Clinical Activity of RET TKI Plus Chemotherapy After Progression on a RET TKI in a RET Fusion–Positive NSCLC Real-World Cohort: A Brief Report

Introduction: fusion-driven NSCLC accounts for 2% of advanced lung adenocarcinomas, and selective RET tyrosine kinase inhibitors (RETis) are the current first-line standard-of-care treatment. However, acquired resistance to RETi can arise, and improved therapies for RETi-resistant tumors are needed. Methods: This real-world retrospective cohort evaluated the outcomes of the combinations of chemotherapy with RETi (chemo/RETi) and chemotherapy with immunotherapy (chemo/IO) in patients with NSCLC who experienced progression while receiving RETi. For both groups, we assessed the overall response rate, using the Response Evaluation Criteria in Solid Tumors version 1.1; estimated progression-free survival (PFS) and overall survival using the Kaplan-Meier method; described the genomic features potentially related to RETi resistance; and analyzed safety data using the Common Terminology Criteria for Adverse Events version 5.0. Results: = 0.0063). The overall response rate was 38% in the chemo/RETi group and 25% in the chemo/IO group; one metabolic complete response was observed in the chemo/RETi group. Overall survival did not differ significantly between groups. Although chemo/RETi demonstrated improved outcomes, it was associated with more grade 3 treatment-related adverse events, including anemia, febrile neutropenia, and thrombocytopenia, compared with chemo/IO. Conclusions: Our data support the potential efficacy of chemo/RETi after progression on RETi, with significantly better PFS than chemo/IO, albeit with higher rates of hematologic toxicities.