PMID- 37025943 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230411 IS - 2589-5559 (Electronic) IS - 2589-5559 (Linking) VI - 5 IP - 5 DP - 2023 May TI - Efficacy and safety of frontline systemic therapy for advanced HCC: A network meta-analysis of landmark phase III trials. PG - 100702 LID - 10.1016/j.jhepr.2023.100702 [doi] LID - 100702 AB - BACKGROUND & AIMS: Direct comparisons across first-line regimens for advanced hepatocellular carcinoma are not available. We performed a network metanalysis of phase III of trials to compare first-line systemic treatments for hepatocellular carcinoma in terms of overall survival (OS), progression-free survival (PFS), objective response rate, disease control rate, and incidence of adverse events (AEs). METHODS: After performing a literature review from January 2008 to September 2022, we screened 6,329 studies and reviewed 3,009 studies, leading to identification of 15 phase III trials for analysis. We extracted odds ratios for objective response rate and disease control rate, relative risks for AEs, and hazard ratios (HRs) with 95% CIs for OS and PFS, and used a frequentist network metanalysis, with fixed-effect multivariable meta-regression models to estimate the indirect pooled HRs, odds ratios, relative risks, and corresponding 95% CIs, considering sorafenib as reference. RESULTS: Of 10,820 included patients, 10,444 received active treatment and 376 placebo. Sintilimab + IBI350, camrelizumab + rivoceranib, and atezolizumab + bevacizumab provided the greatest reduction in the risk of death compared with sorafenib, with HRs of 0.57 (95% CI 0.43-0.75), 0.62 (95% CI 0.49-0.79), and 0.66 (95% CI 0.52-0.84), respectively. Considering PFS, camrelizumab + rivoceranib and pembrolizumab + lenvatinib were associated with the greatest reduction in the risk of PFS events compared with sorafenib, with HRs of 0.52 (95% CI 0.41-0.65) and 0.52 (95% CI 0.35-0.77), respectively. Immune checkpoint inhibitor (ICI) monotherapies carried the lowest risk for all-grade and grade >/=3 AEs. CONCLUSIONS: The combinations of ICI + anti-vascular endothelial growth factor, and double ICIs lead to the greatest OS benefit compared with sorafenib, whereas ICI + kinase inhibitor regimens are associated with greater PFS benefit at the cost of higher toxicity rates. IMPACT AND IMPLICATIONS: In the last few years, many different therapies have been studied for patients with primary liver cancer that cannot be treated with surgery. In these cases, anticancer drugs (alone or in combination) are given with the intent to keep the cancer at bay and, ultimately, to prolong survival. Among all the therapies that have been investigated, the combination of immunotherapy (drugs that boost the immune system against the cancer) and anti-angiogenic agents (drugs that act on tumoural vessels) has appeared the best to improve survival. Similarly, the combination of two types of immunotherapies that activate the immune system at different levels has also shown positive results. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022366330. CI - (c) 2023 The Author(s). FAU - Fulgenzi, Claudia Angela Maria AU - Fulgenzi CAM AD - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. AD - Medical Oncology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. FAU - Scheiner, Bernhard AU - Scheiner B AD - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. FAU - Korolewicz, James AU - Korolewicz J AD - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. FAU - Stikas, Charalampos-Vlasios AU - Stikas CV AD - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. FAU - Gennari, Alessandra AU - Gennari A AD - Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy. FAU - Vincenzi, Bruno AU - Vincenzi B AD - Medical Oncology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. FAU - Openshaw, Mark R AU - Openshaw MR AD - University Hospitals Birmingham Cancer Centre, Birmingham, UK. FAU - Silletta, Marianna AU - Silletta M AD - Medical Oncology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. FAU - Pinter, Matthias AU - Pinter M AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. FAU - Cortellini, Alessio AU - Cortellini A AD - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. AD - Medical Oncology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. FAU - Scotti, Lorenza AU - Scotti L AD - Department of Translational Medicine, Universita del Piemonte Orientale UPO, Novara, Italy. FAU - D'Alessio, Antonio AU - D'Alessio A AD - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. AD - Department of Biomedical Sciences, Humanitas University, Milan, Italy. FAU - Pinato, David J AU - Pinato DJ AD - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. AD - Department of Translational Medicine, Universita del Piemonte Orientale UPO, Novara, Italy. LA - eng PT - Journal Article DEP - 20230218 PL - Netherlands TA - JHEP Rep JT - JHEP reports : innovation in hepatology JID - 101761237 PMC - PMC10070142 OTO - NOTNLM OT - First-line treatment OT - Immune checkpoint inhibitors OT - Liver cancer OT - Targeted therapy OT - Tyrosine kinase inhibitors COIS- DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, EISAI, BMS, and Roche and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, DaVolterra, Mursla, IPSEN, Exact Sciences, Avamune, EISAI, Roche, and Astra Zeneca; and research funding (to institution) from MSD, GSK, and BMS. BS received travel support from AbbVie, Gilead, and Ipsen. AC received consulting fees from MSD, Astra Zeneca, Roche, and BMS. He also received speaker fees from Novartis, Astra Zeneca, and EISAI. AD received educational support for conference attendance and consultancy fees by Roche. There are no other personal or financial conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details. EDAT- 2023/04/08 06:00 MHDA- 2023/04/08 06:01 PMCR- 2023/02/18 CRDT- 2023/04/07 02:35 PHST- 2022/11/07 00:00 [received] PHST- 2023/01/11 00:00 [revised] PHST- 2023/02/02 00:00 [accepted] PHST- 2023/04/08 06:01 [medline] PHST- 2023/04/07 02:35 [entrez] PHST- 2023/04/08 06:00 [pubmed] PHST- 2023/02/18 00:00 [pmc-release] AID - S2589-5559(23)00033-2 [pii] AID - 100702 [pii] AID - 10.1016/j.jhepr.2023.100702 [doi] PST - epublish SO - JHEP Rep. 2023 Feb 18;5(5):100702. doi: 10.1016/j.jhepr.2023.100702. eCollection 2023 May.