Clinicopathologic features and therapeutic outcomes in EGFR/ALK-aberrations NSCLC with histologic transformation.

[BACKGROUND] The aim of this study is to delineate clinicopathologic features, therapeutic outcomes, and tumor microenvironment (TME) remodeling in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALK) aberrations who experience histologic transformation (HT), with emphasis on post-transformation treatment efficacy.

[METHODS] This single-center retrospective cohort study included 6,230 patients with advanced NSCLC treated between December 2017 and January 2024. Patients who experienced histologic transformation after progression were identified through high-quality tumor biopsies or cytological samples. Treatment regimens for post-HT, including chemotherapy combined with tyrosine kinase inhibitors (CTK), chemotherapy combined with anti-angiogenic/immunotherapy (CAI), and palliative care (PC), were analyzed. Multiplex immunofluorescence was used to profile the tumor microenvironment in a subset of patients.

[RESULTS] Of the 6,230 patients, 84 (1.35%) experienced HT, with 73.81% transforming to small cell lung cancer (SCLC). The median time to HT was 22.27 months. Patients receiving CTK exhibited significantly longer median overall survival (OS) after HT (OS: 15.40 months) compared to CAI (11.23 months) and PC (4.37 months;  = 0.003). While CTK improved OS, progression-free survival (PFS) did not differ significantly across groups. In second-line treatment, incorporating tyrosine kinase inhibitors (TKIs) significantly prolonged PFS (PFS; median: 6.70 months, compared with 2.87 months for regimens not incorporating TKIs;  = 0.016). Uncommon EGFR mutants exhibited paradoxical tumor microenvironment (TME) features, with elevated CD8 infiltration (128.5 vs. 64.2 cells/mm²;  = 0.028) accompanied by Treg dominance (Foxp3CD25/CD8 ratio: 0.41 vs. 0.19;  = 0.039). Immunotherapy-containing regimens improved PFS in uncommon mutants (3.10 vs. 1.83 months;  = 0.007); however, overall survival remained comparable. Conclusions: Histologic transformation poses a significant challenge in advanced NSCLC management. Chemotherapy combined with TKIs appears to offer the best survival benefit for post-HT, while second-line inclusion of TKIs improves PFS. Personalized strategies accounting for histologic subtype, molecular alterations, and immune contexture are essential for optimizing outcomes in this clinically distinct population. Further large-scale studies are warranted to refine therapeutic approaches.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12967-025-07540-w.