Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer

Abstract

SummaryBackground MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. Methods Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. Results 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0–25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0–25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). Conclusion This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy.

Clinicopathological and prognostic significance of c-Met overexpression in breast cancer

“…The clinical relevance of c-Met inhibitors is now under investigation, phase II and III clinical trials in a variety of malignancies including non-small cell lung cancer [ 20 – 22 ], colorectal cancer [ 23 ], gastroesophageal cancer [ 24 ] are ongoing. With regard to breast cancer, a phase II trial examining tivantinib in patients with recurrent or metastatic TNBC [ 25 ] and a randomized phase II study evaluating the safety and efficacy of onartuzumab and/or bevacizumab in combination with paclitaxel in patients with metastatic TNBC are currently ongoing [ 26 ].…”

Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date

“…Notably, in vivo studies have not documented evidence of neurotoxicity, which is known to be a major adverse effect of microtubule inhibitors 23. Similarly, tivantinib has demonstrated only minimal, if any, response in patients who have tumors with low levels of MET expression, while those tumors with high levels of MET have had the most profound responses to the drug 33,34…”

A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors

“…Monotherapy with tivantinib has led to prolonged periods of disease control but the response rate has been low. No responses were seen in single arm studies of patients with germ cell tumors [10], gastric cancer [11], and hepatocellular carcinoma [12, 13] and a response rate of only 5% was noted in patients with triple-negative breast cancer [14]. …”