Taxanes Versus Pemetrexed After Osimertinib Resistance in EGFR-Mutated NSCLC: A Retrospective Cohort with Two-Model In Vitro Validation

Purpose: To evaluate whether chemotherapy backbone selection influences outcomes in epidermal growth factor receptor (EGFR)‑mutated non-small cell lung cancer (NSCLC) after acquired resistance to osimertinib, addressing the absence of a preferred post‑osimertinib chemotherapy approach. Methods: Outcomes were retrospectively compared between taxane‑based and pemetrexed‑based chemotherapy using propensity score matching and multivariable Cox models; progression was stratified as gradual or dramatic. An exploratory in vitro assay compared chemosensitivity between osimertinib‑resistant sublines and parental cells. Results: After 1:1 matching, taxanes showed numerically longer progression‑free survival (PFS; median 8.8 vs 7.9 months; hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.48-1.03) and overall survival (OS; 18.8 vs 15.9 months; HR: 0.70, 95% CI: 0.45-1.09) versus pemetrexed, without statistical significance. In the gradual‑progression cohort, outcomes were comparable. By contrast, in the dramatic‑progression cohort, taxanes were associated with longer PFS (7.7 vs 6.4 months; HR: 0.51, 95% CI: 0.30-0.86; P=0.009) and OS (16.1 vs 12.7 months; HR: 0.54, 95% CI: 0.30-0.97; P=0.034). Multivariable analysis identified taxanes as an independent favorable factor in dramatic progression for PFS (adjusted hazard ratio [aHR]: 0.48, 95% CI: 0.27-0.84; P=0.011) and OS (aHR: 0.51, 95% CI: 0.27-0.96; P=0.036). Non‑hematologic toxicities were more frequent with taxanes than pemetrexed (56/74, 75.7% vs 52/95, 54.7%). Additionally, osimertinib‑resistant sublines exhibited reduced half-maximal inhibitory concentration (IC50) to taxanes versus parental cells (P