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

Zhu, Andrew X.; Finn, Richard S.; Edeline, Julien; Cattan, Stéphane; Ogasawara, Satoshi; Palmer, Daniel H.; Verslype, Chris; Zagonel, Vittorina; Fartoux, Lætitia; Vogel, Arndt; Sarker, Debashis; Verset, Gontran; Chan, Stephen L.; Knox, Jennifer J.; Daniele, Bruno; Webber, Andrea L.; Ebbinghaus, Scot; Ma, Junshui; Siegel, Abby B.; Cheng, Ann‐Lii; Kudo, Masatoshi; Alistar, Angela; Asselah, Jamil; Blanc, Jean‐Frédéric; Borbath, Ivan; Cannon, Timothy Lewis; Chung, Ki Young; Cohn, Allen Lee; Cosgrove, David; Damjanov, Nevena; Gupta, Mukul; Karino, Yoshivasu; Karwal, Mark; Kaubisch, Andreas; Kelley, Robin Kate; Laethem, Jena-Luc Van; Larson, Timothy; Lee, James; Li, Daneng; Manhas, Atisha; Manji, Gulam A.; Numata, Kazushi; Parsons, Benjamin M.; Paulson, Andrew Scott; Pinto, Carmine; Ramirez, Robert A.; Ratnam, Suresh; Rizell, Magnus; Rosmorduc, Olivier; Sada, Yvonne; Sasaki, Yutaka; Stål, Per; Strasser, Simone I.; Trojan, Joerg; Vaccaro, Gina M.; Vlierberghe, Hans Van; Weiss, Alan; Weiss, Karl-Heinz; Yamashita, Tatsuya

doi:10.1016/s1470-2045(18)30351-6

Cited by 2,059 publications

(1,782 citation statements)

References 28 publications

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“…Besides nivolumab, other PD-1/PD-L1 antibodies have shown comparable effects in manifold cancer entities. In the context of HCC, long-awaited results on the efficacy of checkpoint inhibition have recently been published [9, 10]. In the CheckMate 040, an open-label, noncomparative, phase 1/2 dose escalation and expansion trial including patients with histologically confirmed advanced HCC, nivolumab demonstrated objective response rates of about 20%, both in patients that were pre-treated with sorafenib and in therapy-naïve patients.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…Blockade of immune checkpoint pathways such as the programmed cell death receptor-1 (PD-1) pathway or the cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway can potentially offer a treatment strategy to reinstate host immune response against HCC and ultimately tumor regression [8]. Just recently, both the CheckMate 040 trial and the KEYNOTE-224 trial, large single-arm phase I/II trials, have reported promising results for nivolumab and pembrolizumab when used as salvage therapy after failure of a sorafenib-based first-line therapy in patients with advanced or metastatic HCC [9, 10]. In both trials, fatigue, pruritus, and rash embodied the most prevalent adverse events.…”

Section: Introductionmentioning

confidence: 99%

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Excellent Response to Anti-PD-1 Therapy in a Patient with Hepatocellular Carcinoma Intolerant to Sorafenib

et al. 2019

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Background: Hepatocellular carcinoma (HCC) represents the most common primary carcinoma of the liver. Most patients present with advanced or metastatic HCC at diagnosis and face a very limited prognosis. Systemic treatment with the tyrosine-kinase inhibitors sorafenib or lenvatinib is considered as the treatment of choice in these patients. In patients intolerant to tyrosine-kinase inhibitors, no standard therapy is approved so far, but several agents have demonstrated efficacy in clinical trials. As such, the checkpoint inhibitors nivolumab and pembrolizumab have been shown to induce tumor response and to prolong survival in patients with advanced HCC, both when intolerant to sorafenib or after failure of a first-line therapy with sorafenib. Case Report: We here report the case of a patient with advanced HCC that demonstrated severe toxicity upon first-line treatment with sorafenib. Administration of sorafenib was discontinued and after careful consideration the patient started a second-line treatment with the PD-1 antibody nivolumab. Strikingly, this treatment led to a significant regression of tumor size and a drastic reduction of alpha-fetoprotein serum concentrations. At 17 months after initiation of treatment, the patient is still alive in excellent condition with sustained tumor response. Conclusion: In summary, we report on a very rare case of a patient with HCC demonstrating an almost complete response to checkpoint inhibitor treatment.

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Section: Discussion/conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Excellent Response to Anti-PD-1 Therapy in a Patient with Hepatocellular Carcinoma Intolerant to Sorafenib

et al. 2019

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“…Similar to nivolumab, pembrolizumab received the FDA’s accelerated approval on November 10, 2018 as a second-line agent for the treatment of HCC after sorafenib therapy based on the results of the KEYNOTE-224 phase II trial [19]. The next section outlines the results of the KEYNOTE-224 trial and discusses the future outlook of HCC treatment.…”

Section: Pembrolizumab In Hccmentioning

confidence: 99%

Pembrolizumab for the Treatment of Hepatocellular Carcinoma

Kudo

2019

Liver Cancer

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“…Treatment with checkpoint inhibitors is established in several solid malignancies including melanoma, lung cancer, renal cell carcinoma, and head-and-neck cancer [19] and seems to be a promising therapeutic approach in HCC [15, 16]. Several tumor characteristics seem to favor a response towards checkpoint inhibitors: tumor-inherent genomic instability and high mutational load are associated with an improved overall survival [19, 20].…”

Section: Discussionmentioning

confidence: 99%

“…Via modulation of regulatory T-cell answers, they revoke suppression of tumor-specific immunoreactivity associated with an enhanced immunoreaction against tumor cells [14]. Phase II studies indicate that antibodies against PD-L1 – the ligand for the inhibitory checkpoint molecule PD-1 – are of reasonable efficiency in advanced HCC [15, 16]. However, it remains unknown to date whether FLC is responsive to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Progression after Immunotherapy for Fibrolamellar Carcinoma

et al. 2019

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Background: Fibrolamellar carcinoma (FLC) is a rare malignancy of the liver that differs from typical hepatocellular carcinoma (HCC) in several aspects such as the absence of underlying liver disease and occurrence in younger patients. Even though the survival rates in FLC are slightly better than in typical HCC, the prognosis of metastatic FLC remains deleterious. Several reports suggest that systemic chemotherapy regimens can successfully be used to halt disease progression in FLC, while targeted tumor therapy with sorafenib seems to be of limited efficiency. However, results from controlled clinical trials investigating systemic therapies in FLC are virtually nonexistent. Therefore, the choice of treatment often relies on case series with limited numbers of patients. Immunotherapy with checkpoint inhibitors is an emerging cancer therapy in several solid malignancies including HCC. Currently, there do not exist any reports on the use of checkpoint inhibitors in FLC. Case Report: Here, we describe a case of advanced FLC in a young man receiving immunotherapy, who progressed after 3 months of treatment – similar to 2 other patients with advanced FLC at our hospital. Conclusion: While immunotherapy seems to be a promising treatment with limited side effects in several other tumor entities, there is currently no data supporting tumor response in FLC.

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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

Cited by 2,059 publications

References 28 publications

Excellent Response to Anti-PD-1 Therapy in a Patient with Hepatocellular Carcinoma Intolerant to Sorafenib

Excellent Response to Anti-PD-1 Therapy in a Patient with Hepatocellular Carcinoma Intolerant to Sorafenib

Pembrolizumab for the Treatment of Hepatocellular Carcinoma

Progression after Immunotherapy for Fibrolamellar Carcinoma

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