Tivantinib (ARQ 197)

Tivantinib (ARQ 197) is an oral, non–adenosine triphosphate-competitive, selective, small-molecule met proto-oncogene (c-MET) inhibitor. The calculated inhibitory constant (Ki) for tivantinib to inhibit recombinant human c-MET was approximately 355 nmol/L.

c-MET, a type of receptor tyrosine kinase, is a high-affinity receptor of the hepatocyte growth factor (HGF). Dysregulated HGF/c-MET-signaling pathway frequently occurs in human cancer [1].

Tivantinib had weak inhibitory effects on VEGF receptor-3 (Flt4), p21-activated kinase 3, calmodulin-dependent kinase II delta, and Pim-1 [1]. Tivantinib displayed cytotoxic activity against a wide panel of human tumor cell lines with an EC50 ranging from 300-600 nmol/L [4]. Remarkably, A549, H3122, PC9 (Del E746_A750), PC9 GR4 (Del E746_A750/T790M), HCC827, HCC827 GR6, H1993 and EBC-1 cell lines showed some degree of sensitivity to tivantinib, with IC50s ranging between 0.36 and 0.8 μM [5]. In tumor cell lines, GTL-16, MKN-45, Hs746T, SNU-5, EBC-1, H1993, NCI-H441, A549, HCT-116, U87-MG, A2780, and TOV-112D, tivantinib indiscriminately inhibited cell proliferation independently of c-MET gene amplification and MET protein expression with an EC50 ranging from 60 to 600 nmol/L. Further research showed that tivantinib promotes mitotic arrest, prevents cells from re-entering G1, and drives them to apoptosis, and induces programmed cell death regardless of the presence or absence of a functional MET kinase [4].

Tivantinib has demonstrated antitumor activity in a wide range of human tumor cell lines and in xenograft models of human lung, colon, prostate, pancreas, and breast cancer [1] [2] [3]. Female 4-week-old athymic nude (nu/nu) mice were used as experimental animals. Tivantinib at a dose of 120 mg/kg significantly inhibited tumor burden in the bone of treated animals compared with the controls, starting from 14 to 21 days after cell injection. Increasing doses of tivantinib decreased the number and the extent of osteolytic lesions [6].

References:
[1].  Ryohei Katayama, Aki Aoyama, Takao Yamori, et al. Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition. Cancer Research, 2013, 73(10): 3087-3097.
[2].  Andrew J.Wagner, John M. Goldberg, Steven G. DuBois, et al. Tivantinib (ARQ 197), a Selective Inhibitor of MET, in Patients with Microphthalmia Transcription Factor–Associated Tumors. Cancer, 2012: 5894-5902.
[3].  N. Yamamoto, H. Murakami, T. Nishina, et al. The effect of CYP2C19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (ARQ 197): results from a phase I trial in advanced solid tumors. Annals of Oncology, 2013, 00: 1–7.
[4].  Cristina Basilico, Selma Pennacchietti, Elisa Vigna, et al. Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET. Clin Cancer Res, 2013, 19(9):2381-92.
[5].  Cristina Basilico, Selma Pennacchietti, Elisa Vigna, et al. Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET. Clinical Cancer Research, 2013, 19(9): 2381–92.
[6].  Sara Previdi, Giovanni Abbadessa, Francesca Dalò, et al. Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown. Mol Cancer Ther, 2011, 11(1):214-23.

Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib.[Pubmed:27843623]

ESMO Open. 2016 Jul 21;1(4):e000063.

BACKGROUND: Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, Tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. METHODS: This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. RESULTS: The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. CONCLUSIONS: Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. TRIAL REGISTRATION NUMBER: NCT01580735.

Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma.[Pubmed:28337527]

Ann Hematol. 2017 Jun;96(6):977-985.

The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest.

Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: role of Mcl-1, Bcl-xl and Cyclin B1.[Pubmed:26259250]

Oncotarget. 2015 Sep 8;6(26):22167-78.

Tivantinib, a c-MET inhibitor, is investigated as a second-line treatment of HCC. It was shown that c-MET overexpression predicts its efficacy. Therefore, a phase-3 trial of tivantinib has been initiated to recruit "c-MET-high" patients only. However, recent evidence indicates that the anticancer activity of tivantinib is not due to c-MET inhibition, suggesting that c-MET is a predictor of response to this compound rather than its actual target. By assessing the mechanisms underlying the anticancer properties of tivantinib we showed that this agent causes apoptosis and cell cycle arrest by inhibiting the anti-apoptotic molecules Mcl-1 and Bcl-xl, and by increasing Cyclin B1 expression regardless of c-MET status. However, we found that tivantinib might antagonize the antiapoptotic effects of c-MET activation since HGF enhanced the expression of Mcl-1 and Bcl-xl. In summary, we show that the activity of tivantinib is independent of c-MET and describe Mcl-1, Bcl-xl and Cyclin B1 as effectors of its antineoplastic effects in HCC cells. We suggest that the predictive effect of c-MET expression in part reflects the c-MET-driven overexpression of Mcl-1 and Bcl-xl in c-MET-high patients and that these molecules are considered as possible response predictors.

A randomized, placebo-controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild-type KRAS who have received first-line systemic therapy.[Pubmed:26891420]

Int J Cancer. 2016 Jul 1;139(1):177-86.

Cetuximab in combination with an irinotecan-containing regimen is a standard treatment in patients with KRAS wild-type (KRAS WT), metastatic colorectal cancer (mCRC). We investigated the addition of the oral MET inhibitor tivantinib to cetuximab + irinotecan (CETIRI) based on preclinical evidence that activation of the MET pathway may confer resistance to anti-EGFR therapy. Previously treated patients with KRAS WT advanced or mCRC were enrolled. The phase 1, open-label 3 + 3, dose-escalation study evaluated the safety and maximally tolerated dose of tivantinib plus CETIRI. The phase 2, randomized, double-blinded, placebo-controlled study of biweekly CETIRI plus tivantinib or placebo was restricted to patients who had received only one prior line of chemotherapy. The phase 2 primary endpoint was progression-free survival (PFS). The recommended phase 2 dose was tivantinib (360 mg/m(2) twice daily) with biweekly cetuximab (500 mg/m(2)) and irinotecan (180 mg/m(2)). Among 117 patients evaluable for phase 2 analysis, no statistically significant PFS difference was observed: 8.3 months on tivantinib vs. 7.3 months on placebo (HR, 0.85; 95% confidence interval, 0.55-1.33; P = 0.38). Subgroup analyses trended in favor of tivantinib in patients with MET-High tumors by immunohistochemistry, PTEN-Low tumors, or those pretreated with oxaliplatin, but subgroups were too small to draw conclusions. Neutropenia, diarrhea, nausea and rash were the most frequent severe adverse events in tivantinib-treated patients. The combination of tivantinib and CETIRI was well tolerated but did not significantly improve PFS in previously treated KRAS WT mCRC. Tivantinib may be more active in specific subgroups.