AUTHOR=Nie Yuhui , Song Chen , Wu Kun , Yu Mingxin , Hu Jia , Liu Shuzhen , Hui Fu 

TITLE=Efficacy and prognostic analysis of chemo-immunotherapy after TKI resistance in EGFR-mutant non-small cell lung cancer with TP53 or KRAS co-mutations

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1684089

DOI=10.3389/fimmu.2025.1684089

ISSN=1664-3224

ABSTRACT=ObjectiveTo investigate the impact of co-mutations of EGFR with TP53 or KRAS on the prognosis of non-small cell lung cancer (NSCLC) patients, and the efficacy of platinum-based doublet chemotherapy plus immunotherapy after EGFR-TKI resistance.MethodsThis was a retrospective study that included 168 patients with locally advanced or advanced NSCLC who had next-generation sequencing (NGS) performed at our institution between January 1, 2021, and October 31, 2023. Based on their genomic profiles, patients were categorized into three groups: EGFR single mutation, EGFR/TP53 co-mutation, and EGFR/KRAS co-mutation. Baseline clinical data were collected, including gender, age, smoking history, histological subtype, clinical stage, ECOG performance status, gene testing results, and treatment regimens. All patients were treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy, including first-, second-, or third-generation agents. Upon disease progression, patients received platinum-based doublet chemotherapy plus immunotherapy as second-line treatment. The primary endpoint was progression-free survival (PFS). Survival curves were generated using the Kaplan-Meier method and compared by log-rank test. Baseline characteristics among the three groups were compared using the chi-square test. Multivariate Cox regression analysis was performed to evaluate independent prognostic factors for PFS by incorporating all baseline clinical variables and gene mutation status into the model.ResultsA total of 168 patients were included in the analysis: 36 with EGFR single mutation, 80 with EGFR/TP53 co-mutation, and 52 with EGFR/KRAS co-mutation. There were no statistically significant differences among the three groups with respect to baseline characteristics, including gender, age, smoking history, histological type, clinical stage, and ECOG performance status (P > 0.05). Immune-related marker expression was significantly different between the EGFR single mutation group and the two co-mutation groups (P < 0.05), while no significant difference was observed between the co-mutation groups (P = 0.945). Following first-line EGFR-TKI therapy, the EGFR single mutation group showed a significantly longer median PFS compared with the EGFR/TP53 and EGFR/K-RAS co-mutation groups (P < 0.0001). No significant difference in PFS was observed between the two co-mutation groups (P = 0.174). Following progression on EGFR-TKIs, all patients received platinum-based doublet chemotherapy plus immunotherapy. In second-line treatment, the median PFS in the EGFR single-mutation group, which was shorter than in the EGFR/TP53 and EGFR/KRAS co-mutation groups (overall log-rank P < 0.0001), with no significant difference between the two co-mutation cohorts (P = 0.174). However, in multivariable Cox models adjusting for age, sex, smoking history, clinical stage, histology, and ECOG performance status, both EGFR/TP53 and EGFR/KRAS co-mutations were independently associated with a higher hazard of progression. ECOG PS ≥2 was associated with a numerically higher hazard that did not reach statistical significance. No significant associations were observed for other covariates (age, sex, smoking history, clinical stage, histology; all P>0.05).ConclusionIn the first-line setting, patients with an EGFR single mutation treated with EGFR-TKIs had a longer median PFS than those with EGFR/TP53 and EGFR/KRAS co-mutations (14.1 vs 10.4 and 10.9 months, respectively; both P < 0.0001), whereas no statistically significant difference was observed between the two co-mutation subgroups (P = 0.174). Following the development of resistance, all patients received platinum-based doublet chemotherapy plus immunotherapy; in the second-line setting, median PFS was modestly longer in the co-mutation groups compared with the single-mutation group (EGFR/TP53: 5.2 months; EGFR/KRAS: 5.0 months; EGFR single mutation: 3.9 months; overall log-rank P < 0.0001), with no significant difference between the TP53 and KRAS subgroups (P = 0.174). These associations were evident on Kaplan–Meier curves (with numbers at risk) and log-rank testing, and were supported by multivariable Cox models adjusted for age, sex, smoking history, clinical stage, histology, and ECOG performance status.