Journal of thoracic disease · 2026
Small-cell transformation of advanced non-small-cell lung cancer harboring driver mutations following tyrosine kinase inhibitor therapy: a multicenter real-world study.
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Lu Yuhai, Kang Xiaoliang, Xu Qiang, Zhou Yu, Li Changbo, Hu Hongxia, Chen Mao
Аннотация
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are a mainstay of therapy for advanced non-small-cell lung cancer (NSCLC) harboring actionable driver mutations. However, histologic transformation from NSCLC to small-cell lung cancer (SCLC) represents a particularly challenging mechanism of treatment resistance. This study aimed to characterize the incidence, timing, and clinical outcomes of SCLC transformation in this population in routine clinical practice.
METHODS: This multicenter real-world cohort study included consecutive patients with stage III-IV NSCLC treated at three hospitals in Sichuan Province, China, between January 2018 and December 2021. Eligible patients had pathologically confirmed NSCLC, driver mutations, baseline whole-body imaging, complete clinical data, and received TKIs. Re-biopsy was performed to evaluate histologic changes. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared with the log-rank test.
RESULTS: Among 387 enrolled patients, driver mutations included EGFR (73.4%), ALK (12.6%), ROS1 (8.3%), and HER2 (5.7%). First-line treatment was TKI monotherapy in 75.2% and TKI-based combinations in 24.8%. Of the 251 patients (64.9%) who underwent re-biopsy, SCLC transformation was identified in 36 patients (14.3%). Transformation occurred predominantly after first-line TKI therapy (27/36), with additional cases after second-line therapy (9/36). OS and PFS were significantly shorter in patients with transformed SCLC than in non-transformed patients.
CONCLUSIONS: In this multicenter real-world cohort study of driver-mutated advanced NSCLC treated with TKIs, SCLC transformation was not rare among re-biopsied patients and occurred mainly after first-line therapy. These findings support a low threshold for repeat tissue sampling at disease progression to detect SCLC transformation and guide timely transition to SCLC-directed treatment.
METHODS: This multicenter real-world cohort study included consecutive patients with stage III-IV NSCLC treated at three hospitals in Sichuan Province, China, between January 2018 and December 2021. Eligible patients had pathologically confirmed NSCLC, driver mutations, baseline whole-body imaging, complete clinical data, and received TKIs. Re-biopsy was performed to evaluate histologic changes. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared with the log-rank test.
RESULTS: Among 387 enrolled patients, driver mutations included EGFR (73.4%), ALK (12.6%), ROS1 (8.3%), and HER2 (5.7%). First-line treatment was TKI monotherapy in 75.2% and TKI-based combinations in 24.8%. Of the 251 patients (64.9%) who underwent re-biopsy, SCLC transformation was identified in 36 patients (14.3%). Transformation occurred predominantly after first-line TKI therapy (27/36), with additional cases after second-line therapy (9/36). OS and PFS were significantly shorter in patients with transformed SCLC than in non-transformed patients.
CONCLUSIONS: In this multicenter real-world cohort study of driver-mutated advanced NSCLC treated with TKIs, SCLC transformation was not rare among re-biopsied patients and occurred mainly after first-line therapy. These findings support a low threshold for repeat tissue sampling at disease progression to detect SCLC transformation and guide timely transition to SCLC-directed treatment.