Clinical validation of a blood-based multimodal immune-response score in a real-world cohort of advanced non–small cell lung cancer.

e20581 Background: Immune checkpoint inhibitors (ICIs) have transformed care for advanced non-small cell lung cancer (aNSCLC), but predictive biomarkers remain imperfect. We previously developed a multimodal immunotherapy response score (MIRS), which integrated ctDNA epigenomic signatures with microsatellite instability (MSI) and tumor mutational burden (TMB) from a single blood draw, and validated its use as a predictive biomarker for ICI response. In this study, we assess the ability of MIRS to predict clinical outcomes in real-world patients treated with ICIs. Methods: MIRS was trained and validated using de-identified patient data from InfinityAI Data Library and expressed as percentile based on MIRS distribution with >20,000 aNSCLC samples. In this study, we validated the signature in an independent cohort of 32 aNSCLC patients by analyzing baseline plasma on Guardant360 Liquid (Guardant Health, Palo Alto, CA); 27/32 received PD-1/PD-L1 monotherapy and 7/32 had tumor PD-L1 TPS <1%. Patients with MIRS ≥50% were defined as MIRS-High. The primary endpoint was real-world progression-free survival (rwPFS). We fitted Cox proportional hazards models (adjusted for covariates such as sex, age, tissue PD-L1 expression, histologic subtype, ECOG, TNM stage and baseline methylation tumor fraction) and reported adjusted hazard ratios (aHR) with 95% CIs. Median rwPFS was estimated by Kaplan–Meier method. Model discrimination was summarized using concordance index (c-index). Results: MIRS-High patients (18/32) had significantly longer rwPFS (median 15.1 vs 7.2 months; aHR 0.24, 95% CI 0.07–0.82, p=0.02; c-index = 0.80). As a continuous variable, MIRS percentile was associated with improved rwPFS (p=0.04). Stratification by PD-L1 ≥50% (n=14) showed a consistent, but not statistically significant trend toward longer rwPFS (aHR 0.60, 95% CI 0.19–1.87, p=0.38; c-index = 0.75). When both biomarkers were combined, patients with PD-L1 ≥50% or MIRS-High (n=25) had significantly longer rwPFS (aHR 0.24, 95% CI 0.07–0.90, p=0.034). All complete responses (n=4) were MIRS-High (median MIRS score of 80th percentile in aNSCLC); patients with progressive disease (n=6) had a median MIRS of 27th percentile in aNSCLC (partial responders (n=15) had a median of 51th percentile in aNSCLC, and stable disease cases (n=7) had median of 55th percentile in aNSCLC). Conclusions: Patients with MIRS-High scores had a 76% lower adjusted hazard of progression or death even after accounting for key covariates. Additionally, all complete responses were MIRS-High and MIRS was associated with significantly improved PFS compared to known biomarkers such as tissue-based PDL1. These data indicate that the multimodal score taken via a single baseline blood sample strongly predicts ICI benefit and may be useful in ICI vs chemo combination decisions pending further ongoing validation.