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

Ning Yang,1,* Ning Wan,2,3,* Ya Guo,2,3 Lijuan Xiong,4 Xiting Chen,4 Dou Du,4 Bo Xie,1,4 Juan Zhou1,4 1Department of Oncology, General Hospital of Southern Theater Command, Guangzhou, People’s Republic of China; 2Department of Clinical Pharmacy, General Hospital of Southern Theater Command, Guangzhou, People’s Republic of China; 3School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People’s Republic of China; 4Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Juan Zhou, Department of Oncology, General Hospital of Southern Theater Command, No. 111 Liuhua Road, Guangzhou, 510010, People’s Republic of China, Tel +86 20 88686608, Email juanzhn@163.com Bo Xie, Department of Oncology, General Hospital of Southern Theater Command, No. 111 Liuhua Road, Guangzhou, 510010, People’s Republic of China, Tel +86 20 88686606, Email xiebodoctor@163.comPurpose: 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< 0.05).Conclusion: Taxane‑based chemotherapy was associated with more favorable outcomes than pemetrexed in dramatic progression after osimertinib resistance, with higher non‑hematologic toxicity. These findings, supported by exploratory in vitro sensitivity, warrant prospective validation.Keywords: osimertinib, acquired resistance, NSCLC, EGFR, chemosensitivity