Background: Pts included in the buparlisib (BKM120) module were analyzed by a tissue-agnostic genetic alteration–specific protocol that matches pts to treatments that target tumors harboring PI3K pathway–activated tumors. The pts are identified via standard of care physician-directed profiling. Methods: Pts with measurable advanced malignancies and no established standard therapy options were eligible. A local CLIA-certified test was sufficient for eligibility, and broad molecular profiling of pt tumors (confirmatory analysis of inclusion genetic alteration) was performed centrally post hoc. The primary objective was to assess clinical benefit (CB; CR + PR + SD at 16 weeks) by local investigator assessment. Buparlisib was given orally (100 mg once daily). Analysis correlating GMP with treatment outcomes will help determine the significance of these mutations. Results: GMP data were available for 76 pts across 19 tumor types (colorectal [14; 18%], sarcoma [11; 15%], ovarian [10; 13%], and head and neck [9; 12%]. Rare tumors included vaginal [1] and appendix [1]]. Median age: 60 years (range, 24-80), 49 women (65%), median number of prior therapies: 3 (range, 1-16). Baseline actionable alterations (local labs) included 38 PIK3CA mutations (50%), 17 PTEN mutations (22%), 16 PTEN losses (21%; IHC), 7 PIK3CA amplifications (9%), and 2 PIK3R1 mutations (3%). The concordance of baseline actionable alterations between local and central labs was 67%. Overall, 11 pts (15%) achieved CB. DNA from all pts was assayed by NGS, covering a panel of 288 cancer genes. Based on the assay, the tumors had a median of 4 mutations (range, 0-12) and tissue-specific patterns of mutation burden (lowest in cervix and sarcomas: 2; highest in colorectal and vaginal: 5+). The number of prior therapies did not correlate with the mutation load. Fewer mutations were noted in pts with CB. Most commonly altered genes (8+ pts): PIK3CA, PTEN, KRAS, TP53, APC, CDKN2A, RB1, and ERBB2. Aberrations in APC, BRCA2, CDKN2A, EP300, FBXW7, LRP1B, MLL2, PTEN, RB1, and SMAD4 were enriched in pts with no CB. Conclusions: Buparlisib showed activity in some pts, indicating that specific mutations may correlate with poor outcome. Clinical trial information: NCT01833169