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. 2014 Jan 29;1(2):181–188. doi: 10.2217/hep.14.3

Tivantinib in MET-high hepatocellular carcinoma patients and the ongoing Phase III clinical trial

Lorenza Rimassa 1,1,*, Camillo Porta 2,2, Ivan Borbath 3,3, Bruno Daniele 4,4, Richard S Finn 5,5, Jean-Luc Raoul 6,6, Lawrence H Schwartz 7,7, Aiwu Ruth He 8,8, Joerg Trojan 9,9, Markus Peck-Radosavljevic 10,10, Giovanni Abbadessa 11,11, Terri Goldberg 12,12, Armando Santoro 1,1, Jordi Bruix 13,13
PMCID: PMC6095177  PMID: 30190953

SUMMARY

There is no available effective systemic treatment for patients with advanced hepatocellular carcinoma (HCC) who are intolerant of sorafenib or who have disease that has progressed on sorafenib. In Phase I and II studies, tivantinib (ARQ 197), an oral inhibitor of MET, demonstrated promising antitumor activity in patients with HCC, both as monotherapy and in combination with sorafenib. A randomized Phase II trial in second-line HCC showed improved overall survival (hazard ratio: 0.38; p = 0.01) in patients with MET-high tumors, as demonstrated by immunohistochemistry, treated with tivantinib versus placebo. Here we present the treatment rationale and study design of the METIV-HCC Phase III study. This randomized, double-blind study will investigate tivantinib monotherapy as second-line treatment in patients with advanced, pretreated, MET-high HCC. Approximately 303 patients will be randomized 2:1 to tivantinib or placebo for the purpose of analyzing the primary end point. Tivantinib will be dosed at 120 mg twice daily, and treatment will continue until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The primary end point of this study is overall survival, while secondary end points include progression-free survival and safety. All patients will be tested for biomarkers. If the primary objective is achieved, this study will provide the first effective therapy for a biologically selected patient population in HCC.

Practice Points.

  • Sorafenib is the only approved therapy in hepatocellular carcinoma (HCC). Second-line treatment for patients who fail or cannot tolerate sorafenib is a high unmet medical need.

  • Multiple Phase III studies based on uncontrolled Phase II data in first- and second-line unselected populations have recently failed.

  • Tivantinib, a MET inhibitor, has demonstrated single-agent activity in a randomized controlled Phase II second-line study in HCC, the largest effect being noted in the MET-high molecular subset of patients.

  • Ideally, experimental studies in HCC, nowadays, need biopsy and biological patient characterization to better interpret and analyze results.

  • Moving forward, molecular-based trial design should be considered and Phase III studies should be designed for biologically selected patient populations.

Hepatocellular carcinoma (HCC) is an aggressive primary tumor of the liver that occurs primarily in patients with chronic liver disease, hepatitis B or C, and/or cirrhosis. HCC is a common malignancy worldwide, one of the leading causes of cancer-related death [1].

Standard chemotherapy for advanced or unresectable HCC has been limited by a lack of efficacy. The approval of sorafenib, a multikinase inhibitor of VEGFR-2, VEGFR-3, PDGFR and Raf, was a significant step forward, with a demonstrable survival benefit compared to placebo of 10.7 versus 7.9 months, despite the lack of a significant increase in the response rate [2]. Similar results were confirmed by a Phase III study conducted in Asia [3].

The complexity of HCC, driven by multiple pathways and growth factor systems [4], is increased by the concurrent underlying cirrhosis, and by the lack of validated prognostic factors for patients who progress the first-line therapy [5]. Successful HCC therapy requires inhibition of the right target(s) and an optimal drug safety profile.

