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

## TL;DR

This study compares lung cancer patients with primary and acquired BRAF mutations, finding differences in age, gender, and treatment outcomes, and suggests triple-targeted therapy may benefit certain groups.

## Contribution

The study identifies distinct clinical and molecular differences between primary and acquired BRAF-mutated NSCLC patients and explores the effectiveness of triple-targeted therapy in specific subgroups.

## Key findings

- Primary BRAF-mutated patients are older, more often male, and have a smoking history compared to acquired BRAF-mutated patients.
- Triple-targeted therapy (dabrafenib, trametinib, and third-generation EGFR TKIs) improved outcomes in primary BRAF/EGFR non-19del co-mutated patients.
- Acquired BRAF/EGFR co-mutated patients showed a median progression-free survival of 8.6 months with no major safety concerns.

## Abstract

The differences in clinical characteristics and treatment prognosis in NSCLC patients harboring primary and acquired BRAF mutations are still poorly understood.

From Oct 2017 to Dec 2023, 10, 211 lung cancer patients at Shanghai Ruijin Hospital were reviewed. 88 primary and 15 acquired BRAF-mutated NSCLC patients resistant to EGFR TKIs were included in the study.

Primary BRAF-mutated patients preferentially occurred in the elderly (median age: 67 vs 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 patients. Significant differences in gender (33.3% vs 62.3%, p=0.012), smoking history (22.2% vs 43.1%, p=0.063), and adenocarcinomas (100% vs 83.6%, p=0.028) were observed between primary BRAF/EGFR co-mutated and non-co-mutated groups. While primary and acquired BRAF/EGFR co-mutated patients had similar clinical characteristics, with EGFR mutations being the most common coexisting oncogene (30.7% and 93.3%). The genotype of EGFR mutations differed, with acquired BRAF-mutated cases showing more complexity and a higher rate of dual EGFR mutations (35.7%) compared to primary cases. 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.

Together, our study demonstrates that primary and acquired BRAF-mutant patients show distinct differences in some clinical and molecular characteristics, but acquired BRAF/EGFR co-mutated and primary BRAF/EGFR non-19del co-mutated patients may both respond to triple-targeted therapy.