Efficacy and safety of immune checkpoint inhibitors in EGFR-mutant NSCLC patients with EGFR-TKI resistance: an updated systematic review and meta-analysis

Background: Treatment options for lung cancer patients with epidermal growth factor receptor (EGFR) mutations are limited after tyrosine kinase inhibitor (TKI) resistance. We aimed to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with EGFR-TKI-resistant non-small cell lung cancer (NSCLC).

Methods: We retrieved randomized controlled trials (RCTs) on ICIs in patients with EGFR-TKI resistance from PubMed, Cochrane Library, Web of Science, and EMBASE databases from creation to March 25, 2025. We focused on the endpoints median overall survival (OS), median progression-free survival (PFS), objective response rate (ORR), and safety data.

Results: Twelve eligible RCTs were included in this meta-analysis. The combination of ICIs and chemotherapy was better than chemotherapy alone [PFS: hazard ratio (HR) =0.76, 95% confidence interval (CI): 0.66–0.87, P<0.001; OS: HR =0.86, 95% CI: 0.75–1.00, P=0.045]. ICIs plus anti-angiogenic agents and chemotherapy also improved PFS (HR =0.51, 95% CI: 0.43–0.61), P<0.001), but not OS (HR =0.91, 95% CI: 0.76–1.10, P=0.34). No significant differences were observed in all-grade treatment-related adverse events (TRAEs) between ICIs-based treatment and chemotherapy (RR =1.34, 95% CI: 0.71–2.54, P=0.27).

Conclusions: In patients with EGFR-TKI-resistant NSCLC, the combination of ICIs with chemotherapy significantly improved both PFS and OS compared to chemotherapy alone, while ICIs, chemotherapy, and anti-angiogenic drugs only enhanced PFS. The ICIs-chemotherapy regimen demonstrates acceptable safety, suggesting its potential as a therapeutic option that deserve further investigation.

Keywords: Non-small cell lung cancer (NSCLC); epidermal growth factor receptor mutation (EGFR mutation); tyrosine kinase inhibitors (TKIs); immune checkpoint inhibitors (ICIs); meta-analysis

 

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Key findings

• Immune checkpoint inhibitors (ICIs) combined with chemotherapy appears as a viable treatment option with acceptable safety for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant non-small cell lung cancer (NSCLC) patients.

What is known and what is new?

• Treatment options for lung cancer patients with EGFR mutations are limited after TKI resistance. Chemotherapy is the gold standard of treatment recommended by the guidelines; however, it has limited patient benefits.

• For EGFR-TKI-resistant NSCLC patients, ICIs-based combination therapy led to superior progression-free survival compared to chemotherapy with acceptable safety.

What is the implication, and what should change now?

• The successful use of ICIs-based combination therapy in EGFR-TKI-resistant NSCLC patients highlights its feasibility and effectiveness in this setting. It provides favorable evidence for immunotherapy in EGFR-TKI-resistant NSCLC patients.