Association Between EGFR ‐ TKI –Associated Skin Rash and Recorded Mortality in Non‐Small Cell Lung Cancer: A Real‐World Analysis Accounting for Immortal Time Bias

PURPOSE: Skin rash during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy has been associated with better outcomes in non-small cell lung cancer (NSCLC), but previous studies may have overestimated this association because of immortal time bias. We evaluated the association between EGFR-TKI-associated skin rash and mortality while accounting for rash timing. METHODS: We identified patients with NSCLC who initiated first-line EGFR-TKIs between August 2018 and December 2024 using a Japanese claims database. EGFR-TKI-associated skin rash was defined using a qualifying diagnosis and rash-related treatment recorded in the same calendar month. We performed time-dependent propensity score sequential matching: each patient who newly developed skin rash was matched on the rash-onset day to patients still at risk who had not yet developed skin rash; follow-up started on the matched day. For comparison, we also performed an analysis that did not account for immortal time bias and landmark analyses. RESULTS: Among 11 830 eligible patients, 560 developed incident skin rash. In the time-dependent propensity score sequential matching analysis, 560 patients with skin rash were matched to 5600 patients without skin rash, and skin rash was associated with lower recorded mortality (HR, 0.621; 95% CI, 0.404-0.953). The estimate was stronger in the analysis not accounting for immortal time bias (HR, 0.410), whereas the association was attenuated in landmark analyses. CONCLUSIONS: EGFR-TKI-associated skin rash was associated with lower recorded mortality, but the association was weaker after accounting for immortal time bias. Prior studies may have overestimated this association.