Molecular markers associated with survival in PD-L1– high non-small cell lung cancer treated with first-line immunotherapy versus chemoimmunotherapy.

Abstract

e20607 Background: It is unclear which patients with advanced non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) tumor proportion score (TPS ≥50%) benefit from single-agent immunotherapy versus adding chemotherapy. We aimed to identify genetic alterations associated with differential survival from first-line immunotherapy (I) versus chemoimmunotherapy (IC) among these patients. Methods: From the nationwide (US-based) deidentified Flatiron Health-Foundation Medicine NSCLC Clinico-Genomic Database, containing data originated from ~280 US cancer clinics, we analyzed patients with advanced non-squamous NSCLC who had high PD-L1 expression and were treated with first-line I (pembrolizumab, atezolizumab, or cemiplimab) or IC starting 2017-2023. For cases with multiple PD-L1 TPS measurements, the earliest recorded value was used. Patients were excluded if they had squamous cell or unknown histology, or mutations in EGFR or ALK. DNA Alteration data was utilized to evaluate associations between specific genetic mutations and OS using multivariable Cox proportional hazards models. Covariates included age, birth sex, baseline ECOG performance status, race, number of metastatic sites, and the presence of brain, bone, or liver metastases. Results: Among 527 patients (303 I and 224 CI), older patients were more likely to receive I (mean 70.9 vs 67.0, p<0.001). However, patients were more likely to receive IC when they had bone metastases (41.1% vs. 30.7%, p=0.018). Mutations in ATM (Hazard Ratio [HR]=0.65, 95% Confidence Interval [CI]: 0.48–0.88, p=0.005), NOTCH2 (HR = 0.49, CI: 0.28-0.88, p=0.016), NOTCH4 (HR= 0.35, CI: 0.14-0.86, p=0.022), and SMAD4 (HR=0.35, CI: 0.16-0.79, p=0.011) were associated with improved OS. While OS was similar between patients receiving I and IC overall (HR = 0.94, CI: 0.76-1.17, p=0.590), patients with mutations in NOTCH2 (HR = 0.46, CI: 0.21-0.96, p=0.038), ATRX (HR = 0.51, CI: 0.25-1.03, p=0.038), and SMAD4 (HR = 0.20, CI: 0.05-0.79, p=0.022) demonstrated improved OS when treated with I compared to IC. The presence of co-mutations in all 3 of STK11, KEAP1, and SMARCA4 was associated with worse OS (HR= 2.31, CI: 1.19-4.51, p=0.014). Conclusions: Advanced NSCLC patients with high PD-L1 expression and mutations in NOTCH2, ATRX, or SMAD4 were found to have significantly higher overall survival when treated with first-line immunotherapy rather than chemoimmunotherapy. Further studies are warranted to validate these biomarkers and assess their potential role in optimizing treatment strategies.