Paired ctDNA analysis reveals diverse resistance mechanisms to mobocertinib in EGFR exon 20 insertion NSCLC.

Background: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations in non-small cell lung cancer (NSCLC) represent a distinct molecular subset with limited response to conventional tyrosine kinase inhibitors (TKIs). Mobocertinib, a targeted EGFR exon 20 inhibitor, shows clinical activity, yet the genomic resistance mechanisms remain poorly characterized, particularly through circulating tumor DNA (ctDNA) analysis. Methods: In this single-center prospective observational study, 22 patients with EGFR exon 20 insertion-positive NSCLC treated with mobocertinib were analyzed. Clinical outcomes were evaluated using Response Evaluation Criteria for Solid Tumors v1.1. Paired circulating tumor DNA (ctDNA) sequencing was performed pre- and post-treatment to characterize baseline mutations and acquired resistance mechanisms. Results: Mobocertinib achieved an objective response rate (ORR) of 59% and a disease control rate (DCR) of 82%, with a median progression-free survival (PFS) of 5.6 months (95% CI 3.5-9.3). Subjects who previously received amivantamab (n = 14) showed an ORR of 57.1% with median duration of response and PFS of 5.1 and 5.8 months, respectively. Insertion site variability influenced treatment efficacy, with better responses observed in helical region insertions. Baseline ctDNA absence correlated with favorable outcomes and Conclusions: Mobocertinib demonstrated clinically meaningful activity, regardless of previous exposure to amivantamab, in EGFR exon 20 insertion-positive NSCLC subjects. Acquired resistance mechanisms to mobocertinib were diverse, which poses challenges to sustained efficacy, emphasizing the need for development of a tailored subsequent therapeutic strategy.