Adding immunotherapy to chemotherapy may improve survival after SCLC transformation in EGFR-mutant NSCLC: a multicenter real-world study

Abstract

Background: Histologic transformation to small-cell lung cancer (SCLC) is an aggressive resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) therapy in EGFR-mutant non-small cell lung cancer (NSCLC). Real-world data on this population remain limited. Methods: We conducted a multicenter retrospective cohort study across 26 oncology centers (2016-2025). Patients with histologically confirmed EGFR-mutant NSCLC and biopsy-proven SCLC transformation were included. Primary endpoints included PFS during first-line EGFR-TKI therapy (PFS1), time to transformation (TTT), PFS after transformation (PFS2), overall survival from metastatic diagnosis (OS-1), post-transformation survival (OS-2), and overall survival from initial NSCLC diagnosis (OS-3). Survival was assessed with Kaplan-Meier and Cox regression analyses. Results: A total of 59 patients were included (median age 57.8 years; 52.5 % male; exon 19 deletion 76.3 %). Median PFS1 was 14.0 months (95 % CI, 11.3-16.7); median TTT was 22.0 months (range, 3-110). Following transformation, 54 patients (91.5 %) received systemic therapy: carboplatin plus etoposide (CE) alone in 37 (68.5 %) and CE plus immunotherapy (atezolizumab, durvalumab, or durvalumab plus osimertinib) in 16 (29.6 %). ORR was 37.8 % with CE alone versus 71.4 % with CE plus immunotherapy; median PFS2 was 5.0 months (95 % CI, 3.5-6.5). Median OS-1 was 38.0 months (95 % CI, 32.0-53.0). Median OS-2 was 11.0 months (95 % CI, 7.5-14.5) overall, and significantly longer with CE plus immunotherapy versus CE alone (17.0 vs. 9.0 months; log-rank p = 0.026; HR 0.327, 95 % CI 0.139-0.767). Median OS-3 was 41.1 months. Conclusion: In this large multicenter cohort, adding immune checkpoint inhibitors (ICIs) to CE was associated with improved post-transformation survival, challenging prior evidence of immunotherapy inefficacy in this setting. Systematic re-biopsy at progression on EGFR-TKI therapy is essential to confirm transformation and guide treatment. Prospective biomarker-driven studies are warranted.