Differential predictive impact of PD-L1 expression on immunotherapy outcomes and immunophenotype in squamous versus non-squamous NSCLC.

Abstract

8562 Background: PD-L1 tumor proportion score (TPS) is a key biomarker for immune checkpoint inhibitors (ICIs) efficacy in non-small cell lung cancer (NSCLC), but its predictive value in patients (pts) with squamous (SQ) histology remains uncertain, highlighting the need for histology-specific studies. Methods: Clinicopathologic, genomic, and outcomes data were collected and analyzed from advanced NSCLC pts treated with ICIs ± chemotherapy (CT) at Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center. Cox regression tested the association between PD-L1 levels and survival to ICIs by histology, adjusting for potential confounders such as treatment regimen and line. Multiplexed immunofluorescence (mIF) on baseline tissue samples quantified CD8+, PD1+, CD8+/PD1+, and FOXP3+ densities, stratifying by PD-L1 TPS and histology. Results: Among 4967 NSCLC pts treated with ICIs ± CT, 727 (14.6%) had SQ histology. Among pts with available PD-L1 TPS, 1359 (37.9%) had TPS <1%, 1061 (29.6%) 1–49%, and 1167 (32.5%) ≥50%. Increasing PD-L1 TPS of <1%, 1–49% and ≥50% correlated with significant stepwise improvements in progression-free (PFS) and overall survival (OS) in pts with NonSQ NSCLC but not in those with SQ (Table 1). In SQ NSCLCs, there was no difference in PFS and OS between pts with PD-L1 TPS of 1–49% vs ≥50%, while only a dichotomized PD-L1 TPS (<1% vs ≥1%) was predictive of longer survival in this histology (PFS adjusted hazard ratio [aHR]: 0.72, p<0.01; OS aHR: 0.76, p=0.02). Comparing histologies, PFS and OS to ICIs ± CT were similar between SQ and NonSQ NSCLCs in PD-L1 TPS subgroups of <1% and 1–49%. However, among pts with a PD-L1 TPS ≥50%, those with NonSQ NSCLC had longer survival compared to SQ (PFS aHR: 1.30, p=0.01; OS aHR: 1.43, p<0.01), indicating stronger predictive value of increasing PD-L1 TPS levels only in NonSQ. mIF analysis (229 samples: 22 SQ, 207 NonSQ) showed lower intratumoral CD8+, PD1+, CD8+/PD1+, and FOXP3+ densities in SQ vs NonSQ. Increasing PD-L1 TPS significantly correlated with higher CD8+ cells in NonSQ NSCLCs (R = 0.25, p<0.01) but not in SQ (R = -0.034, p = 0.89). A similar association was observed for PD1+, CD8+/PD1+, and FOXP3+ cells. Conclusions: Increasing PD-L1 levels show stepwise PFS and OS improvements in NonSQ but not in SQ NSCLCs, where TPS acts as a dichotomous (<1% vs ≥1%) rather than continuous predictor. These findings have implications for treatment decision making as well as ICIs trial design and interpretation. PD-L1 TPS<1% vs 1-49% PD-L1 TPS<1% vs ≥50% PD-L1 TPS1-49% vs ≥50% SQ PFS mo aHR, p 4.0 vs 6.6 0.72, <0.01 4.0 vs 6.2 0.71, 0.01 6.6 vs 6.2 0.99, 0.95 NonSQ PFS mo aHR, p 4.6 vs 5.8 0.79, <0.01 4.6 vs 8.2 0.56, <0.01 5.8 vs 8.2 0.70, <0.01 SQ OS mo aHR, p 13.0 vs 17.0 0.77, 0.04 13.0 vs 17.5 0.76, 0.06 17.0 vs 17.5 0.98, 0.92 NonSQ OS mo aHR, p 14.7 vs 18.3 0.81, <0.01 14.7 vs 27.7 0.59, <0.01 18.3 vs 27.7 0.72, <0.01