title: Phase II and Biomarker Study of Cabozantinib in Metastatic Triple-Negative Breast Cancer Patients.
abstract: Currently, no targeted therapies are available for metastatic triplenegative breast cancer (mTNBC). We evaluated the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase inhibitor, in patients with mTNBC. We conducted a single arm phase II and biomarker study that enrolled patients with measurable mTNBC. Patients received cabozantinib (60 mg daily) on a 3-week cycle and were restaged after 6 weeks and then every 9 weeks. The primary endpoint was objective response rate. Predefined secondary endpoints included progression-free survival (PFS), toxicity, and tissue and blood circulating cell and protein biomarkers. Of 35 patients who initiated protocol therapy, 3 (9% [95% confidence interval (CI): 2, 26]) achieved a partial response (PR). Nine patients achieved stable disease (SD) for at least 15 weeks, and thus the clinical benefit rate (PR+SD) was 34% [95% CI: 19, 52]. Median PFS was 2.0 months [95% CI: 1.3, 3.3]. The most common toxicities were fatigue, diarrhea, mucositis, and palmar-plantar erythrodysesthesia. There were no grade 4 toxicities, but 12 patients (34%) required dose reduction. Two patients had TNBCs with MET amplification. During cabozantinib therapy, there were significant and durable increases in plasma placental growth factor, vascular endothelial growth factor (VEGF), VEGF-D, stromal cell-derived factor 1a, and carbonic anhydrase IX, and circulating CD3 + cells and CD8 + T lymphocytes, and decreases in plasma soluble VEGF receptor 2 and CD14+ monocytes (all p < .05). Higher baseline concentrations of soluble MET (sMET) associated with longer PFS (p = .03). In conclusion, cabozantinib showed encouraging safety and efficacy signals but did not meet the primary endpoint in pretreated mTNBC. Exploratory analyses of circulating biomarkers showed that cabozantinib induces systemic changes consistent with activation of the immune system and antiangiogenic activity, and that sMET should be further evaluated a potential biomarker of response.
  
  
  
  Triple-negative breast cancer (TNBC)-a disease with a dearth of effective therapies-often overexpress MET, which is associated with poor clinical outcomes. However, clinical studies of agents targeting MET and VEGF pathways-alone or in combination-have shown disappointing results. This study of cabozantinib (a dual VEGFR2/MET) in metastatic TNBC, while not meeting its prespecified endpoint, showed that treatment is associated with circulating biomarker changes, and is active in a subset of patients. Furthermore, this study demonstrates that cabozantinib therapy induces a systemic increase in cytotoxic lymphocyte populations and a decrease in immunosuppressive myeloid populations. This supports the testing of combinations of cabozantinib with immunotherapy in future studies in breast cancer patients.
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Sara M
authors: SM
authors: Tolaney
authors: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
authors: David R
authors: DR
authors: Ziehr
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Hao
authors: H
authors: Guo
authors: Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Boston, Massachusetts, USA.
authors: Mei R
authors: MR
authors: Ng
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: William T
authors: WT
authors: Barry
authors: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
authors: Michaela J
authors: MJ
authors: Higgins
authors: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
authors: Steven J
authors: SJ
authors: Isakoff
authors: Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Jane E
authors: JE
authors: Brock
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Elena V
authors: EV
authors: Ivanova
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Cloud P
authors: CP
authors: Paweletz
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Michelle K
authors: MK
authors: Demeo
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Nikhil H
authors: NH
authors: Ramaiya
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Beth A
authors: BA
authors: Overmoyer
authors: Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Boston, Massachusetts, USA.
authors: Rakesh K
authors: RK
authors: Jain
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Eric P
authors: EP
authors: Winer
authors: Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Boston, Massachusetts, USA.
authors: Dan G
authors: DG
authors: Duda
mesh_terms: D000328:Adult; D000368:Aged; D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D000072483:Placenta Growth Factor / Q000097:blood; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D064726:Triple Negative Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D042643:Vascular Endothelial Growth Factor D / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000813:Anilides; D014408:Biomarkers, Tumor; C000608036:PGF protein, human; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; D000072483:Placenta Growth Factor; C558660:cabozantinib; C000588866:KDR protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Cabozantinib; Lymphocytes; Soluble MET; Triple‐negative breast cancer; Vascular endothelial growth factor receptor