Distinct Predictive Effects of PD-L1 Tps on Immunotherapy Outcomes and Immunophenotype in Squamous Versus Non-Squamous NSCLC

Document Type

Conference Proceeding

Publication Date

10-1-2025

Publication Title

J Thorac Oncol

Keywords

alanine aminotransferase, biological marker, CD8 antigen, epidermal growth factor receptor, immune checkpoint inhibitor, programmed death 1 ligand 1, adult, aged, conference abstract, drug dose reduction, drug therapy, female, histology, human, human tissue, immunofluorescence, immunohistochemistry, immunophenotyping, major clinical study, male, non small cell lung cancer, overall survival, progression free survival, response evaluation criteria in solid tumors, special situation for pharmacovigilance

Abstract

Introduction: PD-L1 tumor proportion score (TPS) is a key biomarker for immune checkpoint inhibitors (ICIs) efficacy in non-small cell lung cancer (NSCLC). However, its predictive role in squamous (SQ) histology remains unclear, warranting histology-specific investigation. Methods: Clinicopathologic, genomic, and outcomes data were collected from patients with advanced NSCLC treated with ICIs ± chemotherapy across five international academic centers. Cox regression assessed the association between PD-L1 TPS and survival outcomes to ICIs by histology, adjusting for treatment regimen and line, while spline-based model explored potential non-linear effect across histologic subtypes. Multiplexed immunofluorescence (mIF) on baseline samples quantified immune cell densities, stratifying by PDL1 TPS and histology. Mutation enrichment analysis explored genomic correlates of response to ICIs ± chemotherapy in SQ NSCLCs. Results: Among 5148 patients with NSCLC treated with ICIs ± chemotherapy, 909 (17.7%) had SQ histology. Among patients with available PD-L1 TPS, 37.2% had TPS <1%, 30.1% 1-49%, and 32.7% >50%. Increasing PD-L1 TPS categories (<1%, 1-49%, >50%) were associated with significant stepwise improvements in progression-free (PFS) and overall survival (OS) in NonSQ but not in SQ NSCLCs (Figure 1A). In SQ, only a dichotomized PD-L1 TPS (<1% vs >1%) was predictive of longer PFS (adjusted hazard ratio [aHR]: 0.75, p<0.01) and OS (aHR: 0.78, p=0.02), while no difference was observed between TPS 1-49% and >50%. Comparing histologies, survival outcomes were similar in TPS subgroups of < 1% and 1-49%, but significantly longer in NonSQ vs SQ among patients with TPS >50% (PFS aHR: 1.25, p=0.01; OS aHR: 1.50, p<0.01). Spline-based Cox models confirmed the stepwise association between increasing PD-L1 levels and improved survival in NonSQ NSCLCs, but showed a non-linear, plateauing effect beyond 1% in SQ, with no incremental survival benefit (Figure 1B-E). mIF analysis (229 samples: 22 SQ, 207 NonSQ) revealed lower intratumoral CD8+, non-small cell lung cancer (NSCLC) who have progressed on prior EGFR-TKI therapy. Methods: The study included dose-escalation and dose-expansion phase for patients with locally advanced or metastatic EGFRT790M-positive NSCLC. In the dose-escalation phase, 12 patients received oral FHND9041 at 40 mg (n=3), 80 mg (n=3), 120 mg (n=3), and 180 mg (n=3) once daily (QD). In the expansion phase, 112 pa tients were enrolled to receive FHND9041 at 80 mg (n=73) or 120 mg (n=39) QD. The primary endpoints were safety/tolerability and objective response rate (ORR) according to RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), and overall survival (OS). Results: A total of 112 patients were treated in Phase II. The confirmed ORR (N=109) was 49.5% (54/109; 95% CI: 39.8-59.3), and the disease control rate (DCR) was 96.3% (95% CI: 90.9-99.0). The median PFS in the overall population (N=112) was 15.1 months (95% CI: 11.1-16.6), with censored patients of 36 patients (32.1%). The P75 was 27.6 months (95% CI: 23.4-NE). The mean PFS was 18.5 months (SE: 1.4). Median DoR was 19.4 months (95% CI: 13.8-26.3). The median OS was 29.8 months (95% CI: 21.6-43.2), with 55 patients (49.1%) censored. These results suggest a promising duration of disease control with FHND9041. In the dose-escalation phase, one dose-limiting toxicity (DLT) of elevated alanine aminotransferase (ALT) was observed at the 180 mg dose level. In the 80 mg (the Phase III dose) expansion cohort, grade >3 treatment-related adverse events (TRAEs) occurred in 8.2% (6/73) of patients, with no TRAEs leading to dose reduction. Across both 80 mg and 120 mg expansion cohorts, no treatment-related deaths were reported and grade >3 TRAEs were observed in 14.3% of patients (16/112). Conclusions: FHND9041 showed durable efficacy and a favorable safety profile in patients with EGFR T790M-positive NSCLC who progressed after EGFR-TKI treat ment, supporting its further development as a po ential treatment option.

Volume

20

Issue

10

First Page

S192

Last Page

S193

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