Faculty, Staff and Student Publications

Publication Date

7-24-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-61823-w

PMID

40707438

PMCID

PMC12289920

PubMedCentral® Posted Date

7-24-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Immune checkpoint inhibitors (ICIs), either as monotherapy (ICI-Mono) or combined with chemotherapy (ICI-Chemo), improves survival in advanced non-small cell lung cancer (NSCLC). However, prospective guidance for choosing between these options remains limited, and single-feature biomarkers like PD-L1 prove inadequate. We develop a machine learning model using clinicogenomic data from four cohorts (MD Anderson n = 750; Mayo Clinic n = 80; Dana-Farber n = 1077; Stand Up To Cancer n = 393) to predict individual benefit from adding chemotherapy. Benefit scores are calculated using five distinct functions derived from 28 genomic and 6 clinical features. Our integrated model, A-STEP (Attention-based Scoring for Treatment Effect Prediction), estimates heterogeneous treatment effects and achieves the largest reduction in 3-month progression risk, improving weighted risk reduction by 13-23% over stand-alone models. A-STEP recommends treatment changes for over 50% of patients, most often favoring ICI-Chemo. In simulation on external cohort, patients treated in accordance with A-STEP recommendations show improved 2-year progression-free survival (HR = 0.60 for ICI-Mono treatment arm; HR = 0.58 for ICI-Chemo treatment arm). Predictive features include FBXW7, APC, and PD-L1. In this study, we demonstrate how machine learning can fill critical gaps in immunotherapy selection for NSCLC, by modeling treatment heterogeneity with real-world clinicogenomic data, driving precision medicine beyond conventional biomarker boundaries.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Machine Learning, Lung Neoplasms, Immunotherapy, Immune Checkpoint Inhibitors, Female, Male, Middle Aged, Biomarkers, Tumor, B7-H1 Antigen, Aged

Published Open-Access

yes

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