Mechanistic Learning for Predicting Survival Outcomes in Head and Neck Squamous Cell Carcinoma

We employed a mechanistic learning approach, integrating on-treatment tumor kinetics (TK) modeling with various machine learning (ML) models to address the challenge of predicting post-progression survival (PPS)-the duration from the time of documented disease progression to death-and overall survival (OS) in Head and Neck Squamous Cell Carcinoma (HNSCC). We compared the predictive power of model-derived TK parameters versus RECIST and assessed the efficacy of nine TK-OS ML models against conventional survival models. Data from 526 advanced HNSCC patients treated with chemotherapy and cetuximab in the TPExtreme trial were analyzed using a double-exponential model. TK parameters from the first line and maintenance (TKL1) or after four cycles (TK4) were used to predict PPS and post-cycle 4 OS (OS4), combined with 12 baseline parameters. While ML algorithms underperformed compared to the Cox model for PPS, a random survival forest was superior for OS prediction using TK4 and surpassed RECIST-based metrics. This model demonstrated unbiased OS4 prediction, suggesting its potential for improving HNSCC treatment evaluation. Trial Registration: ClinicalTrials.gov identifier: NCT02268695.