Predicting Targeted Therapy Resistance in Non-Small Cell Lung Cancer Using Multimodal Machine Learning

Lung cancer is the primary cause of cancer death globally, with non-small cell lung cancer (NSCLC) emerging as its most prevalent subtype. Among NSCLC patients, approximately 32.3% have mutations in the epidermal growth factor receptor (EGFR) gene. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI), has demonstrated remarkable efficacy in the treatment of NSCLC patients with activating and T790M resistance EGFR mutations. Despite its established efficacy, drug resistance poses a significant challenge for patients to fully benefit from osimertinib. The absence of a standard tool to accurately predict TKI resistance, including that of osimertinib, remains a critical obstacle. To bridge this gap, in this study, we developed an interpretable multimodal machine learning model designed to predict patient resistance to osimertinib among late-stage NSCLC patients with activating EGFR mutations, achieving a c-index of 0.82 on a multi-institutional dataset. This machine learning model harnesses readily available data routinely collected during patient visits and medical assessments to facilitate precision lung cancer management and informed treatment decisions. By integrating various data types such as histology images, next generation sequencing (NGS) data, demographics data, and clinical records, our multimodal model can generate well-informed recommendations. Our experiment results also demonstrated the superior performance of the multimodal model over single modality models (c-index 0.82 compared with 0.75 and 0.77), thus underscoring the benefit of combining multiple modalities in patient outcome prediction.