Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor–associated tumors

Abstract

BACKGROUND: Microphthalmia transcription factor (MITF)‐associated (MiT) tumors are a family of rare malignancies, including alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS), and translocation‐associated renal cell carcinoma (tRCC) that have dysregulated expression of oncogenic MITF family proteins. The MET receptor tyrosine kinase gene is transcriptionally activated by MITF family proteins, making MET a potential therapeutic target for MiT tumors. This study assessed the activity of tivantinib (ARQ 197), a selective MET inhibitor, in patients with MiT‐associated tumors. METHODS: This multicenter, single‐arm, phase 2 trial enrolled patients with advanced MiT tumors. Patients initially received tivantinib 120 mg orally twice daily, then 360 mg twice daily per protocol amendment. The primary endpoint was overall response rate. Secondary endpoints included safety, progression‐free survival, pharmacokinetics, and correlative studies. RESULTS: A total of 47 patients (median age, 25 years; range, 11‐73 years) with ASPS (n = 27), CCS (n = 11), tRCC (n = 6), or other tumor types (n = 3) were enrolled. Common grade 3/4 drug‐related adverse events included anemia (4%) and neutropenia (4%). Three patients (6.4%) experienced 4 treatment‐related serious adverse events (grade 3 febrile neutropenia, thrombocytopenia, and deep vein thrombosis, and grade 4 thrombocytopenia). Best response was partial response in 1 CCS patient (2%) and stable disease in 28 patients (60%). Median progression‐free survival was 3.6 months (overall), 5.5 months (ASPS), and 1.9 months (CCS and tRCC). Baseline MET expression was strongly or focally positive in tumor samples from 14 of 19 patients (74%). CONCLUSIONS: Tivantinib was safe and tolerable in patients with MiT tumors, but antitumor activity was modest. Cancer 2012. © 2012 American Cancer Society.

Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma

“…These include antagonists to c-Met ribozyme, HGF kringle variants/NK4, and decoy receptors, HGF-neutralizing antibodies, c-Met antagonist antibodies, and small-molecule c-Met inhibitors. 9,[22][23][24][25] Modest clinical activity was seen with the anti-HGF antibody AMG 102, with only one partial response and stable disease in 43% of patients evaluated by RECIST criteria. 24 Recent studies suggest that direct targeting of c-Met might be a more effective antitumor treatment strategy.…”

Papillary renal cell carcinoma: A review of the current therapeutic landscape

“…Several studies are investigating its efficacy in different solid tumors, including RCC. A phase II trial was carried out to evaluate tivantinib in patients with micropthalmia transcription factor (MITF)-associated tumors [90]. MITF-associated tumors are a family of rare malignancies, including alveolar soft part sarcoma, clear cell sarcoma, and translocation-associated renal cell carcinoma (tRCC), that have dysregulated expression of oncogenic MITF family proteins.…”

“…Of note, renal tumors with TFE3 translocation exhibited a predominant papillary morphology [91]. The disease control rate in tRCC was 50%, with a median PFS of 2 months and median OS of 15 months [90]. However, due to the small number of patients with tRCC (6/47) further studies are mandatory to define with higher accuracy the activity of the drug in these patients.…”

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

“…There have also been preclinical reports of acquired resistance to MET targeting TKIs via receptor mutation (17). Although molecules such as XL184, ARQ197, and crizotinib have all showed varying degrees of efficacy in MET positive patients, it is difficult to apportion this solely to their inhibition of a MET phenotype due to their broader inhibitory profile against other kinases (18)(19)(20)(21)(22). Anti-HGF antibodies, such as AMG102, bind circulating ligand and although they may benefit a subset of patients they cannot impact HGF-independent receptor activation (23,24).…”