Correlation between treatments and outcomes of patients with EGFR-mutated non-small-cell lung cancer that transitioned into small-cell lung cancer: an international retrospective study

Background: Histological transformation to small-cell lung cancer (SCLC) is an under-recognized but clinically relevant mechanism of resistance in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). While platinum-based chemotherapy (CT) has emerged as standard treatment after small-cell transformation, optimal treatment strategies are not defined, particularly with regard to the role of immune checkpoint inhibitors (ICIs) or continuation of EGFR-tyrosine kinase inhibitors (TKIs). Materials and methods: We conducted an international, retrospective, observational study on patients with EGFR-mutated NSCLC that transformed to SCLC, focusing on treatment and outcomes. Results: Twenty-five patients across 11 centers were included. Twenty-four changed systemic treatment following SCLC transformation: CT (12 patients), CT plus EGFR-TKI (5 patients), CT plus ICI (6 patients), or CT plus ICI plus EGFR-TKI (1 patient). Median follow-up was 9 months (range 1-45 months). All patients experienced relapse with a median progression-free survival of 2 months [95% confidence interval (CI) 2-3 months] and 23 patients died, with a median overall survival (OS) of 9 months (95% CI 7-16 months). Median OS was comparable between patients treated with CT alone [9.5 months; 95% CI 5 months-not reached (NR)], CT plus EGFR-TKI (8 months; 95% CI 8 months-NR), and CT plus ICI (10 months; 95% CI 7 months-NR). Three patients survived >24 months from SCLC transformation; these patients were treated with CT alone (one patient), CT plus EGFR-TKI (one patient), and CT plus ICI and EGFR-TKI (one patient). OS was longer if SCLC transformation occurred >12 months from initial NSCLC diagnosis (19 patients) versus those with transformation within 12 months (6 patients): 31 versus 8 months (P < 0.001). Conclusions: The prognosis of patients with transformed SCLC remains poor, with only a minority achieving meaningful survival. Survival was similar in patients treated with CT alone or with the addition of ICI or EGFR-TKI. A time interval >12 months between NSCLC diagnosis and SCLC transformation was associated with longer survival and may reflect a different biology than early transformation.