cabozantinib and Triple-Negative-Breast-Neoplasms

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.

Topics: Adult; Aged; Anilides; Biomarkers, Tumor; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Placenta Growth Factor; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-2

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chalcone; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pyrazines; Structure-Activity Relationship; Triple Negative Breast Neoplasms

Targeting of somatic MET mutations using crizotinib has led to strong clinical responses, most frequently in patients with lung cancer, raising the possibility of adopting similar treatment strategies in patients with MET alterations in other cancer types.. We describe a patient with advanced triple-negative breast cancer with a 30-fold amplification of MET. Next-generation sequencing of pre- and postprogression biopsies was performed to identify the resistance mechanism emerging after an initial exceptional response to crizotinib. The response of the resistance mutant to type I and II MET inhibitors was assessed in cultured cells.. After progressing on crizotinib, a MET-D1228N mutation was detected, which is located in the crizotinib-binding region of the MET kinase domain. Experimental studies demonstrated that this mutation confers complete resistance to crizotinib yet retains cabozantinib sensitivity. Treatment of the patient with cabozantinib led to a subjective improvement in clinical symptoms, but the patient progressed after 7 weeks.. Although MET mutations are rare in breast cancer, these patients may experience substantial clinical benefit from crizotinib treatment. Nevertheless, drug resistance owing to on-target MET mutations will likely be frequently encountered and comprehensive mechanistic studies to assess sensitivity of these mutants to a series of potential second-line therapies may help guide subsequent treatment for these patients.

Topics: Adult; Amino Acid Substitution; Anilides; Biopsy; Breast; Crizotinib; Disease Progression; DNA Mutational Analysis; Drug Resistance, Neoplasm; Female; Gene Amplification; Humans; Male; Positron Emission Tomography Computed Tomography; Primary Cell Culture; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Treatment Outcome; Triple Negative Breast Neoplasms; Tumor Cells, Cultured

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is associated with poor clinical outcome. There is a vital need for effective targeted therapeutics for TNBC patients, yet treatment strategies are challenged by the significant intertumoral heterogeneity within the TNBC subtype and its surrounding microenvironment. Receptor tyrosine kinases (RTK) are highly expressed in several TNBC subtypes and are promising therapeutic targets. In this study, we targeted the MET receptor, which is highly expressed across several TNBC subtypes.. Using the small-molecule inhibitor cabozantinib (XL184), we examined the efficacy of MET inhibition in preclinical models that recapitulate human TNBC and its microenvironment. To analyze the dynamic interactions between TNBC cells and fibroblasts over time, we utilized a 3D model referred to as MAME (Mammary Architecture and Microenvironment Engineering) with quantitative image analysis. To investigate cabozantinib inhibition in vivo, we used a novel xenograft model that expresses human HGF and supports paracrine MET signaling.. XL184 treatment of MAME cultures of MDA-MB-231 and HCC70 cells (± HGF-expressing fibroblasts) was cytotoxic and significantly reduced multicellular invasive outgrowths, even in cultures with HGF-expressing fibroblasts. Treatment with XL184 had no significant effects on MET(neg) breast cancer cell growth. In vivo assays demonstrated that cabozantinib treatment significantly inhibited TNBC growth and metastasis.. Using preclinical TNBC models that recapitulate the breast tumor microenvironment, we demonstrate that cabozantinib inhibition is an effective therapeutic strategy in several TNBC subtypes.

Topics: Anilides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Female; Fibroblasts; Humans; Lung Neoplasms; Mice, Inbred C3H; Mice, SCID; Neoplasm Invasiveness; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; Triple Negative Breast Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays