EGFR-TKI rechallenge in patients with EGFR-mutated non-small-cell lung cancer who progressed after first-line osimertinib treatment: A multicenter retrospective observational study.

BACKGROUND: Rechallenge therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is known to confer some clinical benefit for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC). However, little is known about the efficacy of EGFR-TKI rechallenge after resistance to first-line (1L) osimertinib. This study aimed to assess the efficacy and safety of EGFR-TKI rechallenge therapy after resistance to 1L osimertinib in a Japanese clinical setting. METHODS: Between April 2018 and August 2022, 26 patients who progressed after treatment with 1L osimertinib and received EGFR-TKI rechallenge were included in this multicenter retrospective analysis. Patients in whom 1L osimertinib was discontinued owing to toxicity and had subsequent disease progression were also included in the analysis. RESULTS: Overall, the objective response rate for rechallenge therapy was 23.1%. The disease control rate was 53.9%, and the median progression-free survival (PFS) was 3.4 months. Patients who discontinued 1L osimertinib for toxicity had a higher response rate (42.9% vs. 15.8%) and longer PFS than those who discontinued it due to disease progression (median: 11.4 vs. 2.7 months, P = 0.001). Three patients (11.5%) developed rechallenge therapy-associated pneumonitis, two of which were grade ≥3. CONCLUSIONS: Rechallenge with EGFR-TKI after 1L osimertinib resistance showed limited clinical efficacy. However, it could be considered as a subsequent salvage therapeutic option for patients in whom 1L osimertinib was discontinued owing to toxicity.

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 ≥20 years) with advanced or recurrent non-squamous 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.