Background: The SWI/SNF complex is an ATP-dependent chromatin remodeler that is enriched at promoters and enhancers of active genes. It has been implicated as both an oncogene and tumor suppressor. Specific subunit mutations have even been associated with specific cancers with increased PRC2 component EZH2 activity. EZH2/ EED inhibitors are in early stage development to target SWI/SNF complex. Methods: We analyzed 539 consecutive patients with diverse malignancies who were referred for Phase 1 clinical trials and had CLIA certified targeted next-generation sequencing (Foundation one) for presence of aberrations in SWI/SNF complex genes (ARID1A, ARID2, PBRM1, SMARCA4, SMARCB1). Patient charts were reviewed for general demographics (sex, age at diagnosis and death, performance status), tumor histology, stage, metastatic sites, treatment history, outcomes and co-occurring alterations. Results: Fifty patients had mutations in SWI/SNF subunits. Median age at diagnosis was 56 (14-79 years) and M:F ratio 21:29. Kidney, colorectal, ovary and breast were the most common among 15 different cancers. Most were stage IV at diagnosis (68%), had a strong family history of cancer (80%) & were smokers (42%). The most common mutated subunit was ARID1A (50%) followed by PBRM1 (16%), ARID2 (12%), SMARCA4 (12%), and SMARCB1 (10%). All mutations were predicted to be inactivating. Actionable co-occurring pathway alterations were found in 58% of patients, most commonly PI3K (26%), FGFR(16%), and NOTCH1/2 (10%). The majority of patients (62%) were enrolled on a clinical trial. Best responses on other targeted agents included 1 CR (BRAF^V600E colon), 4 PR (transformed teratoma, skin SCC, ovarian, NSCLC), 12 SD. Exceptional responders included BRAF^V600E colon cancer on BRAFi based therapy for 66 cycles, NSCLC on Nivolumab for 34 cycles, and MSI-H colon cancer on regorafenib/cetuximab for 27 cycles. Conclusions: The role of SWI/SNF in patients with extended clinical benefit from other targeted agents should be explored. Co-occurring genetic alterations are observed in PI3K, FGFR, and NOTCH pathways. Future pre-clinical and/or clinical studies could target these pathways in combination with EZH2/EED inhibitors.