Prognostic implications of antitumour efficacy and adverse events of EGFR-TKIs in non-small cell lung cancer: an ambispective cohort study

The objective of this study was to quantify the impact of longitudinal tumour dynamics, time-varying drug-related adverse events (DRAEs), and other clinical characteristics on long-term outcomes in patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). An ambispective cohort of 277 patients was analysed and externally validated using independent clinical trial data from 470 patients in the Project Data Sphere. Individual tumour growth trajectories were characterised by predicted sum of the longest diameters (SLD) using tumour growth inhibition (TGI) modelling. Time-dependent Cox and parametric time-to-event models were then applied to evaluate the influence of predicted tumour growth trajectories, observed dynamic DRAE profiles, cross-sectional variables derived from these measures, and additional covariates on time-to-treatment failure (TTF) and progression-free survival (PFS). The TGI models effectively captured individual tumour dynamics. Across both Cox and parametric time-to-event models, prognostic factors consistently included DRAEs, baseline metastasis, EGFR-TKI treatment history, and the specific EGFR-TKI administered. Notably, grade 2 DRAEs were associated with an optimal balance between efficacy and safety, and this association remained robust in sensitivity analyses and was preliminarily validated using external data. These findings emphasise the clinical relevance of DRAE grades in indicating long-term clinical benefit. By linking manageable toxicity with durable therapeutic outcomes, the study provides valuable insights for developing safe and effective EGFR-TKI treatment strategies in patients with NSCLC.