Background: BRAF alterations (alts) account for ~4% of non-small cell lung cancers (NSCLC) with 50% being non-V600 alts. Because these alts are functionally heterogeneous and have a poorly characterized genomic landscape, determining appropriate treatment strategies is a challenge. Methods: The Guardant360 clinical database was queried for NSCLC patients (pts) with BRAF alts. Alts were categorized by clonality, type and class (1 and 2: BRAF monomer and dimer signaling; 3: requires co-occurring upstream RAS-mediated signaling). Functionality and drug screen assays were performed in Ba/F3 cells. Pts with non-V600 mutations were analyzed for sensitivity to MEK +/- BRAF inhibitors (M+Bi). Results: 306 unique BRAF alts were identified and the majority were observed once (233/306; 76%). Amplifications (806/1663; 48.5%) and missense alts (795/1663; 47.8%) were the most common occurrences. Missense alts were predominantly clonal (58%), and of known functionality (428/795; 54%). All class 1-2 alts were activating in Ba/F3 cells, while class 3 alts were found to have variable functionality (activating: 4/9). Functionality was correlated with clonality as demonstrated by class 1-3 alts having higher clonality compared to variants of unknown significance (VUS) (1: 56%; 2: 54%; 3: 45%; VUS: 38%; P<0.01). Drug screens for G469V and L597R alts showed resistance to first generation BRAF inhibitors (IC50 ≥100nM), but sensitivity to M+Bi (IC50 0.02-36nM). Growth inhibition was more pronounced for dabrafenib + trametinib (D+T) (IC50 <0.1nM) compared to encorafenib + binimetinib (IC50 8-35nM) and vemurafenib + cobimetinib (IC50 2-36nM). BRAF D594G mutation (class 3) was not activating in Ba/F3 cells. Three pts with non-V600 alts were treated with M+Bi. G469V and D594G had rapid disease progression (PFS 2 and 4 mos respectively), while pt with L597R has ongoing partial response (PFS 8+ mos). Conclusions:BRAF alts show correlation between clonality and functionality, which provides important clinical information given the numerous VUS in the BRAF non-V600 setting. Drug screens reveal non-V600 alts may be sensitive to M+Bi and suggest D+T is the most active combination. Clinical data supports that some non-V600 BRAF mutations may be sensitive to M+Bi.