Recently, two different randomized Phase III trials of HCC therapies in the second-line setting did not meet their prespecified targets. These studies explored brivanib versus placebo after failure of sorafenib therapy (BRISK-PS) [6] and everolimus (Afinitor®, Novartis, Basel, Switzerland) in second-line treatment of advanced liver cancer (EVOLVE-1) [Novartis, Data on File]. Brivanib, a tyrosine kinase inhibitor of VEGF and FGF with potent preclinical activity in HCC, did not significantly improve overall survival (OS) in patients with HCC who had been treated with sorafenib. This may suggest that, unlike in other diseases, progressive disease while on sorafenib may be due to acquired resistance to antiangiogenic agents, and an alternative targeted approach that does not target VEGF or FGF may be needed. Furthermore, everolimus, an mTOR inhibitor, did not meet the primary end point of improved OS in patients with advanced HCC after progression on or intolerance to sorafenib [Novartis, Data on File].

Therapies in patients with HCC and cirrhosis are also influenced by altered metabolism and a delicate equilibrium in their overall physical condition. Several recent unsuccessful first-line therapy Phase III trials may be ascribed to poor treatment tolerability and the required dose reductions (sorafenib plus erlotinib; linifanib vs sorafenib; sunitinib vs sorafenib; brivanib vs sorafenib [7–10]). These results underscore the enormous unmet need for active systemic therapies in HCC, especially in the second-line setting.

The inhibition of signaling through the HGF and c-Met (MET or MNNG HOS transforming gene) is being explored as a therapeutic strategy for advanced tumors [11]. MET is a high-affinity tyrosine kinase receptor for HGF, which is secreted by stromal cells, and is particularly relevant in HCC [12].

MET expression or activation is triggered by hypoxia [13], and therefore, MET may have a role in resistance to antiangiogenic agents. MET also can be upregulated by multiple mechanisms, including genetics, transcriptional factors, HGF stimulus and autocrine activation [14,15].

Recently, MET expression was related to prognosis in second-line HCC after sorafenib treatment [16]. In the placebo group of this randomized Phase II trial, comparison of outcomes by MET status showed that patients with MET-high tumors (tumor samples scoring at least 2+ in at least 50% of the cells) had significantly shorter survival (median 3.8 vs 9.0 months; hazard ratio [HR]: 2.94; 95% CI: 1.16–7.43; p = 0.02). These results suggest the prognostic role of MET expression in second-line advanced HCC. MET amplification in patients with non-small-cell carcinoma (NSCLC) was studied in a randomized Phase II study [17], but correlation between the clinical activity of tivantinib and MET status was found only when testing for MET with immunohistochemistry (IHC) [18,16].

Tivantinib (ARQ 197) is an oral MET tyrosine kinase inhibitor currently being tested in clinical trials. Tivantinib binds to MET, occupying a novel binding pocket, freezing the receptor in the inactive conformational status, therefore, preventing its phosphorylation, and enhancing the receptor degradation in a novel, non-ATP-competitive manner [19]. Tivantinib demonstrated antitumor activity in a wide range of human tumor cell lines, as well as in xenograft models [20,21].

Although details on the mechanism of action of tivantinib have been questioned in works led by Basilico and Katayama, hypothesizing a tubulin-related cytotoxic activity [22,23], with the former stating that tivantinib does not inhibit MET because it has activity in MET-low cells [22], three other independent groups recently confirmed the inhibitory activity of tivantinib on MET, adding involvement of Cyclin B1, proteasome and GSK3-α as additional targets of tivantinib [24–27]. Furthermore, paired tumor biopsies taken in patients before and after treatment with tivantinib showed inhibition of MET [28].

As pointed out by Rimassa et al., results in the clinical setting often diverge from findings in artificial in vitro conditions [29]. In fact, in large, randomized clinical trials in nonsquamous NSCLC, and HCC, tivantinib significantly improved OS only in patients with MET-high tumors; a clear response rate and survival advantage was observed only in MET-high patients in a randomized study in colorectal cancer. In addition, neurotoxicity, a hallmark of tubulin inhibitors, does not appear to be a prevalent side effect in over 1000 patients who received tivantinib, even in those who were exposed to very high drug concentrations [16,30,31].

Tivantinib Phase I studies in HCC

Two Phase I studies have evaluated tivantinib in HCC. In the ARQ 197–114 Phase Ib study, tivantinib 360 mg twice daily did not worsen liver function in 21 patients with HCC and Child-Pugh A or B cirrhosis. Despite a higher than expected rate of neutropenia, tivantinib demonstrated a manageable safety profile and preliminary antitumor activity. The best response was stable disease (SD) in nine out of 16 evaluable patients (56%) lasting for a median 5.3 months; while median time to progression (TTP) was 3.3 months.

