Efficacy and challenges of immunotherapy in advanced

Non-small cell lung cancer (NSCLC) harboring EGFR-sensitizing mutations is typically characterized as an immunologically "cold" phenotype, exhibiting limited response to immune checkpoint inhibitors (ICIs). While EGFR tyrosine kinase inhibitors (EGFR-TKIs) represent the standard of care, acquired resistance is inevitable. Herein, we report a case of advanced NSCLC with an EGFR exon 19 deletion (19del). Following progression on multiple lines of TKI therapy and chemotherapy, the patient achieved a progression-free survival (PFS) of 8 months and an overall survival (OS) of 16 months upon receiving a PD-L1 inhibitor-based combination immunotherapy. To elucidate the mechanisms underlying this unexpected clinical benefit, multiplex immunofluorescence (mIF) analysis was performed on serial biopsy specimens obtained pre-immunotherapy (post-osimertinib progression) and post-immunotherapy progression. Results demonstrated that despite low PD-L1 expression in the pre-immunotherapy "responsive" specimen, the tumor immune microenvironment (TIME) exhibited a highly "inflamed" profile, characterized by high-density infiltration of T cells and B cells, as well as the formation of mature tertiary lymphoid structures (TLS). Notably, these TLS structures were virtually absent in the post-progression specimen. These preliminary, single-case observations raise the hypothesis that mature TLS formation following EGFR-TKI resistance may be associated with an immunotherapy-responsive TIME in EGFR-mutation NSCLC - A feature not captured by PD-L1 expression alone. Given the inherent limitations of single-case evidence, these findings are strictly exploratory and hypothesis-generating, and merit further prospective validation in adequately powered cohort studies.