OT3-01-11: A Randomized, Phase II Multicenter, Double-Blind, Placebo-Controlled Trial Evaluating MetMAb and/or Bevacizumab in Combination with Weekly Paclitaxel in Patients with Metastatic Triple-Negative Breast Cancer.

Abstract

Background Dysregulation of the HGF/Met pathway has been associated with tumorigenesis in many malignancies, including the basal sub-type of triple-negative breast cancer. MetMAb (RG3638) is a recombinant, humanized, monovalent monoclonal antibody directed against Met. By binding to the extracellular domain of Met, MetMAb selectively blocks ligand binding and subsequent activation by HGF. Pre-clinical data support the efficacy of combining MetMAb with numerous chemotherapy agents and with targeted agents including bevacizumab and erlotinib. In clinic, MetMAb has been generally well tolerated as a single agent (Phase I), in combination with bevacizumab (Phase Ib) and with bevacizumab in a dose escalation/expansion study (Phase Ib)1 as well as in combination with erlotinib in patients with previously treated NSCLC2. The combination of MetMAb + erlotinib in NSCLC demonstrated significant benefit in both PFS and OS in patients with Met diagnostic positive tumors whereas those patients with Met diagnostic negative tumors demonstrated a detrimental effect in both PFS and OS. The most commonly reported adverse events associated with MetMAb are peripheral edema and fatigue. Methods: This clinical trial is a randomized three-arm Phase II study in patients with triple-negative metastatic breast cancer, which makes up the majority of basal sub-type breast cancer. Patients will be randomized (1:1:1) to either paclitaxel + bevacizumab + placebo; paclitaxel + placebo + MetMAb; or paclitaxel + bevacizumab + MetMAb. The primary endpoint of this study is PFS in all patients and by Met diagnostic status. Secondary endpoints include an evaluation of OS, ORR, safety, and pharmacokinetics. To date, 11 patients have been enrolled, and 10 patients have been treated. Primary and secondary analyses will include all randomized patients, with patients analyzed according to the treatment arm to which they were assigned. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm. An estimate of the HR with 95% CI will be determined using a Cox regression model with an indicator variable for the MetMAb-containing arm. Safety will be assessed through summaries of adverse events and will include all patients who receive any amount of study treatment. This study remains open for accrual; further details on the trial can be found on the ClinicalTrials.gov website under NCT01186991. 1. Moss et al, In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2–6; Orlando, FL; AACR 2011 (abstr 4717). 2. Spigel et al, J Clin Oncol 29:2011 (suppl; abstr 7505). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-11.

Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?

“…Appropriately, co-inhibition of EGFR and c-MET suppressed tumor growth in preclinical models [ 37 ]. However, initial results with c-MET inhibitors were disappointing, with no improvement of progression-free survival when onartuzumab was given with paclitaxel/bevacizumab-based regimens in unselected metastatic TNBC patients [ 38 ]. However, with better understanding of pathway and possible expanded target group including BL2 TNBCs showing enriched in genes associated with the c-MET pathway [ 5 ], this pathway still holds future potential.…”