Explainable machine learning models based on clinical trial surrogate outcomes for predicting overall survival in...

This study aimed to evaluate the relationship between surrogate efficacy outcomes and overall survival (OS) in clinical trials for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), and to develop a predictive model for OS that incorporates these surrogate outcomes while accounting for baseline patient characteristics.

Data were systematically collected from first-line trials published between January 2010 and March 2025 for R/M HNSCC. Five machine learning models were assessed to predict OS based on surrogate outcomes [objective response rate (ORR), disease control rate, progression free survival (PFS), duration of response, 1-year OS rate] and patient characteristics [human papillomavirus (HPV) status, Eastern Cooperative Oncology Group (ECOG) performance status, programmed death-ligand 1 (PD-L1) expression]. Retrospective data from a single institution was utilized to create simulated datasets for additional validation.

Analysis included 90 treatment arms [26 immune checkpoint inhibitor (ICI)-based and 64 non-ICI], extracted from 52 publications. The strongest correlation with median OS was the 1-year OS rate (r = 0.87, P < 0.001). ORR and median PFS showed positive correlations with OS overall, but these correlations were not significant within the ICI subgroup. The Elastic Net model demonstrated strong performance on the held-out test set (r = 0.74, P < 0.001) and the simulated validation set (r = 0.75, P < 0.001). Model interpretation showed that 1-year OS rate and ORR had the strongest impact on predicted OS among surrogate outcomes. Among patient characteristics, the proportion of ECOG 0 and HPV positivity impacted predicted OS across all regimens, while PD-L1 positivity impacted OS only in ICI-based regimens.

The Elastic Net model effectively bridges surrogate efficacy endpoints and median OS, facilitating the interpretation of early clinical trial outcomes and assisting in the prediction of OS benefit in R/M HNSCC.