Immunotherapy in EGFR-mutant NSCLC after TKI resistance: role of mutation subtypes and progression patterns

Background

Patients with EGFR-sensitizing mutations in non-small cell lung cancer (NSCLC) predominantly receive first-line tyrosine kinase inhibitors (TKIs). Subsequent TKI resistance manifests through heterogeneous clinicopathological features, including distinct resistance subtypes (primary vs. acquired), PD-L1 expression levels, and molecular profiles from re-biopsies. While immunotherapy represents a potential subsequent option, the predictive biomarkers guiding optimal patient selection remain undefined.

Patients and methods

This multicenter retrospective study analyzed 1,396 EGFR-mutant NSCLC patients from five Chinese institutions, with 312 meeting stringent inclusion criteria. Comprehensive treatment data encompassing EGFR-TKIs, platinum-based chemotherapy, anti-angiogenic agents, and immune checkpoint inhibitors (ICIs) were collected. Cox proportional hazards regression identified progression-free survival (PFS)-associated variables, enabling resistance subtyping. Comparative effectiveness analyses across therapeutic modalities were performed.

Results

Multivariable Cox regression identified two independent predictors of immunotherapy PFS: EGFR mutation subtypes (exon21 L858R vs. exon19del; HR 0.84, 95 % CI [0.70–0.99], P = 0.042) and TKI resistance classification (acquired vs. primary: HR 2.28, 95 % CI [1.52–3.43], P = 0.001). Patients with primary TKI resistance showed improved outcomes with ICIs (median PFS 8.5 vs. 4.0 months; HR 0.46, 95 % CI [0.29–0.76], P = 0.002), particularly in L858R-mutant subgroups. In contrast, acquired resistance cohorts—especially those with exon19del mutations—derived limited clinical benefit (HR 1.09, 95 % CI [0.84–1.42]; P = 0.510). These findings suggest that resistance subtype and mutation profile may aid immunotherapy selection in EGFR-mutant NSCLC, requiring validation through prospective studies.

Conclusions

This multicenter analysis demonstrates that immunotherapy outcomes in EGFR-mutant NSCLC after TKI failure are influenced by both resistance subtypes (primary vs. acquired) and specific EGFR mutation profiles (L858R vs. exon19del). Patients with primary resistance and L858R mutations derive clinically meaningful benefit from ICIs, while those with acquired resistance, particularly exon19del variants, showed limited efficacy. These findings support further investigation of resistance-phenotype-guided therapeutic algorithms in prospective trials to optimize treatment sequencing strategies.