Background: Data suggests that MET expression and activation are important for initiation and progression of TNBC. We evaluated the efficacy of cabozantinib (XL184), a novel inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2, in patients with metastatic TNBC. Methods: In this single-arm, two-stage Phase 2 study, patients with metastatic TNBC with measurable disease by RECIST v1.1 and up to 3 lines of prior chemotherapy in the metastatic setting received cabozantinib 60 mg daily on a 21-day cycle. Patients were restaged 6 weeks following treatment initiation and every 9 weeks thereafter. The primary endpoint was objective response rate (ORR). If ≥ 1/13 pts responded at stage 1, 22 more will be enrolled. If ≥ 4/35 responded, the null rate (5%) would be rejected in favor of a 20% rate of activity. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Results: Thirty-five patients (median age 50 years, range 31-78) initiated protocol therapy and were included in this analysis. Patients had 0 (n = 6, 17%), 1 (n = 18, 51%), 2 (n = 4, 11%), or 3 (n = 7, 20%) prior lines of chemotherapy for metastatic disease. Two patients achieved confirmed PR (ORR 9% [95% CI 1-25%]) and 3 achieved unconfirmed PR; 18 patients (51%, 95% CI: 34-69%) had SD as their best response. The clinical benefit rate at 15 weeks was 31% (95% CI 17-49%) and the median PFS was 1.9 months (95% CI 1.3-3.3). The most common toxicities (all grades) were fatigue (77%), diarrhea (40%), mucositis (37%), and palmar-plantar erthrodysesthesia (PPE) (37%). There were no grade 4 toxicities. Twelve (34%) patients required dose reduction, 4 due to PPE and 8 due to other toxicities. Ongoing studies are exploring MET expression and amplification in archival tumor samples, MET amplification in circulating tumor cells, and plasma biomarkers of response to cabozantinib. Conclusions: In patients with metastatic TNBC, cabozantinib monotherapy showed evidence of antitumor activity. Adverse events requiring dose reduction occurred in about one-third of patients. Biomarker changes and their association with outcome will be presented at the meeting. Clinical trial information: NCT02260531