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

Sara M Tolaney, Sally Tan, Hao Guo, William Barry, Eliezer Van Allen, Nikhil Wagle, Jane Brock, Katherine Larrabee, Cloud Paweletz, Elena Ivanova, Pasi Janne, Beth Overmoyer, John J Wright, Geoffrey I Shapiro, Eric P Winer, Ian E Krop, Sara M Tolaney, Sally Tan, Hao Guo, William Barry, Eliezer Van Allen, Nikhil Wagle, Jane Brock, Katherine Larrabee, Cloud Paweletz, Elena Ivanova, Pasi Janne, Beth Overmoyer, John J Wright, Geoffrey I Shapiro, Eric P Winer, Ian E Krop

Abstract

Background: 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.

Trial registration: ClinicalTrials.gov NCT01575522.

Keywords: ARQ 197; MET; Tivantinib; Triple-negative breast cancer.

Figures

Fig. 1
Fig. 1
Progression-free survival curves depicting final response to therapy
Fig. 2
Fig. 2
FISH analysis of MET gene on archival tissue of patient with partial response. Most of the 100–120 cells analyzed had ploidy level up to 4n, and the two (~2 % of cells) illustrated below had MET copy number increase (1.5-fold gain and 3.5-fold amplification, respectively)

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