Chemotherapy Plus EGFR-TKI as First-Line Treatment Provides Better Survival for Advanced EGFR-Positive Lung Adenocarcinoma Patients: Updated Data and Exploratory In Vitro Study

Background Previously, we demonstrated that treatment with gefitinib combined with pemetrexed plus carboplatin chemotherapy improved progression-free survival (PFS) compared to gefitinib or chemotherapy alone in lung adenocarcinoma patients with sensitizing EGFR mutations. Objective In the present study, we updated the long-term overall survival (OS) of the combination therapy and the gefitinib groups. Furthermore, the possible mechanisms underlying the effects of combination therapy were investigated. Patients and methods Lung adenocarcinoma patients harboring sensitizing EGFR mutations received either gefitinib plus chemotherapy ( n = 40) or gefitinib alone ( n = 41), and long-term survival was assessed. The pharmacological interaction between gefitinib and pemetrexed was evaluated in the PC-9 lung adenocarcinoma cell line using a colorimetric assay for assessing cell metabolic activity (MTT assay). The influence of combined treatment with gefitinib plus pemetrexed on gene expression profiles and signaling pathways was investigated using microarrays and Ingenuity Pathway Analysis (IPA). Results On the last day of follow-up (28 September 2018), 30 (75.0%) patients in the combination group and 35 (85.4%) patients in the gefitinib group had died. The 2-year and 3-year survival rates of the combination versus gefitinib were 85.0% versus 56.1% ( P = 0.004) and 52.5% versus 24.4% ( P = 0.009), respectively. The median OS was 37.9 months (95% CI: 17.3–58.6) for the combination group and 25.8 months (95% CI: 19.2–32.3) for the gefitinib group (HR = 0.56, 95% CI: 0.34–0.91, P = 0.02). A synergistic inhibitory effect between gefitinib and pemetrexed was observed in the lung adenocarcinoma cell line PC-9. Furthermore, widespread gene expression changes and critical signaling pathways such as AKT signaling were identified, which might be responsible for the synergism seen with the combination treatment. Conclusions Combined treatment with gefitinib plus pemetrexed resulted in improved OS over gefitinib alone. A synergistic inhibitory effect between gefitinib and pemetrexed was observed on lung adenocarcinoma cell growth. Gene expression profile analysis revealed potential signaling pathways, including AKT signaling, contributing to the synergism. Clinical trial registration number NCT02148380.