Unraveling relatlimab (RELA)-specific biology: Biomarker analyses in patients (pts) with metastatic non-small cell lung cancer (mNSCLC) treated with 1L nivolumab (NIVO) + RELA high-dose (HD) and platinum-doublet chemotherapy (PDCT).

Abstract

8527 Background: The addition of RELA HD, a lymphocyte activation gene-3 (LAG-3) inhibitor, to NIVO + PDCT has improved clinical benefits vs NIVO + PDCT for pts with PD-L1 expression ≥1% and NSQ histology in RELATIVITY-104 study. We report exploratory biomarker analyses from this study to elucidate mechanisms underlying NIVO + RELA HD + PDCT activity. Methods: Baseline and on-treatment blood samples were analyzed by flow cytometry for pharmacodynamic (PD) changes in immune cell populations including proliferating LAG-3-expressing CD4+ and CD8+ effector memory (EM) and central memory (CM) T cells. Baseline tumor samples were analyzed by monoplex immunohistochemistry (IHC) for tumor cell PD-L1, LAG-3, and CD8 expression. Associations between biomarkers and overall response rate (ORR) and progression free survival (PFS) were assessed. Results: NIVO + RELA HD + PDCT significantly modulated levels of proliferating LAG-3 expressing EM and CM T cells in the periphery on-treatment; no such PD change was observed with NIVO + PDCT. Among pts with NSQ histology, baseline tumor LAG-3 expression ≥1% showed improved ORR and median PFS in both treatment arms compared with LAG-3 <1%. Further, the benefit of RELA HD addition to NIVO + PDCT was also seen in patients with LAG-3 <1%, suggesting that baseline LAG-3 expression at 1%, unlike PD-L1 expression, would not help identify patients who can benefit from LAG-3 inhibition (Table). In contrast to NSQ, the same association trend of PD-L1 and LAG-3 expression with efficacy was not observed in pts with SQ histology, which could be partly attributable to the limited sample size in some SQ subgroups. Interestingly, PD-L1 ≥1% is more strongly correlated with CD8 T cells in NSQ as compared to SQ. Conclusions: These data represent the first in-depth biomarker analyses from a randomized phase 2 study to reveal that RELA can expand proliferating LAG-3 expressing T cells in NSCLC. NIVO + RELA HD + PDCT activity might be particularly robust in pts with NSQ histology and PD-L1 expression ≥1%, where CD8 T cells are enriched. The ongoing phase 3 RELATIVITY-1093 study is evaluating 1L NIVO + RELA HD + PDCT vs standard-of-care pembrolizumab + PDCT in mNSCLC. Clinical trial information: NCT04623775 . Efficacy of NIVO + RELA HD + PDCT vs NIVO + PDCT in pts with NSCLC by baseline histology, PD-L1 and LAG-3 expression. NIVO + RELA HD + PDCTvsNIVO + PDCT NSQ, PD-L1 ≥1%(n = 50 vs 48) NSQ, PD-L1 <1%(n = 48 vs 46) NSQ,LAG-3 ≥1%(n = 56 vs 42) NSQ,LAG-3 <1%(n = 38 vs 42) SQ,PD-L1 ≥1%(n = 29 vs 23) SQ,PD-L1 <1%(n = 22 vs 21) SQ,LAG-3 ≥1%(n = 38 vs 34) SQ,LAG-3 <1%(n = 13 vs 10) PFS HR(90% CI) 0.55(0.36–0.85) 1.24(0.84, 1.83) 0.81(0.54, 1.22) 0.79(0.51, 1.23) 0.78(0.46, 1.34) 1.25(0.7, 2.23) 0.97(0.61, 1.52) 0.98(0.45, 2.15) ORR, % 58% vs 39.6% 35.4% vs 34.8% 57.1% vs 45.2% 34.2% vs 26.2% 44.8% vs 43.5% 81.8% vs 66.7% 52.6% vs 55.9% 84.6% vs 50%