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Immune Checkpoint Inhibitors in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Resistant

Letian Huang1, Shuling Zhang1, Li Sun1

  • 1Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China.

JCO Precision Oncology
|July 10, 2025
PubMed
Abstract

Insights

Adding immune checkpoint inhibitors (ICIs) to chemotherapy plus antiangiogenic therapy (C/A) improves survival for advanced non-small cell lung cancer (NSCLC) patients resistant to EGFR-TKIs. Careful monitoring for adverse events is necessary.

Area of Science:

  • Oncology
  • Immunotherapy
  • Pharmacology

Background:

  • Advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations often develops resistance to EGFR-tyrosine kinase inhibitors (TKIs).
  • The role of immune checkpoint inhibitors (ICIs) in combination strategies for TKI-resistant EGFR-mutant NSCLC is not well-established.

Purpose of the Study:

  • To evaluate the efficacy and safety of combining ICIs with chemotherapy plus antiangiogenic therapy (C/A) versus C/A alone in patients with advanced NSCLC resistant to EGFR-TKIs.
  • To identify patient subgroups who may benefit most from ICI combination therapy.

Main Methods:

  • Systematic review and meta-analysis of randomized controlled trials (RCTs).
  • Searched major databases (PubMed, Cochrane Library, Embase, Web of Science) and meeting abstracts.
  • Calculated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and risk ratios (RRs) for objective response rate (ORR) and adverse events (AEs).

Main Results:

  • Combination of ICIs with C/A significantly improved PFS, OS, and ORR compared to C/A alone in 2,269 patients across 8 RCTs.
  • Benefits were more pronounced in patients with PD-L1 expression ≥50%, specific EGFR mutations (Leu858Arg), absence of Thr790Met mutation, and those treated with pemetrexed-platinum.
  • No significant increase in severe (grade 3+) AEs, but higher rates of discontinuation, rash, hypothyroidism, and hypertension were observed with ICI+C/A.

Conclusions:

  • Adding ICIs to C/A offers improved survival outcomes for advanced NSCLC patients with EGFR-TKI resistance.
  • Specific subpopulations, including those with high PD-L1 expression or particular EGFR mutations, show greater benefit.
  • Close monitoring for specific adverse events is crucial when using ICI combination therapy.

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