BRAF class II-III mutations in NSCLC: a single center experience

Currently, there is no consensus on the optimal treatment sequence for NSCLC patients with class II-III BRAF mutations, where standard of care implies immunochemotherapy and scarce data on targeted therapy is available.

This is an observational, single centre case series of 9 patients collected in a Cancer Institute in Italy diagnosed with NSCLC with a BRAF class II or III mutation between 2020 and April 2025. All clinico-pathological data were anonymously collected with patient consent if they were alive at the time of data collection (2025). All patients were discussed by the Institutional Molecular Tumor Board. When feasible, off-label targeted therapy with dabrafenib and trametinib was administered. Data on type of BRAF mutation, variant allele frequency, co mutations, and clinical outcomes are reported. Progression-free survival was measured in patients treated with dabrafenib and trametinib; overall survival for all patients. Toxicities related to targeted therapy were graded using CTCAE v5.0.

The most common mutation was BRAF G469 (class IIb), observed in 4 of 9 patients. Median age was 76 years. Only three patients received dabrafenib and trametinib for longer than one month, achieving stable disease as the best response. Among these patients, median progression-free survival was 7.5 months and median overall survival was 18.7 months. Across the entire cohort, median overall survival was 16.6 months. Independently of the prior treatment received, only one patient experienced grade 3 treatment-related toxicity.

This case series highlights the clinical heterogeneity and poor prognosis of NSCLC patients with BRAF class II-III mutations. While dabrafenib and trametinib were well tolerated, treatment feasibility was restricted. These findings emphasize the urgent need for more robust research to identify effective therapeutic strategies for this molecular subgroup.