Background: Activation of Phosphatidylinositol-3-kinase (PI3K) pathway may confer resistance to taxanes and in preclinical models concomitant inhibition of the PI3K pathway enhances efficacy of taxanes. Alpelisib is a potent oral, class I inhibitor of PI3K alpha isoforms with antitumor activity in tumors that harbor PI3KCA mutations. Methods: Eligible patients had HER-2 negative MBC with any number of prior chemotherapy. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250mg, 300mg, 350mg) PO daily (D1-28) and nab-Paclitaxel (nP) 100 mg/m² D 1, 8, 15 every 28 days. Phase II was designed according to Simon’s Minimax design. Aims were to determine 1) Recommended Phase II Dose (RPTD), 2) Objective Response Rate (ORR), 3) Progression-free survival (PFS). PIK3CA activating mutations in tumor and circulating tumor DNA (ctDNA) were assessed using next-generation sequencing. Results: There were no DLTs in the three dose levels of phase I (n = 10). 33 patients were treated in phase II on the RPTD (Alpelisib 350mg PO daily plus nP 100mg/m2 D1,8,15 every 28 days). Median age was 55 years; 30% had TNBC. 84% had visceral disease, 74% had received prior chemotherapy for MBC, 84% had received prior taxane. Hyperglycemia (G3:29%,G4:0%), neutropenia (G3:24%,G4:7%), anemia (G3:12%, G4:0%), diarrhea (G3:7%, G4:0%) were the most common grade 3/4 adverse events. In 42 patients evaluable for response, ORR was 57% (24/42) (CR = 2, PR = 22) and an additional 21% demonstrated SD ≥16wks. ORR for patients treated at RPTD was 55% (18/33). Median PFS is 9 months (95% CI: 6-12). Mean duration of treatment is 8 months(2-26 months). 40%(17/42) demonstrated tissue and/or ctDNA PIK3CA mutation (ctDNA/tissue concordance = 70%). Compared to patients without PIK3CA mutation, those with PIK3CA mutation demonstrated significantly better PFS (7 vs 13 months HR = 0.39, p = 0.03). Conclusions: Alpelisib and nP combination shows encouraging efficacy with manageable toxicity in HER2 negative MBC. Efficacy was especially robust in patients with PIK3CA mutation (ORR = 65%, PFS = 13months). Randomized trial of this combination in PIK3CA mutation selected patients is warranted. Clinical trial information: NCT02379247