Patterns of failure in metastatic ALK-positive NSCLC treated with crizotinib: implications for consolidative stereotactic body radiotherapy

Abstract

Acquired resistance limits durable control with crizotinib in metastatic ALK-positive non–small cell lung cancer (NSCLC). We characterized residual disease and initial progression patterns and identified predictors of candidates for consolidative stereotactic body radiation therapy (SBRT). Patients with stage IV ALK-rearranged NSCLC treated with crizotinib (2017–2024) were retrospectively reviewed. Response was assessed per RECIST v1.1. Initial progression was classified as original-site failure (OF), new-site failure (NF), or combined OF and NF (ONF). SBRT eligibility at maximal response was determined using NRG-BR001 criteria and predefined cranial stereotactic radiotherapy criteria. Predictors of eligibility were evaluated using penalized selection followed by logistic regression. Sixty patients were analyzed. Median time to maximal response was 3.5 months; 15 (25.0%) met SBRT eligibility criteria. Progression occurred in 83.3% (median time to progression, 14.1 months), and oligoprogression occurred in 56%. Lung (50%) and brain (35.7%) were the most common progression sites; initial failure occurred as OF in 34%, NF in 40%, and ONF in 26%. Notably, among SBRT-eligible patients, 66.7% progressed—most often in the brain (50%) and lung (33.3%)—with failures skewed toward NF (50%) rather than OF (30%) or ONF (20%). Independent predictors of SBRT eligibility were female sex, N0–2 disease, absence of baseline bone metastases, and involvement of < 2 metastatic organs. Progression on crizotinib is frequently oligoprogressive and commonly involves intrathoracic disease, with substantial contributions from both baseline-lesion progression and new-site failure. Consolidative SBRT appears feasible in a subset at maximal response. The identified predictors of SBRT eligibility should be considered exploratory and require external validation in larger prospective cohorts.