Emergence of EGFR C797S as a resistance mechanism to CLN081 in EGFR exon 20-mutant NSCLC: case report.

EGFR exon 20 insertion mutations represent a distinct subset of non-small cell lung cancer (NSCLC) with limited sensitivity to earlier-generation EGFR tyrosine kinase inhibitors (TKIs). CLN081 (zipalertinib; TAS6417) is a novel covalent EGFR TKI under development with activity against EGFR exon 20 insertion variants. We report the case of a 44-year-old man with stage IVB lung adenocarcinoma harboring an EGFR exon 20 insertion mutation who received multiple lines of systemic therapy, including CLN081. After eight months of treatment with CLN081, liquid biopsy revealed the emergence of a secondary EGFR C797S mutation (p.Cys797Ser; variant allele frequency [VAF] 0.05%), concurrent with a reduction in the exon 20 insertion allele frequency from 35.1% to 0.5%, accompanied by disease progression. Although C797S-mediated resistance has been hypothesized and demonstrated in preclinical models of CLN081 exposure, this represents, to our knowledge, the first reported in vivo identification of an EGFR C797S resistance mutation following CLN081 therapy. This case provides clinically relevant insight into resistance mechanisms associated with emerging EGFR exon 20-targeted therapies.