA2 or its inhibitory receptor KIR3DL3 are in Phase I trials and predictive biomarkers are needed to help direct treatment. We previously reported that efficacy of nivolumab correlated with tumor PD-L1 status in patients with kidney cancer treated in the first line setting (GU16- 260; Atkins, et al. 2022). We hypothesize that HHLA2 expression in combination with PD-L1 expression may provide a clinically significant biomarker for resistance to PD-1 blockade in patients with advanced ccRCC. Methods: HHLA2 expression in tumor cells (TC) was assessed by immunohistochemistry coupled with image analysis algorithms in 63 pre-treatment primary ccRCC tissues from patients enrolled in the HCRN GU16-260 trial. TC PDL-1 positivity had been previously evaluated in this cohort (Atkins, 2022). TC HHLA2 expression in combination with TC PD-L1 expression was correlated with progression-free survival (PFS) and objective response rate (ORR). Results: Consistent with our prior reports, HHLA2 expression did not overlap with PD-L1 expression on tumor cells. TC HHLA2 expression in combination with TC PD-L1 expression identified three groups of patients with different clinical outcomes with regards to ORR (trend test p-value = 0.016) and PFS (trend test p-value = 0.024) (Table). Patients with positive (>0%) TC PD-L1 expression had the best outcomes (ORR=62.5%, median PFS=24.7 months); patients with negative TC PD-L1 expression and low (<61%) TC HHLA2 expression had intermediate outcomes (ORR=38.5%, median PFS=10.6 months) and patients with negative TC PD-L1 expression and high (≥61%) TC HHLA2 expression had the worst outcomes (ORR=12.5%, median PFS=3.5 months). Conclusions: Further investigation of the HHLA2/PD-L1 combined biomarker is warranted as it may be helpful in identifying patients that do not respond to anti-PD-1 therapy but could benefit from agents targeting the HHLA2/KIR3DL3 pathway. HHLA2 and PDL-1 category Number of patients(63 total) ORR PFS (median, months) TC PD-L1 >0% 16 62.5% 24.7 TC PD-L1 = 0% & TC HHLA2 <61% (low) 39 38.5% 10.6 TC PD-L1 = 0% & TC HHLA2 ≥61% (high) 8 12.5% 3.5 Trend test p-value 0.016 0.024