Neutropenia occurred primarily within the first month of treatment, and was managed with dose reductions and growth factors. Pharmacokinetic (PK) data indicated that there was plasma accumulation of tivantinib. However, no correlation was found between PK and severe neutropenia, probably due to high inter-patient variability. Of note, in other tivantinib studies evaluating patients who did not have HCC, the rate of neutropenia occurred at a rate lower than 5% [32].

In the ARQ 197–116 Phase I dose-escalation trial, tivantinib, in doses of 360 mg twice daily and 240 mg twice daily, in combination with sorafenib at the standard dose of 400 mg twice daily, was well tolerated, with preliminary evidence of activity. The study enrolled a cohort of 20 HCC patients, including patients who had previously progressed on sorafenib [20,33].

In the HCC cohort of patients, the best responses were one complete response, one partial response and 12 patients with SD. Overall response rate and disease control rate (DCR) were 10 and 70%, respectively. Median progression-free survival (PFS) was 3.5 months (95% CI: 2.8–11.1 months). Among eight patients previously treated with VEGF inhibitors (six sorafenib; one sunitinib; one sorafenib plus sunitinib), the best responses were one complete response, one partial response and three with SD. The PFS was 15.9 months (95% CI: 1.6–15.9 months).

The most common adverse events (≥25%) were rash (40%), hand–foot skin reaction (35%), fatigue and diarrhea (30% each), as well as nausea and anorexia (25% each), while severe neutropenia was reported in two patients. The combination therapy was otherwise well tolerated at all the tested doses.

Randomized controlled Phase II study HCC

Tivantinib was also tested as second-line therapy in a multicenter, randomized, double-blind, placebo-controlled, Phase II study of 107 patients with advanced HCC and Child-Pugh A cirrhosis [16].

The enrolled patients were well balanced for known prognostic factors. All of the patients had received prior treatment with sorafenib, except for four patients who had received sunitinib in the first-line setting. All patients had progressed on, or were unable to tolerate, one prior line of systemic therapy.

Patients were randomized to receive tivantinib or placebo in a 2:1 fashion and were stratified based on ECOG performance status and vascular invasion status. At radiographic progression, patients on placebo were allowed to cross over to open-label tivantinib. In the final analysis, 38 patients received tivantinib 360 mg twice daily, 33 received tivantinib 240 mg twice daily and 36 received placebo. It is important to note that the tivantinib dose was decreased to 240 mg twice daily after 57 patients were enrolled because of a high incidence of treatment-related grade ≥3 neutropenia. The primary end point was TTP according to independent radiological review in the intention-to-treat (ITT) population. Secondary safety and efficacy end points included analysis according to MET status.

In the ITT population, median TTP was statistically favorable for patients treated with tivantinib (1.6 vs 1.4 months; HR: 0.64, 90% CI: 0.43–0.94; p = 0.04).

The tumor samples were assessed for MET status by IHC prior to unblinding, using the CONFIRM™ anti-total MET (SP44) antibody (Ventana-Roche, AZ, USA); the test was run centrally, in a blinded fashion. MET-high was defined as ≥50% of HCC cells with moderate or strong (≥2+) staining intensity. In total, 77 out of 107 (72%) of samples were assessable for MET testing, and 37 (48%) of these patients had MET-high tumors. Baseline characteristics of patients with MET-high and MET-low tumor samples did not differ significantly.

Patients with MET-high tumors were the only subgroup to show a significant survival benefit associated with tivantinib. In the MET-high subgroup, all efficacy parameters favored tivantinib: median TTP was 2.7 versus 1.4 months (HR: 0.43; 95% CI: 0.19–0.97; p = 0.03); median PFS was 2.2 versus 1.4 months (HR: 0.45; 95% CI: 0.21–0.95; p = 0.02); DCR was 50 versus 20%; and median OS was 7.2 versus 3.8 months (HR: 0.38; 95% CI: 0.18–0.81; p = 0.01) (Figure 1). The survival advantage for patients on tivantinib 240 mg twice daily was at least equivalent to the one observed at the 360 mg twice-daily dose. Of note, half of the patients on placebo crossed over to open-label therapy and a third remained on tivantinib for over 1.4 months. No differences in efficacy were seen between tivantinib and placebo groups in the MET-low population.

