Tivantinib for second-line treatment of advanced hepatocellular carcinoma

A randomised, placebo-controlled phase 2 study

Armando Santoro, Lorenza Rimassa, Ivan Borbath, Bruno Daniele, Stefania Salvagni, Jean Luc Van Laethem, Hans Van Vlierberghe, Jörg Trojan, Frank T. Kolligs, Alan Weiss, Steven Miles, Antonio Gasbarrini, Monica Lencioni, Luca Cicalese, Morris Sherman, Cesare Gridelli, Peter Buggisch, Guido Gerken, Roland M. Schmid, Corrado Boni & 8 others Nicola Personeni, Ziad Hassoun, Giovanni Abbadessa, Brian Schwartz, Reinhard Von Roemeling, Maria E. Lamar, Yinpu Chen, Camillo Porta

Research output: Contribution to journalArticle

389 Citations (Scopus)

Abstract

Background: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. Methods: In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. Findings: 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4-2·8]) than placebo (1·4 months [1·4-1·5]; hazard ratio [HR] 0·64, 90% CI 0·43-0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4-8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4-1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19-0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. Interpretation: Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. Funding: ArQule, Daiichi Sankyo (Daiichi Sankyo Group).

Original languageEnglish (US)
Pages (from-to)55-63
Number of pages9
JournalThe Lancet Oncology
Volume14
Issue number1
DOIs
StatePublished - Jan 2013

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Hepatocellular Carcinoma
Placebos
Therapeutics
Neutropenia
ARQ 197
Neoplasms
Random Allocation
Liver Cirrhosis
Blood Vessels
Disease Progression
Anemia
Fibrosis
Immunohistochemistry

ASJC Scopus subject areas

  • Oncology

Cite this

Santoro, A., Rimassa, L., Borbath, I., Daniele, B., Salvagni, S., Van Laethem, J. L., ... Porta, C. (2013). Tivantinib for second-line treatment of advanced hepatocellular carcinoma: A randomised, placebo-controlled phase 2 study. The Lancet Oncology, 14(1), 55-63. https://doi.org/10.1016/S1470-2045(12)70490-4

Tivantinib for second-line treatment of advanced hepatocellular carcinoma : A randomised, placebo-controlled phase 2 study. / Santoro, Armando; Rimassa, Lorenza; Borbath, Ivan; Daniele, Bruno; Salvagni, Stefania; Van Laethem, Jean Luc; Van Vlierberghe, Hans; Trojan, Jörg; Kolligs, Frank T.; Weiss, Alan; Miles, Steven; Gasbarrini, Antonio; Lencioni, Monica; Cicalese, Luca; Sherman, Morris; Gridelli, Cesare; Buggisch, Peter; Gerken, Guido; Schmid, Roland M.; Boni, Corrado; Personeni, Nicola; Hassoun, Ziad; Abbadessa, Giovanni; Schwartz, Brian; Von Roemeling, Reinhard; Lamar, Maria E.; Chen, Yinpu; Porta, Camillo.

In: The Lancet Oncology, Vol. 14, No. 1, 01.2013, p. 55-63.

