TY - JOUR
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 - Sada, Yvonne
N1 - Funding Information:
The study was funded, administered, and sponsored by Merck & Co, Inc (Kenilworth, NJ, USA). We thank the patients and their families and all the investigators and site personnel. We would also like to acknowledge Roger Dansey and Olga Kuznetsova for helpful discussions and study input, Melissa Buckland for clinical study support, Larry Wu for integrated safety analysis, Himanshu Patel for statistical programming support, Robin Mogg and Anran Wang for statistical biomarker analysis, Joanne E Tomassini for medical writing support, and Sheila Erespe for editorial support, who are current or former employees of Merck & Co.
Funding Information:
AXZ has served as a consultant for Eisai, Bristol-Myers Squibb, Merck & Co, Novartis, Sanofi, AstraZeneca, Bayer, Exelixis, and Eli Lilly and Company; and reports research funding to his institution from Eli Lilly and Company, Bayer, Bristol-Myers Squibb, Novartis, and Merck & Co. RSF has served as a consultant for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, and Merck & Co; and reports research funding to his institution from Pfizer. JE has received honoraria from BTG and travel expenses from Amgen and Bristol-Myers Squibb. SO has served as a consultant for Bayer and Eisai; and has received honoraria from Bayer and Eisai. DP has received honoraria from Bayer, Celgene, NuCana, and Bristol-Myers Squibb; has served as a consultant for Bayer, Celgene, NuCana, and Bristol-Myers Squibb; and has received research funding from Bayer and NuCana. CV has served as a consultant for Bayer, Ipsen, and Novartis; and has received research funding from Ipsen and Bayer. VZ has served as a consultant for Merck Sharp & Dohme, Bristol-Myers Squibb, and Celgene; has been on a speakers' bureau for Bayer, Roche, Pfizer, and Janssen; and has received travel fees from Merck Sharp & Dohme, Roche, and Bayer. AV has served as a consultant for Novartis, Delcath Systems, Eli Lilly and Company, Roche, Amgen, Bayer, and Baxalta; has received travel expenses from Bayer, Roche, and Ipsen; has received honoraria from Novartis, Roche, Bayer, Sanofi, Amgen, Delcath Systems, Eli Lilly and Company, Bristol-Myers Squibb, and Merck Sharp & Dohme; and has received research funding from Novartis. DS has served as a consultant for Eisai, Baxalta, Novartis, and Blueprint Medicines; has received travel expenses from Bayer, Ipsen and MiNA Therapeutics; and has received honoraria from Pfizer, Bayer, and Ipsen. SLC has served as a consultant for Novartis, Merck Sharp & Dohme, and MedImmune (AstraZeneca); has received honoraria from Bayer; and has received research funding from Novartis and Sirtex Medical. JK has served as a consultant for Eli Lilly and Company and Merck & Co; has received honoraria from Novartis; and has received research funding from AstraZeneca. BD has served as a consultant for Eisai and Bayer; has received honoraria from Bayer, Merck Sharp & Dohme, Merck Serono, Eli Lilly and Company, and Bristol-Myers Squibb; and has received travel grants from Janssen, Celgene, and Bristol-Myers Squibb. ALW, SWE, JM, and ABS are employees of Merck Sharp and Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA; and own stock or stock options in the company. A-LC has served as a consultant for Merck Sharp & Dohme, Exillixis, Merck KGaA, Bristol-Myers Squibb, Bayer, BeiGene, and Ono Pharmaceuticals; has served on advisory board for Novartis, and has received honoraria from Bayer and Merck KGaA. MK has served as a consultant for Kowa, Merck Sharp & Dohme, Bristol-Myers Squibb, Bayer, Chugai Pharma, and Taiho Pharmaceuticals; has received honoraria from Bayer, Eisai, Merck Sharp & Dohme, and Ajinomoto; and has received research funding from Chugai Pharma, Otsuka, Takeda Pharmaceuticals, Taiho Pharmaceuticals, Sumitomo Dainippon Pharma, Daiichi Sankyo, Merck Sharp & Dohme, Eisai, Bayer, and AbbVie. SC, LF, and GV declare no competing interests.
PY - 2018/7
Y1 - 2018/7
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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U2 - 10.1016/S1470-2045(18)30351-6
DO - 10.1016/S1470-2045(18)30351-6
M3 - Article
C2 - 29875066
AN - SCOPUS:85047827283
VL - 19
SP - 940
EP - 952
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 7
ER -