Background: We evaluated the changes in circulating immune cell populations in patients enrolled in a phase II study of cabozantinib (cabo), an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2, for metastatic TNBC. Methods: In this single-arm, two-stage phase 2 study, patients with metastatic TNBC with measurable disease by RECIST and up to 3 lines of prior chemotherapy for metastatic disease received cabo 60 mg daily on a 21-day cycle. Patients were restaged at 6 weeks and every 9 weeks thereafter. The primary endpoint was objective response rate (ORR). Predefined secondary endpoints included progression free survival (PFS) and toxicity. Here, we examined cellular biomarkers using flow cytometry in serial blood samples collected at days 0 (baseline/pre-treatment), 8, 22, 43, and 64 of cabo treatment. Mixed effect models were used to evaluate the changes of biomarker levels over time from baseline to day 64. Wilcoxon signed rank test were used to evaluate whether the change of biomarker levels from baseline to day 8 were different by clinical benefit. Results: The analysis included all 35 patients who initiated protocol therapy. As previously reported (ASCO 2015), the ORR was 11%, the clinical benefit rate (PR+SD) at 15 weeks was 34% (95% CI 19-52%) and the median PFS was 2.0 months (95%, CI 1.3-3.3). From baseline to day 64, there were significant increases in the number of circulating CD3+ cells and CD8+ T cells, and decreases in CD14+ monocytes (all p < 0.05) at all time-points. There was a trend for increase in CD4+ cells (p = 0.08) and CD56+ NK cells (p = 0.07) but no significant changes in the fraction of CD133+ progenitor/stem cells, CD4+CD25+ Tregs, CD4+CD127+ memory T cells and CD3+CD56+ NKT cells. The changes of biomarker levels from baseline to day 8 were not significantly different between patients with and without clinical benefit. Conclusions: Analysis of circulating cell biomarkers showed that cabo induces systemic changes consistent with activation of the immune system in metastatic TNBC patients. These hypothesis-generating data support consideration of studies of cabo with immunotherapy in this patient population. Clinical trial information: NCT02260531