17P Acquired BRAF V600E as bypass resistance to EGFR TKIs in EGFR-mutant NSCLC: A global multicenter cohort study

Background: Uncommon epidermal growth factor receptor (EGFR) mutations can be detected in 10-15% of patients with non-small cell lung cancer.Dacomitinib, a second-generation EGFR-TKI, is effective in patients with common EGFR mutations, but its efficacy and safety in patients with uncommon EGFR mutations remain unclear.Methods: This is a single-arm, multicenter, prospective, phase II study.Pathologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring uncommon EGFR mutations (exon 20 insertions were excluded) were included in the study.Eligible patients were orally administered 45 mg of dacomitinib once daily until disease progression, unacceptable toxicity, death, or withdrawal of consent.The primary endpoint of the trial was the objective response rate (ORR) assessed by investigators.The disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety were secondary endpoints.Biomarker analysis was exploratory analysis.Results: Between December 2020 and December 2022, 30 patients were enrolled for analysis.The median age was 66 years, and 26 (86.7%) patients were diagnosed with metastatic disease.The most frequent uncommon type of EGFR mutation was complex mutation (12 cases, 40%), followed by 21L861Q (10 cases, 33.3%).The ORR and DCR were 80.0% (95% CI, 61.4-92.3%)and 100.0%(95% CI, 88.4-100.0%),respectively.The median best response depth of the target lesion from baseline was -48.40%.The median PFS was 14.3 months (95% CI, 10.8-20.9months), with 12month, 18-month, and 24-month PFS rates were 60.0%, 43.3%, and 28.9%, respectively.The median OS was 44.2 months (95% CI, 30.6-NE), and the OS rates at one year, two years, and three years were 93.2%, 82.5%, and 59.4%, respectively.All patients (100%) experienced at least one adverse event (AE) of any grade or cause, and the most common AE was rash (86.7%;Grade 3: 23.3%).Grade 3 or higher AEs were reported in 12 (40.0%)patients.The secondary T790M mutation was the most common resistance mechanism (33.3%).Conclusions: Dacomitinib has high anti-tumor activity and response duration with manageable toxicity in NSCLC patients with uncommon EGFR mutations.