Nazan Demir, Cevat İlteriş Kıkılı, Fatih Kemik, Bahadır Köylü, Deniz Tural, Şahin Laçin, Şeyda Gündüz, Didem Tunalı, Nil Molinas Mandel, Fulden Yumuk, Mevlude Inanc, Ayse Nuransoy Cengiz, Başak Oyan Uluç, Seval Ay Ersoy, Nisanur Sarıyar Busery, Serdar Karakaya, Dilek Erdem, Orhun Akdoğan, Ozan Yazıcı, Elanur Kahraman, İrem Bilgetekin, Umut Demirci, Hasibe Bilge Gür, İlker Nihat Ökten, Gökhan Karakaya, Oğuzhan Yıldız, Melek Karakurt Eryılmaz, Kübra Canaslan, Mustafa Seyyar, Muhammet Ali Kaplan, Erdem Çubukçu, Gül Akın, Mustafa Ersoy, Ahmet Taner Sümbül, Hakan Özçelik, Dilruba İlayda Özel Bozdağ, Ebru Çiçek, Ülviye Oflas, Fatma Paksoy Turkoz, Duygu Bayır Garbioğlu, Fatih Selçukbiricik
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.
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.