Firmonertinib in advanced non-small cell lung cancer with epidermal growth factor receptor P-loop and αC-helix compressing mutations.

P-loop and αC-helix compressing (PACC) mutations comprise a structurally distinct subgroup of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) with limited treatment options. Firmonertinib is a once-daily oral, brain-penetrant, mutant-selective EGFR tyrosine kinase inhibitor with a unique trifluoroethoxy side chain. Firmonertinib had high anti-proliferative efficacy in EGFR PACC-mutant cells and xenografts. In the phase 1b FURTHER study (NCT05364073), patients with metastatic EGFR PACC-mutant NSCLC randomized to receive first-line firmonertinib 160 mg (n = 25) or 240 mg (n = 22) had confirmed objective response rates (ORRs) of 43% and 68%, median duration of response not reached and 14.6 months, and median progression-free survival of 11.1 and 16.0 months, respectively; treatment-related adverse events led to dose reductions (19% and 24%) and discontinuation (3% and 0%). Intracranial ORR among patients with brain metastases at baseline was 47% (8/17). Results support further study of first-line firmonertinib in patients with EGFR PACC-mutant NSCLC.