Scientific publications

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

Apr 20, 2017 | Magazine: The Lancet

Dr Anthony B El-Khoueiry, MD (a), Bruno Sangro, MD (b), †, Thomas Yau, MD (c), †, Todd S Crocenzi, MD (d), Masatoshi Kudo, MD (e), Chiun Hsu, MD (f), Tae-You Kim, MD (g), Su-Pin Choo, BMBS (h), Jörg Trojan, MD (i), Theodore H Welling 3rd, MD (j), Tim Meyer, MDk, Yoon-Koo Kang, MD (l), Winnie Yeo, MD (m), Akhil Chopra, MD (n), Jeffrey Anderson, MD (o), Christine dela Cruz, MD (o), Lixin Lang, PhD (o), Jaclyn Neely, PhD (o), Hao Tang, PhD (o), Homa B Dastani, PhD (o), Ignacio Melero (p, q)
(a) USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
(b) Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
(c) University of Hong Kong, Hong Kong Special Administrative Region, China
(d) Providence Cancer Center, Portland, OR, USA
(e) Kindai University Faculty of Medicine, Osaka, Japan
(f) National Taiwan University Hospital, Taipei, Taiwan
(g) Seoul National University Hospital, Seoul, South Korea
(h) National Cancer Center, Singapore
(i) Goethe University Hospital and Cancer Center, Frankfurt, Germany
(j) University of Michigan School of Medicine, Ann Arbor, MI, USA
(k) Royal Free Hospital, London, UK
(l) Asan Medical Center, University of Ulsan, Seoul, South Korea
(m) Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
(n) Johns Hopkins Singapore International Medical Centre, Singapore
(o) Bristol-Myers Squibb, Princeton, NJ, USA
(p) Biomedical Research Network in Oncology (CIBERONC), Pamplona, Spain
(q) Center for Applied Medical Research (CIMA), Pamplona, Spain 

For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis.

We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection.

Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan).

At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection.

We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1–10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected.

Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with, number NCT01658878.

Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing.

During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events.

Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15–26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6–28) in the dose-escalation phase.

Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.

CITATION  The Lancet, 20 de abril de 2017