Masatoshi Kudo1, Ana Matilla2, Armando Santoro3, Ignacio Melero4, Antonio Cubillo Gracián5, Mirelis Acosta-Rivera6, Su-Pin Choo7, Anthony B El-Khoueiry8, Ryoko Kuromatsu9, Bassel El-Rayes10, Kazushi Numata11, Yoshito Itoh12, Francesco Di Costanzo13, Oxana Crysler14, Maria Reig15, Yun Shen16, Jaclyn Neely16, Marina Tschaika16, Tami Wisniewski16, Bruno Sangro17. 1. Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan. Electronic address: m-kudo@med.kindai.ac.jp. 2. Servicio de Digestivo, Hospital General Universitario Gregorio Marañón, CIBEREHD, Madrid, Spain. 3. Department of Biomedical Sciences, Humanitas University Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy. 4. Department of Immunology and Immunotherapy, Clinica Universidad de Navarra and CIBERONC, Pamplona, Spain. 5. Hospital Universitario HM Sanchinarro, Centro Integral Oncológico Clara Campal (HM CIOCC), Madrid, Spain; Departamento de Ciencias Médicas Clínicas, Facultad de Medicina, Universidad CEU San Pablo, Madrid, Spain. 6. Internal Medicine - Hematology & Oncology, Fundacion de Investigacion, San Juan, Puerto Rico. 7. Division of Medical Oncology, National Cancer Center, Singapore. 8. Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 9. Division of Gastroenterology, Kurume University Hospital, Fukuoka, Japan. 10. Department of Hematology and Medical Oncology, Emory University Winship Cancer Institute, Atlanta, GA, USA. 11. Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan. 12. Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan. 13. Department of Medical Oncology, AOU Careggi, Florence, Italy. 14. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. 15. BCLC Group, Liver Unit, Hospital Clinic de Barcelona, CIBEREHD, Barcelona, Spain. 16. Bristol Myers Squibb, Princeton, NJ, USA. 17. Liver Unit, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
Abstract
BACKGROUND & AIMS: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. METHODS: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. CONCLUSIONS: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. LAY SUMMARY: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. CLINICAL TRIAL NUMBER: NCT01658878.
BACKGROUND & AIMS: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. METHODS: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. CONCLUSIONS: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. LAY SUMMARY: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. CLINICAL TRIAL NUMBER: NCT01658878.
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