Double-dose firmonertinib as first-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer harboring EGFR L858R mutation: a prospective, multicenter, phase II study (FIRM).

Progression-free survival (PFS) with first-line third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors remains suboptimal in EGFR L858R-mutated advanced non-small-cell lung cancer (NSCLC), highlighting a need for strategies to delay resistance. This single-arm, phase II study (FIRM; ChiCTR2200060897) evaluates first-line double-dose firmonertinib (160 mg/day) in adults with L858R-mutated locally advanced or metastatic NSCLC. With a median follow-up of 27.5 months in 33 patients, primary endpoint was a median PFS of 21.1 months. Secondary endpoints include an unreached median overall survival, an objective response rate of 75.8%, a disease control rate of 90.9%, and an 18-month PFS rate of 63.1%. Grade ≥3 treatment-emergent adverse events occur in 6.1% of patients. Baseline circulating tumor DNA (ctDNA) variant allele frequency predicts ctDNA clearance at cycle 3 day 1, which correlates with longer PFS. Double-dose firmonertinib shows promising efficacy and tolerability, supporting its preliminary potential as first-line treatment for EGFR L858R-mutated advanced NSCLC.