Background: Vemurafenib, dabrafenib and tremetinib are FDA approved for treating BRAFV600-mutated melanoma. Vemurafenib has activity in non-melanoma BRAFV600-mutated tumors, as well. Unfortunately, most patients acquire resistance to BRAF monotherapy and mechanisms of resistance remain unknown. Methods: We analyzed CLIA certified clinical next generation sequencing data from BRAFV600E mutated non-melanoma tumors treated with BRAF inhibitor (BRAFi) from May 2012 to January 2016. We evaluated co-occurring genomic alterations and progression-free survival (PFS) of each patient. Results: Of the 30 patients treated with BRAFi monotherapy, 11 (37%) had NSCLC, 5 (17%) had colorectal cancer, 4 (13%) had cholangiocarcinoma, 3 (10%) had thyroid cancer, 3 (10%) had Erdheim Chester disease, and the remaining 4 (13%) had salivary gland carcinoma, glioblastoma, gliosarcoma, or unknown primary. Two of the 5 colorectal cancers were treated with BRAFi plus cetuximab. Three subsets of co-occurring genomic alterations were identified: 14 patients (47%) had no co-occuring alterations, 5 (17%) had PI3K/PTEN/mTOR pathway alterations, and 11 (37%) had other mutations: TP53 (n = 11), SMAD4 (n = 4), LKB1 (n = 2) and IDH (n = 2). Eight patients have ongoing response without progression on BRAFi monotherapy (PFS 222-805 days). Six of 8 responders (75%) have no co-occurring alterations, 2 of 8 (25%) have other mutations. All patients with co-alterations in the mTOR pathway progressed within 77 days. Tumors with mTOR pathway aberrations had a significantly lower median and mean PFS (mPFS, 53 days) compared to tumors with other co-occurring mutations (mPFS 206 days) and tumors without co-alterations (mPFS 276 days) (p = 1.03e-05). Conclusions: Co-occurring genomic alterations may help predict response to BRAFi therapy in BRAF-mutated tumors and PI3K/PTEN/mTOR pathway mutations may contribute to de novo resistance. Next generation sequencing is warranted on all BRAF mutated tumors as are further studies to address whether concurrently targeting co-occurring alterations will improve PFS. A trial combining BRAFi + mTOR inhibitor is underway (NCT01596140).