Heterogeneity and co-occurrence of resistance mechanisms in EGFR-TKI-induced NSCLC to SCLC transformation: a case report

Background: Transformation into small-cell lung carcinoma (SCLC) is a common acquired resistance mechanism to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Re-tumor biopsy is crucial for identifying the definite tumor resistance mechanism. However, multiple mechanisms may occur simultaneously during TKI treatment. A single biopsy specimen is insufficient to accurately represent all resistance mechanisms at progressive sites. Case Description: In this case, we present a 58-year-old male with metastatic pulmonary adenocarcinoma (ADC) who had an EGFR exon 19 mutation and received first-line gefitinib and second-line osimertinib. Biopsy results from different progressive sites confirmed the presence of SCLC in pleural metastatic specimens, while the primary tumor had the EGFR exon 19 mutation and mutations ofPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) andv-Ki-ras2-Kirsten rat sarcoma viral oncogene homolog (KRAS). We utilized an effective combination therapy of permanent radioactive iodine-125 seed implantation (PRISI) as local consolidative therapy (LCT), along with the standard carboplatin-etoposide regimen for SCLC and continued osimertinib. Extracranial tumors were successfully controlled. The patient succumbed to intracranial disease progression without radiotherapy, with an overall survival (OS) of 15 months after SCLC transformation. Conclusions: Confirming SCLC transformation from a single site alone through biopsy may not provide a comprehensive understanding of the resistance mechanisms underlying progression at all sites. This highlights the significance of combined treatment strategies, particularly with LCT, for heterogeneous tumors in SCLC transformation.