David Tai1, Kelvin Loke2, Apoorva Gogna3, Neslihan Arife Kaya4, Sze Huey Tan5, Tiffany Hennedige6, David Ng2, Farah Irani3, Joycelyn Lee7, Jia Qi Lim8, Chow Wei Too3, Matthew C H Ng7, Chee Kian Tham7, Justina Lam7, Si Lin Koo7, Hui Shan Chong9, George Boon-Bee Goh10, Hian Liang Huang2, Nanda Venkatanarasimha11, Richard Lo11, Pierce K H Chow12, Brian K P Goh13, Alexander Chung13, Han Chong Toh7, Choon Hua Thng14, Tony K H Lim15, Joe Yeong16, Weiwei Zhai17, Chung Yip Chan13, Su Pin Choo7. 1. Division of Medical Oncology, National Cancer Centre, Singapore; Duke NUS Medical School, Singapore. Electronic address: david.tai.w.m@singhealth.com.sg. 2. Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore. 3. Vascular and Interventional Radiology, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore. 4. Genome Institute of Singapore, A*STAR, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore. 5. Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore; Duke NUS Medical School, Singapore. 6. Division of Oncologic Imaging, National Cancer Centre, Singapore; Duke NUS Medical School, Singapore. 7. Division of Medical Oncology, National Cancer Centre, Singapore; Duke NUS Medical School, Singapore. 8. Genome Institute of Singapore, A*STAR, Singapore. 9. Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore. 10. Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore. 11. Vascular and Interventional Radiology, Singapore General Hospital, Singapore. 12. Division of Surgery and Surgical Oncology, National Cancer Centre, Singapore; Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore. 13. Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore. 14. Division of Oncologic Imaging, National Cancer Centre, Singapore. 15. Anatomical Pathology, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore. 16. Anatomical Pathology, Singapore General Hospital, Singapore. 17. Genome Institute of Singapore, A*STAR, Singapore; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.
Abstract
BACKGROUND: Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma. METHODS: Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov, NCT03033446 and has been completed. FINDINGS: 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4-48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3-4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). INTERPRETATION: Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread. FUNDING: National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex.
BACKGROUND: Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma. METHODS: Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov, NCT03033446 and has been completed. FINDINGS: 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4-48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3-4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). INTERPRETATION: Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread. FUNDING: National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex.
Authors: Osman Öcal; Kerstin Schütte; Christoph J Zech; Christian Loewe; Otto van Delden; Vincent Vandecaveye; Chris Verslype; Bernhard Gebauer; Christian Sengel; Irene Bargellini; Roberto Iezzi; Alexander Philipp; Thomas Berg; Heinz J Klümpen; Julia Benckert; Maciej Pech; Antonio Gasbarrini; Holger Amthauer; Peter Bartenstein; Bruno Sangro; Peter Malfertheiner; Jens Ricke; Max Seidensticker Journal: Eur J Nucl Med Mol Imaging Date: 2022-08-02 Impact factor: 10.057
Authors: Philippe d'Abadie; Stephan Walrand; Renaud Lhommel; Michel Hesse; Ivan Borbath; François Jamar Journal: Curr Oncol Date: 2022-03-29 Impact factor: 3.109