c-MET receptor tyrosine kinase (RTK) activity has been implicated in establishing the oncogenic phenotype across several human cancers with high levels of the activating c-MET ligand, hepatocyte growth factor (HGF). Malignant plasma cells secrete HGF-activator (HGFA), which converts HGF to its active form, and high HGF levels are correlated with a poor prognosis in multiple myeloma. Syndecan 1 (CD138) on malignant plasma cells binds HGF and potentiates interleukin-6-induced growth and migration. HGF stimulation of myeloma cells also activates autophosphorylation of c-MET and other critical downstream signaling pathways promoting oncogenesis. Finally, pre-clinical studies have shown that suppression of c-MET signaling with a number of small molecules, including ARQ 197, induced myeloma cell apoptosis. Tivantinib-mediated cytotoxic response was observed at concentrations of less than 5 µM, which are achievable in the clinic. These findings supported the hypothesis that suppression of the HGF/c-MET signaling axis could be a rational strategy against RRMM.
In this phase II study, the efficacy and safety of ARQ 197, a non-competitive and highly selective inhibitor of the c-MET RTK, was studied in patients with RRMM. Primary objectives were to determine the overall response rate (ORR) to single-agent tivantinib in patients who had received one to four prior lines of therapy, and to define the toxicities in this population. A Simon’s Minimax 2-stage design was used for the study. ARQ 197 was administered at a starting oral dose of 360 mg twice daily with meals for each day of every 4-week treatment cycle. This dose was selected from prior phase I investigations in solid tumors, and at this dose level, steady-state plasma levels of ARQ 197 were 7 µM. Treatment could continue providing that patients did not experience undue toxicities, or disease progression. Tivantinib is provided through the Cancer Therapy Evaluation Program (CTEP), and this study was supported by CTEP, as well as the MD Anderson Cancer Center SPORE in Multiple Myeloma.
A total of 16 patients were enrolled and treated to date, including 9 men and 7 women, who had received a median of 1 prior line of therapy (range 1-3), including stem cell transplant in ten. The mean patient age was 66 (range 49-76), with ethnicity including 13 Caucasian Americans, 2 African Americans, and 1 Asian American. Patients have received a median of 3 cycles of therapy to date (1-11) with one patient continuing on study, and all were evaluable for toxicity, while 11 were evaluable for response based on having completed two treatment cycles. The most common adverse events (AEs) of any grade seen in at least 25% of patients and felt to be at least possibly drug related included fatigue or decreased neutrophils (94% each), pain (81%), myalgias (56%), diarrhea (38%), memory impairment, respiratory disorders, and rash (31% each), and hypertension (25%), and these were predominantly grade 1 or 2. Grade 3 or 4 AEs included neutropenia (31% and 25%, respectively), syncope, infection, pain (13% of each, all grade 3), and anal fissure, cough, fatigue, hypertension, and pulmonary embolism (6% each, all grade 3). Stable disease (SD) has been seen as the best response in 4/11 (36%) evaluable patients, which was maintained for up to 11 cycles, while the remaining patients showed evidence of disease progression.
Single-agent tivantinib has been well tolerated in patients with RRMM, and the ability to achieve stable disease in patients with previously progressing myeloma does support the possibility that targeting c-MET has some promise. Future studies with rationally designed combination regimens incorporating a c-MET inhibitor and other novel agents may better define the role of this class of drugs in our armamentarium against myeloma.
Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Thomas:Millenium: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Shah:Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.