Research output: Contribution to journalArticle

Santoro, A, Rimassa, L, Borbath, I, Daniele, B, Salvagni, S, Van Laethem, JL, Van Vlierberghe, H, Trojan, J, Kolligs, FT, Weiss, A, Miles, S, Gasbarrini, A, Lencioni, M, Cicalese, L, Sherman, M, Gridelli, C, Buggisch, P, Gerken, G, Schmid, RM, Boni, C, Personeni, N, Hassoun, Z, Abbadessa, G, Schwartz, B, Von Roemeling, R, Lamar, ME, Chen, Y & Porta, C 2013, 'Tivantinib for second-line treatment of advanced hepatocellular carcinoma: A randomised, placebo-controlled phase 2 study', The Lancet Oncology, vol. 14, no. 1, pp. 55-63. https://doi.org/10.1016/S1470-2045(12)70490-4
Santoro, Armando ; Rimassa, Lorenza ; Borbath, Ivan ; Daniele, Bruno ; Salvagni, Stefania ; Van Laethem, Jean Luc ; Van Vlierberghe, Hans ; Trojan, Jörg ; Kolligs, Frank T. ; Weiss, Alan ; Miles, Steven ; Gasbarrini, Antonio ; Lencioni, Monica ; Cicalese, Luca ; Sherman, Morris ; Gridelli, Cesare ; Buggisch, Peter ; Gerken, Guido ; Schmid, Roland M. ; Boni, Corrado ; Personeni, Nicola ; Hassoun, Ziad ; Abbadessa, Giovanni ; Schwartz, Brian ; Von Roemeling, Reinhard ; Lamar, Maria E. ; Chen, Yinpu ; Porta, Camillo. / Tivantinib for second-line treatment of advanced hepatocellular carcinoma : A randomised, placebo-controlled phase 2 study. In: The Lancet Oncology. 2013 ; Vol. 14, No. 1. pp. 55-63.
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abstract = "Background: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. Methods: In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50{\%} of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. Findings: 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65{\%}) patients in the tivantinib group and 26 (72{\%}) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95{\%} CI 1·4-2·8]) than placebo (1·4 months [1·4-1·5]; hazard ratio [HR] 0·64, 90{\%} CI 0·43-0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95{\%} CI 1·4-8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4-1·6] for 15 MET-high patients on placebo; HR 0·43, 95{\%} CI 0·19-0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14{\%}] vs none in the placebo group) and anaemia (eight [11{\%}] vs none in the placebo group). Eight patients (21{\%}) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6{\%}) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34{\%}) patients in the tivantinib group and 14 (39{\%}) patients in the placebo group had serious adverse events. Interpretation: Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. Funding: ArQule, Daiichi Sankyo (Daiichi Sankyo Group).",
author = "Armando Santoro and Lorenza Rimassa and Ivan Borbath and Bruno Daniele and Stefania Salvagni and {Van Laethem}, {Jean Luc} and {Van Vlierberghe}, Hans and J{\"o}rg Trojan and Kolligs, {Frank T.} and Alan Weiss and Steven Miles and Antonio Gasbarrini and Monica Lencioni and Luca Cicalese and Morris Sherman and Cesare Gridelli and Peter Buggisch and Guido Gerken and Schmid, {Roland M.} and Corrado Boni and Nicola Personeni and Ziad Hassoun and Giovanni Abbadessa and Brian Schwartz and {Von Roemeling}, Reinhard and Lamar, {Maria E.} and Yinpu Chen and Camillo Porta",
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T1 - Tivantinib for second-line treatment of advanced hepatocellular carcinoma

T2 - A randomised, placebo-controlled phase 2 study

AU - Santoro, Armando

AU - Rimassa, Lorenza

AU - Borbath, Ivan

AU - Daniele, Bruno

AU - Salvagni, Stefania

AU - Van Laethem, Jean Luc

AU - Van Vlierberghe, Hans

AU - Trojan, Jörg

AU - Kolligs, Frank T.

AU - Weiss, Alan

AU - Miles, Steven

AU - Gasbarrini, Antonio

AU - Lencioni, Monica

AU - Cicalese, Luca

AU - Sherman, Morris

AU - Gridelli, Cesare

AU - Buggisch, Peter

AU - Gerken, Guido

AU - Schmid, Roland M.

AU - Boni, Corrado

AU - Personeni, Nicola

AU - Hassoun, Ziad

AU - Abbadessa, Giovanni

AU - Schwartz, Brian

AU - Von Roemeling, Reinhard

AU - Lamar, Maria E.

AU - Chen, Yinpu

AU - Porta, Camillo

PY - 2013/1

Y1 - 2013/1

N2 - Background: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. Methods: In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. Findings: 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4-2·8]) than placebo (1·4 months [1·4-1·5]; hazard ratio [HR] 0·64, 90% CI 0·43-0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4-8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4-1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19-0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. Interpretation: Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. Funding: ArQule, Daiichi Sankyo (Daiichi Sankyo Group).

AB - Background: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. Methods: In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. Findings: 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4-2·8]) than placebo (1·4 months [1·4-1·5]; hazard ratio [HR] 0·64, 90% CI 0·43-0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4-8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4-1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19-0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. Interpretation: Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. Funding: ArQule, Daiichi Sankyo (Daiichi Sankyo Group).

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