Small-Cell Lung Cancer Transformation as a Mechanism of Resistance to Pralsetinib in RET- Rearranged Lung Adenocarcinoma: A Case Report

The majority of resistance to Rearranged during transfection (RET)-specific tyrosine kinase inhibitors (TKI) described in RET-rearranged non-small cell lung cancer (NSCLC) patients are driven by RET-independent mechanisms. We provide the first case report of a RET-rearranged lung adenocarcinoma (LUAD) transformation into small-cell lung cancer (SCLC) as a mechanism of acquired resistance to pralsetinib. A 43-year-old patient presented with a RET-rearranged LUAD revealed by pleural effusion. After 14 months of response to pralsetinib, biopsy of a progressive pleural lesion found a phenotypic transformation into SCLC. Molecular analysis identified the same RET fusion and TP53 mutation in both primary adenocarcinoma and recurrence as SCLC. The patient achieved partial response after switch to carboplatin and etoposide chemotherapy and presented with progression disease after 6 months. Histological transformation could be a mechanism of resistance to RET-TKIs and rebiopsy should be considered to adapt subsequent treatment.

Automated summary

This study found that resistance to RET-specific tyrosine kinase inhibitors in RET-rearranged non-small cell lung cancer patients is mostly driven by RET-independent mechanisms. It also provides the first case report of a RET-rearranged lung adenocarcinoma transforming into small-cell lung cancer as a mechanism of acquired resistance to pralsetinib. Molecular analysis revealed the presence of the same RET fusion and TP53 mutation in both the primary adenocarcinoma and the recurrent small-cell lung cancer.