Histological transformation in lung cancer: a single-arm meta-analysis and systematic review

Histological transformation represents an important mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant lung cancer; however, its incidence, timing, and post-transformation outcomes remain incompletely characterized.

We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines and Cochrane recommendations. PubMed, Web of Science and Embase were searched up to November 2025 for studies reporting histological transformation in EGFR-mutant lung cancer following EGFR-TKI resistance. Eligible studies included prospective or retrospective studies and consecutive case series (sample size ≥ 10 or ≥3events). Random-effects models were applied to pool transformation proportions and survival outcomes, and Kaplan-Meier-based methods were used to synthesize time-to-event data.

A total of 35 studies were included. Among patients with non-small cell lung cancer (NSCLC) who developed resistance to EGFR-TKIs, the pooled proportion of transformation to high-grade neuroendocrine carcinoma (HGNEC) was 6% (95% CI, 5%-8%), while transformation to non-neuroendocrine NSCLC occurred in 2% of cases (95% CI, 2%-3%). The pooled median time from EGFR-TKI initiation to histological transformation was 19.39 months (95% CI, 16.18-22.60). After transformation, the pooled median progression-free survival (mPFS) was 3.93 months (95% CI, 3.14-4.72), and the pooled median overall survival was 10.69 months (95% CI, 8.34-13.04).

Histological transformation occurs in a clinically relevant proportion of EGFR-TKI-resistant EGFR-mutant lung cancer, and is associated with poor post-transformation outcomes.