Clinical and molecular characteristics, therapeutic strategy, and prognosis of non-small cell lung cancer patients harboring primary and acquired BRAF mutations

Background: BRAF oncogene is a rare genetic alteration in NSCLC. Acquired BRAF mutations are an emerging resistance mechanism to EGFR TKIs. The differences in clinical and genetic characteristics, therapeutic strategies, and outcomes in NSCLC patients harboring primary and acquired BRAF mutations are still poorly understood. Methods: From Oct 2017 to Dec 2023, 10, 211 lung cancer patients at Shanghai Ruijin Hospital were reviewed. 88 primary BRAF-mutated and 15 acquired BRAF-mutated NSCLC patients resistant to EGFR TKIs were included in the study. Findings: Primary BRAF-mutated patients preferentially occurred in the elderly (median age: 67 versus 61, p=0.015), males (53.4% vs 26.7%, p=0.056), former/current smokers (36.5% vs 6.7%, p=0.033), non-adenocarcinoma (11.4% vs 0%, P=0.351) compared to acquired BRAF-mutated patient. There were significant differences between the primary BRAF/EGFR co-mutated group and the non-EGFR co-mutated group in terms of gender (males: 33.3% vs 62.3%, p=0.012), smoking history (22.2% vs 43.1%, p=0.063), and histological types (adenocarcinomas: 100% vs 83.6%, p=0.028). The clinical characteristics between primary and acquired BRAF/EGFR co-mutated patients were similar. The most frequently coexisting oncogenes of primary and acquired BRAF-mutated NSCLC patients were EGFR mutations (30.7% and 93.3%). And the genotype of concomitant EGFR mutation differed. In the acquired BRAF-mutated cohorts, the genotype of EGFR mutations was more complex than primary and contained more dual EGFR mutations (35.7%). For primary BRAF/EGFR co-mutated patients, no matter what kinds of therapies, the EGFR 19del patients had a better prognosis than non-19del patients, and the first line mPFS was NR and 9.0 months (95% CI: 7.7-10.3 months) (p=0.0062), respectively. Dabrafenib and trametinib plus 3rd EGFR TKIs improved the prognosis of primary BRAF/EGFR non-19del co-mutated patients, achieving ORR and mPFS of 100% (3/3) and 12 months. For acquired co-mutated patients, the mPFS for 5 patients was 8.6 months (95% CI: 5.4-11.8 months). No new safety concerns and > grade 3 AEs were noted. Interpretation: The most frequently coexisting oncogenes of primary and acquired BRAF-mutated NSCLC patients were EGFR mutations. There were significant differences between the primary BRAF/EGFR co-mutated group and the non-EGFR co-mutated group in gender, smoking history, and histological types. The primary and acquired BRAF/EGFR co-mutated patients showed similar clinical characteristics but different co-mutated EGFR genotypes. Triple-target therapy (dabrafenib, trametinib plus 3rd EGFR TKIs) could be considered the preferential regimen for acquired BRAF/EGFR co-mutated and primary BRAF/EGFR non-19del co-mutated NSCLC patients. As for the primary BRAF/EGFR 19del co-mutated patients, the preferred first-line treatments still are EGFR TKIs -based targeted therapies in real-world clinical practice.