Figure 1. 1 Overall survival in patients with MET-high hepatocellular carcinoma and prognostic implication of MET (inset).

Figure 1.

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Median overall survival significantly favored tivantinib (7.2 vs 3.8 months; hazard ratio: 0.38; p = 0.01). In patients who received placebo, patients with MET-high hepatocellular carcinoma had a shorter overall survival than those with MET-low hepatocellular carcinoma (3.8 vs 9.0 months; hazard ratio: 2.94; p = 0.02).

Reprinted and adapted from [16], with permission from Elsevier.

These results suggest that, apart from its prognostic role, MET expression is predictive of response to tivantinib. This suggests that a tumor biopsy is mandatory in order to study the biology of the disease, and to select patients with MET-high tumors for treatment with tivantinib.

Except for hematological events, the incidence of adverse events was similar for both doses of tivantinib. At the 240 mg dose, the rate of neutropenia was 21% for all grades and 6% for grades ≥3. Grade 1 or 2 bradycardia was seen in 9% of patients treated with tivantinib 240 mg twice daily.

Population PK results showed that tivantinib reaches higher plasma concentrations in patients with HCC compared to patients with other tumor types. The mean area under the curve for 240 mg tivantinib twice daily was 25,660 ng.h/ml in patients with HCC, compared with 12,050 ng.h/ml for NSCLC patients treated with 360 mg of tivantinib twice daily [34,16].

Ongoing Phase III trial: ARQ 197-A-U303 (METIV-HCC)

Based on the promising results of the randomized Phase II trial, a randomized, double-blind, stratified, placebo-controlled Phase III trial was initiated. METIV-HCC is a trial of tivantinib versus placebo in patients with unresectable, MET-high HCC who have had progressive disease or intolerance to sorafenib in the first-line setting. This trial is registered with ClinicalTrials.gov, number NCT01755767 [35].

Study design

Approximately 303 patients will be randomized 2:1 to tivantinib twice daily or placebo (Figure 2) for the purpose of analyzing the primary end point. The original planned dose of 240 mg twice a day was reduced to 120 mg twice a day following a higher than expected drug exposure and incidence of neutropenia-related adverse events. Such different exposure is to be ascribed to the switch in formulation from capsules (used in the Phase II study) to tablets, and the different metabolism of tivantinib in HCC patients compared with patients with other tumors. Exposure in HCC patients at the 120 mg twice daily tablet dose is equivalent to that of the 240 mg twice daily capsule dose from the Phase II study. Patients will be stratified by three independent factors: vascular invasion, extrahepatic spread and baseline α-fetoprotein. All patients will have confirmed MET-high tumors, from either recent or archival tissue, defined as ≥50% of tumor cells with a membrane staining intensity of ≥2+ for MET as assessed by IHC by the central laboratory. Only samples with histologically confirmed HCC will be tested for MET status.

Figure 2. 2 METIV-HCC study schema.

Figure 2.

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b.i.d.: Twice daily; DCR: Disease control rate; ORR: Overall response rate; OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival; PK: Pharmacokinetic; p.o.: Per os; pts: Patients; TTP: Time to progression.

Tumor assessments per RECIST 1.1 [32] will be performed every 8 weeks, and radiographic efficacy end points will be evaluated by central radiology review. Treatment will continue until unequivocal disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. Crossover will not be allowed.

Participating countries include Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Italy, Germany, New Zealand, Portugal, The Netherlands, Spain, Sweden, Switzerland and the USA.

