BRAF fusions are uncommon driver alterations in a range of cancers. While the BRAF V600E mutation is a recognized target for the BRAF inhibitors, BRAF fusions have not yet been investigated as potential targets for treatment in most cancers, and there is limited literature available to help guide treatment for patients with these fusions with targeted therapies, including direct BRAF inhibitors and downstream MEK inhibitors. This systematic review aims to summarize the available literature on the targeted treatment of solid tumors harboring a BRAF fusion.

We conducted a systematic review to delineate the reported efficacy, response rates and survival outcomes, of targeted treatment in patients with a solid cancer harboring a BRAF fusion. PubMed, Embase, and Cochrane CENTRAL were searched between 2014 and 2024. Data were extracted to assess the details of efficacy.

A total of 37 studies involving 113 patients with BRAF fusion-positive cancer who underwent targeted therapies were included. Most of these studies were case reports and case series (n = 31, 84%), with four clinical trials (11%) that were either phase I or phase II. The review included various cancer types, with central nervous system (CNS) cancers, including gliomas and pilocytic astrocytomas, being the most common (n = 66, 58%), followed by melanoma (n = 20, 18%) and non-small cell lung cancer (NSCLC) (n = 9, 8%). Other cancers (n = 18, 16%) included sarcoma (n = 7), genitourinary (n = 2) and colorectal (n = 1). Among the BRAF fusion gene partners, KIAA1549 was the most frequent (n = 62, 55%), followed by SND1 (n = 6, 5%) and AGK (n = 4, 4%). The targeted therapies used were varied, with MEK inhibitors being used in most patients, selumetinib (n = 36, 32%), followed by trametinib (n = 34, 30%), as well as, binimetinib and cobimetinib. BRAF and pan-RAF inhibitors used included dabrafenib, vemurafenib, tovorafenib and belvarafenib. The response rates were reported for 103 patients, with 2% achieving a complete response (n = 2), 46% showing a partial response (n = 47), and 22% exhibiting stable disease (n = 23). Objective response rate in NSCLC, sarcoma, melanoma and CNS tumors was 88%, 57%, 52% and 41% respectively. Data on survival outcomes was limited.

In conclusion, there is limited data on the efficacy of targeted therapy in solid tumors with a BRAF fusion, with most evidence coming from case reports/series, alongside a few phase I/II trials. While BRAF fusion-positive cancers show varying yet promising responses to BRAF and/or MEK inhibitors, the effectiveness may vary with histology. Given the rarity of these fusions, there is a clear need for international collaboration and innovative trial designs, such as basket and platform trials, to assess targeted treatment strategies more effectively and improve outcomes for these patients.