Background

Oncogenic BRAF mutations can be categorized into three classes (I, II and III) based on their distinct structural and signaling properties. BRAF inhibitors are approved in select cancer types for patients with Class I mutations. However, there are no approved targeted therapies for patients whose tumors bear BRAF Class II or III mutations. This research utilizes a clinico-genomic database to explore the real-world occurrence, characteristics, and outcomes of patients with oncogenic BRAF mutations by distinct classes across solid tumors.

Methods

Analyses utilized a de-identified database containing genomic data from over 55,000 cancer patients whose tumors were profiled using the Tempus xT assay; a 648 gene DNA panel coupled with RNA sequencing. Clinical data was also available for a subset of the patients. Time to treatment discontinuation (TTD) was used as a real-world measure of treatment benefit.

Results

More than 3,000 patients with oncogenic BRAF mutations were identified. Class II and III mutations were present in approximately 2% of all patients tested. Melanoma and NSCLC patients with BRAF Class II or III were commonly treated with immune checkpoint inhibitors (ICI) or chemotherapy +/- ICI. At least 70% of patients with BRAF mutations had stage IV disease, and stage distribution was similar across BRAF classes. Compared to Class I, BRAF Class II and III mutations were more likely to co-occur with other mutations in the MAPK pathway and were associated with higher tumor mutation burden (TMB). In NSCLC, patients with Class II or III mutations experienced shorter times to treatment discontinuation in first line (II vs I; p=0.04, III vs I; p=0.009) and second line (II vs I; p=0.079, III vs I; p=0.039) of therapy.

Conclusions

The analysis of this large real-world dataset identified a substantial number of cancer patients with BRAF Class II and III mutations. BRAF Class II and III mutations were associated with unique tumor characteristics, including higher TMB and more frequent co-occurrence with other MAPK pathway alterations. Relative to NSCLC patients with BRAF Class I, NSCLC patients with Class II or III mutations had inferior outcomes when treated with available therapies.

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