Inclusion criteria

Patients must have received only one prior systemic regimen for advanced disease, and this must have included sorafenib. They must present with ECOG 0–1 performance status, a life expectancy of at least 12 weeks, and adequate end-organ function defined as hemoglobin ≥9.0 g/dl, platelets ≥60 × 109/l, absolute neutrophil count ≥1.5 × 109/l, bilirubin ≤2 mg/dl, ALT/AST ≤5 × upper limit of normality (ULN), albumin ≥2.8 g/dl, creatinine ≤1.5 × ULN and INR 0.8 – ULN (or ≤3 if receiving anticoagulants). Tumors must be measurable by RECIST 1.1 within 21 days of randomization, and at least one lesion must be naive to local therapies.

Exclusion criteria

Key exclusion criteria include more than one prior systemic regimen, prior treatment with MET inhibitors/antibodies, and other previous or concurrent cancers. Excluded will be patients with severe liver disease defined as a Child-Pugh score of B or C, pleural effusion or clinically evident ascites. To ensure appropriate patient selection, blood transfusions or albumin infusion within 5 days prior to screening will be prohibited. Other exclusion criteria are grade ≥3 heart failure or arrhythmia in the last 6 months, a serious, clinically active infection, interferon or anti-HCV therapy, known HIV infection, pregnancy or breastfeeding, history of liver transplant, and significant gastrointestinal bleeding ≤4 weeks prior to randomization.

End points

All randomized patients will be assessed for efficacy. The primary end point is OS in patients randomized to the 120 mg twice daily dose. Secondary end points are PFS and safety, while exploratory end points include TTP, response rate, DCR, type of progression, PK, biomarkers and quality of life analysis. Radiographic end points will be assessed by central radiology review.

Statistics

OS events will be needed in 257 patients for a 90% power to detect HR 0.65 (5 vs 7.7 months). The Data Monitoring Committee will periodically monitor the study and will perform an interim analysis when approximately 60% of the survival events are reached. Safety will be periodically monitored after the first patient is enrolled. The efficacy analyses will be conducted on an ITT basis, based on the assigned treatment at randomization. Kaplan–Meier methodology will be used to estimate median duration of OS, PFS and duration of response in each treatment arm. The treatment comparison of OS and PFS will be based on stratified log-rank test, with a power of 90% to demonstrate a statistically significant difference in OS. Estimates of the treatment effect will be expressed as HRs using a stratified Cox model. Mantel–Haenszel tests will be performed for comparison of overall response rate and disease control rate between treatment arms. The safety analyses will include all enrolled patients receiving any amount of treatment of the study drug. Patient data will be analyzed according to the actual treatment received.

Conclusion

Tivantinib is most effective across different tumor types when MET is highly expressed.

In the HCC randomized Phase II study, MET was a negative, independent prognostic factor. Tivantinib significantly increased survival in patients with MET-high liver cancers.

Many clinical trials with systemic therapy did not show a benefit in HCC, and second-line treatment remains a high unmet medical need. If the primary end point of improved OS in the Phase III trial METIV-HCC is achieved, treatment with tivantinib will be a rational alternative to best supportive care in patients with MET-high HCC who have had disease progression on, or intolerance to, first-line sorafenib therapy.

Acknowledgements

The authors would like to thank Hazem Hallak for editorial support, and Brian Schwartz, Yinpu Chen, Maria Lamar from ArQule, and Reinhard Von Roemeling, Yibin Wang from Daiichi-Sankyo for key contributions to the study design.

Footnotes

Financial & competing interests disclosure

J Bruix collaborates on hepatocellular carcinoma-related research with the following companies: Abbott, ArQule, Bayer Shering Pharma, Biocompatibles, BMS, Chugai, Glaxo-Welcome, Imclone, Kowa, Lilly, Novartis, OSI, Shering-Plough (Merck) and Terumo. JL Raoul participated in advisory boards for Bayer, Bristol-Myers Squibb and Taiho, and received lecture fees from Bayer and Taiho. L Rimassa has participated in an advisory board for Daiichi Sankyo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance from Dr Hazem Hallak was utilized in the production of this manuscript, which was funded by ArQule.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Open access

This work is licensed under the Creative Commons Attribution-NonCommercial 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

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