Prognostic analysis and beneficiary population exploration of subsequent treatment regimens after third-generation EGFR-TKIs failure in EGFR-mutated advanced non-small cell lung cancer: a retrospective cohort study

Background: Lung cancer accounts for the highest cancer-related mortality worldwide. Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show significant efficacy in the treatment of lung cancer with EGFR mutations, but resistance inevitably occurs. Although immune checkpoint inhibitor treatment regimens have expanded post-resistance therapeutic options, head-to-head comparisons of diverse subsequent strategies and precise identification of beneficiary populations remain insufficient. This leads to inconsistent clinical decision-making. This study aimed to explore the efficacy of different subsequent treatment regimens and identify beneficiary populations for each regimen in patients at our center with resistance to third-generation EGFR-TKIs.

Methods: The retrospective study enrolled 225 patients at Jiangsu Cancer Hospital from 2017 to 2023. All patients had pathologically confirmed EGFR-mutant lung adenocarcinoma and received multi-line subsequent treatment after third-generation EGFR-TKIs resistance. Patients were classified into an ICI (I+O) group (N=131) and a No ICIs group (N=94), further divided into immunotherapy plus bevacizumab plus chemotherapy (IBC), immunotherapy plus anlotinib (IA), immunotherapy plus chemotherapy (IC), bevacizumab plus chemotherapy (BC), chemotherapy alone (C), and Based on mutation subgroups. Baseline characteristics were compared using Chi-squared tests. Survival outcomes [progression-free survival (PFS), overall survival (OS)] were analyzed via Kaplan-Meier curves and log-rank tests. Multivariate Cox proportional hazards regression was used to adjust for potential confounding variables. Least absolute shrinkage and selection operator (LASSO) regression and Cox proportional hazard models were applied to screen prognostic factors. All follow-up data were analyzed using right-censoring methods. The cut-off date for the last follow-up was March 31, 2025.

Results: The median progression-free survival (mPFS) of the I+O group (9.10 months) was significantly better than that of the No ICIs group (7.15 months, P<0.001); however, no significant difference in median overall survival (mOS) was observed between two groups. Among all subgroups, the IBC subgroup achieved the longest mPFS (11.40 months), which was significantly longer than that of the other subgroups. After multivariate Cox proportional hazards regression, its PFS remained significantly prolonged compared with other groups. Its disease control rate (DCR) reached 92.4%, while its objective response rate (ORR) was 29.11%. The statistical analyses revealed that in the IBC subgroup, patients aged 51–79 years, those receiving third-generation EGFR-TKIs monotherapy, and those without baseline liver metastasis derived the greatest treatment benefit. In the BC subgroup, patients without baseline liver metastasis derived the greatest treatment benefit (mPFS =8.50 months). In the IA subgroup, patients aged 51–79 years derived the greatest treatment benefit (mPFS =9.30 months). In the IC subgroup, male patients (mPFS =8.50 months) and patients with body mass index (BMI) >23.9 kg/m2 (mPFS =9.00 months) derived the greatest treatment benefit.

Conclusions: In conclusion, the IBC regimen presents a favorable PFS trend in real-world post-resistance management. Each sequential treatment corresponds to unique beneficiary baseline features. Individualized regimen selection may improve clinical prognosis. Given the single-center retrospective nature and limited sample size of certain subgroups, these observational trends require further validation in large-scale prospective studies.