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

Andrew X Zhu, Richard S Finn, Julien Edeline, Stephane Cattan, Sadahisa Ogasawara, Daniel Palmer, Chris Verslype, Vittorina Zagonel, Laetitia Fartoux, Arndt Vogel, Debashis Sarker, Gontran Verset, Stephen L Chan, Jennifer Knox, Bruno Daniele, Andrea L Webber, Scot W Ebbinghaus, Junshui Ma, Abby B Siegel, KEYNOTE-224 investigatorsAnn-lii Cheng, Masatoshi Kudo, Angela Alistar, Jamil Asselah, Jean-frederic Blanc, Ivan Borbath, Timothy Cannon, Ki Chung, Allen Cohn, David P Cosgrove, Nevena Damjanov, Mukul Gupta, Yoshivasu Karino, Mark Karwal, Andreas Kaubisch, Robin Kelley, Jena-luc Van Laethem, Timothy Larson, James Lee, Daneng Li, Atisha Manhas, Gulam Abbas Manji, Kazushi Numata, Benjamin Parsons, Andrew S. Paulson, Carmine Pinto, Robert Ramirez, Suresh Ratnam, Magnus Rizell, Olivier Rosmorduc, Yvonne Sada

Research output: Contribution to journalArticlepeer-review

1793 Citations (Scopus)


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.

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 number NCT02702414.

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.

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.

Merck & Co, Inc.
Original languageEnglish
Pages (from-to)940-952
JournalThe Lancet Oncology
Issue number7
Early online date3 Jun 2018
Publication statusPublished - 1 Jul 2018


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