Impact of Dosage Modifications on Efficacy: Insights from Select Tyrosine Kinase Inhibitors Approved for Treatment of Non-Small Cell Lung Cancer with EGFR Mutations

PURPOSE: Dosage modifications, including dose interruptions and reductions, are commonly implemented to manage adverse reactions observed with oncology drugs. However, their impact on efficacy is not well understood. Here, we explored the impact of dosage modifications on progression free survival (PFS) and overall survival (OS) for four US FDA-approved tyrosine kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. METHODS: We collected patient-level data from clinical trials supporting the original FDA approvals of afatinib, dacomitinib, mobocertinib, and osimertinib. We identified the daily dose received (DDR; a measure of the dosage received by a patient each day), dose interruptions and reductions over the treatment period. In this exploratory analysis, we used a time-dependent Cox proportional hazards model to assess the impact of DDR on PFS and landmark time-fixed Cox models at 30, 60, and 90 days from treatment initiation to assess the impact of early dose interruptions and reductions on PFS and OS. RESULTS: While the impact of dose interruptions and reductions on the risk of death varied among the studied drugs, dose interruptions, such as interruptions for four or more consecutive days, were more often associated with a higher risk of progression or death than dose reductions. CONCLUSION: For the evaluated drugs as monotherapy in NSCLC with EGFR mutations, our analysis suggests that dose reductions might have a lower impact on efficacy than missing or interrupting treatment. Further studies are needed to evaluate other EGFR treatments, drug classes, and cancer types.