Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study)

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for EGFR-mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon EGFR mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against EGFR-dependent resistance after osimertinib treatment, although these have not been prospectively investigated. Methods: The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged & GE;20 years) with advanced or recurrent nonsquamous NSCLC harboring drug-sensitive EGFR mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023. Discussion: The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established. Registration: UMIN Clinical Trial Registry: UMIN000049225.