Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial

KEYNOTE-224 investigators

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

Background: Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods: KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings: Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation: Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding: Merck & Co, Inc.

Original languageEnglish (US)
Pages (from-to)940-952
Number of pages13
JournalThe Lancet Oncology
Volume19
Issue number7
DOIs
StatePublished - Jul 1 2018

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Hepatocellular Carcinoma
pembrolizumab
sorafenib
Therapeutics
Disease Progression
Safety
Hyperbilirubinemia
Esophagitis
Aspartate Aminotransferases
Alanine Transaminase

ASJC Scopus subject areas

  • Oncology

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Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224) : a non-randomised, open-label phase 2 trial. / KEYNOTE-224 investigators.

In: The Lancet Oncology, Vol. 19, No. 7, 01.07.2018, p. 940-952.

Research output: Contribution to journalArticle

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abstract = "Background: Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods: KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings: Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16{\%}) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17{\%}; 95{\%} CI 11–26) of 104 patients. The best overall responses were one (1{\%}) complete and 17 (16{\%}) partial responses; meanwhile, 46 (44{\%}) patients had stable disease, 34 (33{\%}) had progressive disease, and six (6{\%}) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73{\%}) of 104 patients, which were serious in 16 (15{\%}) patients. Grade 3 treatment-related events were reported in 25 (24{\%}) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7{\%}) patients, increased alanine aminotransferase concentration in four (4{\%}) patients, and fatigue in four (4{\%}) patients. One (1{\%}) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3{\%}) patients, but there were no reported cases of viral flares. Interpretation: Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding: Merck & Co, Inc.",
author = "{KEYNOTE-224 investigators} and Zhu, {Andrew X.} and Finn, {Richard S.} and Julien Edeline and Stephane Cattan and Sadahisa Ogasawara and Daniel Palmer and Chris Verslype and Vittorina Zagonel and Laetitia Fartoux and Arndt Vogel and Debashis Sarker and Gontran Verset and Chan, {Stephen L.} and Jennifer Knox and Bruno Daniele and Webber, {Andrea L.} and Ebbinghaus, {Scot W.} and Junshui Ma and Siegel, {Abby B.} and Cheng, {Ann Lii} and Masatoshi Kudo and Angela Alistar and Jamil Asselah and Blanc, {Jean Frederic} and Ivan Borbath and Timothy Cannon and Ki Chung and Allen Cohn and Cosgrove, {David P.} and Nevena Damjanov and Mukul Gupta and Yoshivasu Karino and Mark Karwal and Andreas Kaubisch and Robin Kelley and {Van Laethem}, {Jena Luc} and Timothy Larson and James Lee and Daneng Li and Atisha Manhas and Manji, {Gulam Abbas} and Kazushi Numata and Benjamin Parsons and Paulson, {Andrew S.} and Carmine Pinto and Robert Ramirez and Suresh Ratnam and Magnus Rizell and Olivier Rosmorduc and Gina Vaccaro",
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T1 - Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224)

T2 - a non-randomised, open-label phase 2 trial

AU - KEYNOTE-224 investigators

AU - Zhu, Andrew X.

AU - Finn, Richard S.

AU - Edeline, Julien

AU - Cattan, Stephane

AU - Ogasawara, Sadahisa

AU - Palmer, Daniel

AU - Verslype, Chris

AU - Zagonel, Vittorina

AU - Fartoux, Laetitia

AU - Vogel, Arndt

AU - Sarker, Debashis

AU - Verset, Gontran

AU - Chan, Stephen L.

AU - Knox, Jennifer

AU - Daniele, Bruno

AU - Webber, Andrea L.

AU - Ebbinghaus, Scot W.

AU - Ma, Junshui

AU - Siegel, Abby B.

AU - Cheng, Ann Lii

AU - Kudo, Masatoshi

AU - Alistar, Angela

AU - Asselah, Jamil

AU - Blanc, Jean Frederic

AU - Borbath, Ivan

AU - Cannon, Timothy

AU - Chung, Ki

AU - Cohn, Allen

AU - Cosgrove, David P.

AU - Damjanov, Nevena

AU - Gupta, Mukul

AU - Karino, Yoshivasu

AU - Karwal, Mark

AU - Kaubisch, Andreas

AU - Kelley, Robin

AU - Van Laethem, Jena Luc

AU - Larson, Timothy

AU - Lee, James

AU - Li, Daneng

AU - Manhas, Atisha

AU - Manji, Gulam Abbas

AU - Numata, Kazushi

AU - Parsons, Benjamin

AU - Paulson, Andrew S.

AU - Pinto, Carmine

AU - Ramirez, Robert

AU - Ratnam, Suresh

AU - Rizell, Magnus

AU - Rosmorduc, Olivier

AU - Vaccaro, Gina

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Background: Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods: KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings: Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation: Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding: Merck & Co, Inc.

AB - Background: Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods: KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings: Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation: Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding: Merck & Co, Inc.

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