Efficacy and Prognostic Analysis of Chemo-Immunotherapy After TKI Resistance in EGFR-Mutant Non-Small Cell Lung Cancer with TP53 or KRAS Co-Mutations

Yuhui Nie^1,2Chen Song²Kun Wu²Mingxin Yu²Jia Hu²Shuzhen Liu^1*Fu Hui^1*

• ¹Weifang People's Hospital, Shandong Second Medical University, Weifang, China
• ²School of Clinical Medicine, Shandong Second Medical University, Wei Fang, China

Objective: To assess whether EGFR co‑mutations with TP53 or KRAS affect prognosis in NSCLC and the efficacy of platinum‑doublet chemotherapy plus immunotherapy after EGFR‑TKI resistance. Methods: We retrospectively analyzed 168 patients with locally advanced or advanced NSCLC who underwent next‑generation sequencing at our institution between January 1, 2021 and October 31, 2023. Genomic groups were EGFR single mutation (n=36), EGFR/TP53 (n=80), and EGFR/KRAS (n=52). All received first‑line EGFR‑TKIs (first‑, second‑, or third‑generation); upon progression, all received platinum‑doublet chemotherapy plus immunotherapy. The primary endpoint was progression‑free survival (PFS). Kaplan–Meier curves with log‑rank tests compared PFS; baseline characteristics were compared by χ²; multivariable Cox models adjusted for age, sex, smoking history, clinical stage, histology, and ECOG performance status (PS). Results: Baseline features were balanced across groups (all P>0.05). Immune‑related marker expression differed between the EGFR single‑mutation and co‑mutation groups (P<0.05) but not between EGFR/TP53 and EGFR/KRAS (P=0.945). With first‑line EGFR‑TKIs, median PFS was longer in the EGFR single‑mutation cohort than in the EGFR/TP53 and EGFR/KRAS cohorts (14.1 vs 10.4 and 10.9 months; both P<0.0001), with no difference between the co‑mutation subgroups (P=0.174). After TKI resistance, second‑line platinum‑doublet plus immunotherapy yielded median PFS of 3.9 months in the single‑mutation group and 5.2 and 5.0 months in the EGFR/TP53 and EGFR/KRAS groups, respectively (overall log‑rank P<0.0001), again without a difference between the two co‑mutant cohorts (P=0.174). In multivariable analyses, both EGFR/TP53 and EGFR/KRAS co‑mutations were independently associated with a higher hazard of progression; ECOG PS≥2 showed a nonsignificant trend toward worse outcomes, and other covariates were not significant (all P>0.05). Conclusions: In NSCLC, isolated EGFR mutations confer longer PFS on first‑line EGFR‑TKIs than EGFR/TP53 or EGFR/KRAS co‑mutations. Following resistance, chemotherapy plus immunotherapy affords modestly longer PFS in co‑mutant disease compared with single‑mutation disease. These patterns were evident on Kaplan–Meier and log‑rank analyses and supported by adjusted Cox models.