Final results from a randomized, placebo-controlled, double-blind, phase II clinical trial with the selective MET inhibitor tivantinib(ARQ 197;ArQule, Inc. andDaiichi Sankyo Company, Limited) as a single-agent, investigational, second-line treatment in hepatocellular carcinoma (HCC) shows positive results. The data was presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) (abstract number 4006) held in Chicago from June 1 – 5, 2012.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer.[1] Globally, liver cancer is the sixth most common cancer (749,000 new cases per year), accounting for 7% of all cancers, and is the third cause of cancer related death (692,000 cases per year).[2]. HCC represents more than 90% of primary liver cancers. [3] Chronic hepatitis B and C are recognized as the major factors worldwide increasing the risk of HCC, with risk being even greater in the presence of co-infection with these viruses.[4] Cirrhosis is also a risk factor for development of HCC.

An orally administered, selective inhibitor of MET
Tivantinib is a selective MET inhibitor. In healthy adult cells, MET is present in normal levels to support natural cellular function, but in cancer cells MET is inappropriately and continuously activated for unknown reasons. When abnormally activated, MET plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis.

c-Met is a member of a class of enzymes known as receptor tyrosine kinases or RTKs. Receptor tyrosine kinaseshave a significant potential for anti-cancer therapy. Encouraging results seen with agents such as Imatinib against cancers with the constitutively active Bcr-Abl mutation, as well as Erlotinib (Tarceva, Genentech/Roche), an inhibitor of mutated and over-expressed EGF receptor kinase, have provided an important proof-of-principle that molecularly targeted RTK inhibitors can have an important and broad impact against various cancers.

While tivantinibhas not yet been approved for any indication, research shows thatithas the potential to be a first-in-class MET inhibitor for the treatment of non-small cell lung cancer (NSCLC) and is currently being studied for other indications including liver and colorectal cancers, including HCC.In this phaseII trial,significant improvements were shown in time to progression (TTP) and overall survival (OS) observed in patients on tivantinib vs. on placebo whose tumors were MET-high. In earlier phase I studies the experimental drug alsoshowed promising results in HCC, both asmonotherapy and in combination with sorafenib. Based on these results, a phase III study among previously treated HCC patients with MET-high tumors is currently being planned with tivantinib

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Tivantinib after first-line therapy
In this trial,107 patientshad unresectable HCC and had disease progression after first-line therapy or were unable to tolerate the first-line therapy. Patients were randomized to receive tivantinib at 360 milligrams (mg) twice daily or 240 mg twice daily or placebo (2:1 tivantinib:placebo). The primary endpoint was time to progression (TTP) in the intent to treat (ITT) population. Other study endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), as well as safety for the ITT population and pre-defined MET-high or MET-low cohorts (as defined by immunohistochemistry).

A statistically significant 56% percent improvement as compared to placebo was seen in TTP in the ITT population (hazard ratio [HR] = 0.64; 90% confidence intervals [CI] = 0.43-0.94; log rank p-value = 0.04). The median TTP in tivantinib arm was 1.6 months and 1.4 months in the placebo arm.

In the MET-high cohort, there were statistically significant improvements in TTP, PFS and OS:

  • Median OS in tivantinib arm was 7.2 months and 3.8 months in the placebo arm (HR = 0.38; 95% CI = 0.18-0.81; log rank p-value = 0.01)
  • Median TTP was 2.9 months in the tivantinib arm and 1.5 months in the placebo arm (HR = 0.43; 95% CI = 0.19-0.97; log rank p-value = 0.03)
  • Median PFS was 2.4 months in the tivantinib arm and 1.5 months in the placebo arm (HR = 0.45; 95% CI = 0.21-0.95; log rank p-value = 0.02).

There was no significant difference in TTP or OS between tivantinib and placebo in the MET-low cohorts. Adverse events were reported at similar rates in the treatment and placebo arms of the trial, except for a higher incidence of fatigue and hematologic events, including neutropenia and anemia, in tivantinib-treated patients. The incidence of hematologic events decreased following dose reduction of tivantinib from 360 mg twice daily to 240 mg twice daily. Due to increased incidence of neutropenia in the 360 mg treatment group, the tivantinib dose was reduced to 240 mg twice daily for all patients.

“Patients living with this disease need more options to slow progression. The findings from this tivantinib study represent the first randomized data reported in HCC with an investigational MET inhibitor, as single-agent therapy in second-line treatment,” said Lorenza Rimassa, Deputy Director, Medical Oncology Unit, Humanitas Cancer Center, Milan, Italy. “The data suggest that patients significantly benefited in time to progression and, importantly, those in a biologically relevant MET-high subgroup had an additional significant advantage in overall survival.”

“Research has shown that MET is a signaling pathway associated with poor outcomes in many cancers, including liver cancer and non-small cell lung cancer (NSCLC),” said Glenn Gormley, MD, PhD, Global Head of Research & Development and Senior Executive Officer, Daiichi Sankyo Co., Ltd. “The strong overall survival results among HCC patients in this trial whose tumors were MET-high reinforce this previous research that defines MET as a critical pathway in cancer as well as the activity of tivantinib as a MET inhibitor.”

For more information:
Rimassa L, Porta C, Borbath I, Daniele B,Salvagni S,Van Laethem JL,Van Vlieberghe H, et al. Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: Results of a randomized controlled phase II trial (RCT). J Clin Oncol 30, 2012(suppl; abstr 4006).

Session: Gastrointestinal (Noncolorectal) Cancer
Type: Oral Abstract Session
Time:Saturday June 2, 3:00 PM to 6:00 PM
Location: E Hall D1

[1]. Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis. World Journal of Gastroenterology 14(27): 4300-08, 2008.
[2]. EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology. 2012;56: 908-943
[3]. EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology. 2012;56: 908-943
[4]. Chiaramonte M, Stroffolini T, Vian A, et al.: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85 (10): 2132-37, 1999.

Clinical trials:
NCT00988741– Trial of ARQ 197in Patients With Unresectable Hepatocellular Carcinoma (HCC) Who Have Failed One Prior Systemic Therapy
NCT00802555 – Safety Study of ARQ 197in Cirrhotic Patients With Hepatocellular Carcinoma (HCC)rior Systemic Therapy.

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