Background: Vemurafenib, dabrafenib and trametinib are FDA approved for treating BRAFV600-mutant melanoma. Vemurafenib has activity in multiple BRAFV600-mutant non-melanoma, as well. Unfortunately, patients acquire resistance to BRAF targeted monotherapy. Because preclinical data suggest mTOR activation may mediate resistance, we conducted a phase I study adding mTOR inhibitor everolimus to vemurafenib and evaluated tolerability, maximum tolerated dose (MTD) and response in all patients including those who progressed on prior BRAF targeted monotherapy. Methods: We performed a dose escalation study of vemurafenib twice daily and everolimus daily in 28 day cycles with an expansion cohort treated at MTD. Results: Twenty patients (14 male) with BRAF-mutated tumors (17-V600E, 2-V600K, 1-G469A) were enrolled. 7 had melanoma, 5 had CNS tumors, 4 had thyroid cancer, and 1 each had appendiceal, colorectal, NSCLC, and unknown primary cancer. Median age of 18 adult patients was 64; 2 pediatric patients were 10 and 13. 10 patients had prior therapy with BRAF inhibitor (50%), 10 had prior phase I trial (50%), 18 had surgery (90%), 11 had radiation (55%), 14 had chemo (70%). No DLT was observed with vemurafenib 720 mg BID and everolimus 5 mg QD. 3 patients experienced DLTs (rash, fatigue) when everolimus 10 mg QD was added to vemurafenib. Overall, 13/20 patients (65%) responded: 4 patients (26%) had a partial response, 9 (47%) had stable disease as best response. Of the 10 patients who previously progressed on BRAF inhibitor without mTOR inhibition, 2 had partial response and 4 had stable disease with the addition of everolimus. Two patients with CNS tumors remain on protocol after 7 and 19 cycles. Conclusions: The combination of vemurafenib 720 mg BID and everolimus 5 mg QD is safe, well-tolerated, and has demonstrated activity in patients with BRAF-mutant advanced cancers, including those previously treated with a BRAF inhibitor. Studies to help identify patients warranting up-front dual BRAF/mTOR inhibition are ongoing. Clinical trial information: NCT01596140