Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study

Lorenza Rimassa, Eric Assenat, Markus Peck-Radosavljevic, Marc Pracht, Vittorina Zagonel, Philippe Mathurin, Elena Rota Caremoli, Camillo Porta, Bruno Daniele, Luigi Bolondi, Vincenzo Mazzaferro, William Harris, Nevena Damjanov, Davide Pastorelli, María Reig, Jennifer Knox, Francesca Negri, Jörg Trojan, Carlos López López, Nicola PersoneniThomas Decaens, Marie Dupuy, Wolfgang Sieghart, Giovanni Abbadessa, Brian Schwartz, Maria Lamar, Terri Goldberg, Dale Shuster, Armando Santoro, Jordi Bruix

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial.METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767.FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome).INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma.FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).
Original languageEnglish
Pages (from-to)682-693
Number of pages12
JournalThe Lancet Oncology
Volume19
Issue number5
DOIs
Publication statusPublished - May 2018

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Hepatocellular Carcinoma
Placebos
Therapeutics
ARQ 197
Survival
Anemia
Fetal Proteins
Intention to Treat Analysis
Liver Failure
Feasibility Studies
Acute Coronary Syndrome
Random Allocation
Neutropenia
New Zealand
Acute Kidney Injury
Ascites
Disease-Free Survival
Blood Vessels
Disease Progression
Cause of Death

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Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC) : a final analysis of a phase 3, randomised, placebo-controlled study. / Rimassa, Lorenza; Assenat, Eric; Peck-Radosavljevic, Markus; Pracht, Marc; Zagonel, Vittorina; Mathurin, Philippe; Rota Caremoli, Elena; Porta, Camillo; Daniele, Bruno; Bolondi, Luigi; Mazzaferro, Vincenzo; Harris, William; Damjanov, Nevena; Pastorelli, Davide; Reig, María; Knox, Jennifer; Negri, Francesca; Trojan, Jörg; López López, Carlos; Personeni, Nicola; Decaens, Thomas; Dupuy, Marie; Sieghart, Wolfgang; Abbadessa, Giovanni; Schwartz, Brian; Lamar, Maria; Goldberg, Terri; Shuster, Dale; Santoro, Armando; Bruix, Jordi.

In: The Lancet Oncology, Vol. 19, No. 5, 05.2018, p. 682-693.

Research output: Contribution to journalArticle

Rimassa, L, Assenat, E, Peck-Radosavljevic, M, Pracht, M, Zagonel, V, Mathurin, P, Rota Caremoli, E, Porta, C, Daniele, B, Bolondi, L, Mazzaferro, V, Harris, W, Damjanov, N, Pastorelli, D, Reig, M, Knox, J, Negri, F, Trojan, J, López López, C, Personeni, N, Decaens, T, Dupuy, M, Sieghart, W, Abbadessa, G, Schwartz, B, Lamar, M, Goldberg, T, Shuster, D, Santoro, A & Bruix, J 2018, 'Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study', The Lancet Oncology, vol. 19, no. 5, pp. 682-693. https://doi.org/10.1016/S1470-2045(18)30146-3
Rimassa, Lorenza ; Assenat, Eric ; Peck-Radosavljevic, Markus ; Pracht, Marc ; Zagonel, Vittorina ; Mathurin, Philippe ; Rota Caremoli, Elena ; Porta, Camillo ; Daniele, Bruno ; Bolondi, Luigi ; Mazzaferro, Vincenzo ; Harris, William ; Damjanov, Nevena ; Pastorelli, Davide ; Reig, María ; Knox, Jennifer ; Negri, Francesca ; Trojan, Jörg ; López López, Carlos ; Personeni, Nicola ; Decaens, Thomas ; Dupuy, Marie ; Sieghart, Wolfgang ; Abbadessa, Giovanni ; Schwartz, Brian ; Lamar, Maria ; Goldberg, Terri ; Shuster, Dale ; Santoro, Armando ; Bruix, Jordi. / Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC) : a final analysis of a phase 3, randomised, placebo-controlled study. In: The Lancet Oncology. 2018 ; Vol. 19, No. 5. pp. 682-693.
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title = "Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study",
abstract = "BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial.METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50{\%} of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767.FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95{\%} CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95{\%} CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56{\%}) of 225 patients in the tivantinib group and in 63 (55{\%}) of 114 patients in the placebo group, with the most common being ascites (16 [7{\%}] patients]), anaemia (11 [5{\%}] patients), abdominal pain (nine [4{\%}] patients), and neutropenia (nine [4{\%}] patients) in the tivantinib group. 50 (22{\%}) of 226 patients in the tivantinib group and 18 (16{\%}) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4{\%}] patients) and hepatic failure (four [2{\%}] patients) were the most common causes of death in the tivantinib group. Three (1{\%}) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome).INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma.FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).",
author = "Lorenza Rimassa and Eric Assenat and Markus Peck-Radosavljevic and Marc Pracht and Vittorina Zagonel and Philippe Mathurin and {Rota Caremoli}, Elena and Camillo Porta and Bruno Daniele and Luigi Bolondi and Vincenzo Mazzaferro and William Harris and Nevena Damjanov and Davide Pastorelli and Mar{\'i}a Reig and Jennifer Knox and Francesca Negri and J{\"o}rg Trojan and {L{\'o}pez L{\'o}pez}, Carlos and Nicola Personeni and Thomas Decaens and Marie Dupuy and Wolfgang Sieghart and Giovanni Abbadessa and Brian Schwartz and Maria Lamar and Terri Goldberg and Dale Shuster and Armando Santoro and Jordi Bruix",
note = "Copyright {\circledC} 2018 Elsevier Ltd. All rights reserved.",
year = "2018",
month = "5",
doi = "10.1016/S1470-2045(18)30146-3",
language = "English",
volume = "19",
pages = "682--693",
journal = "The Lancet Oncology",
issn = "1470-2045",
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TY - JOUR

T1 - Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC)

T2 - a final analysis of a phase 3, randomised, placebo-controlled study

AU - Rimassa, Lorenza

AU - Assenat, Eric

AU - Peck-Radosavljevic, Markus

AU - Pracht, Marc

AU - Zagonel, Vittorina

AU - Mathurin, Philippe

AU - Rota Caremoli, Elena

AU - Porta, Camillo

AU - Daniele, Bruno

AU - Bolondi, Luigi

AU - Mazzaferro, Vincenzo

AU - Harris, William

AU - Damjanov, Nevena

AU - Pastorelli, Davide

AU - Reig, María

AU - Knox, Jennifer

AU - Negri, Francesca

AU - Trojan, Jörg

AU - López López, Carlos

AU - Personeni, Nicola

AU - Decaens, Thomas

AU - Dupuy, Marie

AU - Sieghart, Wolfgang

AU - Abbadessa, Giovanni

AU - Schwartz, Brian

AU - Lamar, Maria

AU - Goldberg, Terri

AU - Shuster, Dale

AU - Santoro, Armando

AU - Bruix, Jordi

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

PY - 2018/5

Y1 - 2018/5

N2 - BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial.METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767.FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome).INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma.FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).

AB - BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial.METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767.FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome).INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma.FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).

U2 - 10.1016/S1470-2045(18)30146-3

DO - 10.1016/S1470-2045(18)30146-3

M3 - Article

VL - 19

SP - 682

EP - 693

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 5

ER -