title: Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?
abstract: BACKGROUND
  The increasing knowledge of the genomic landscape of hepatocellular carcinoma (HCC) and the development of molecular targeted therapies are a promising background for increasing the number of effective drugs for HCC patients. In recent years, many new drugs have been tested as an alternative to sorafenib or after sorafenib failure.
  
  
  METHODS
  In this review, our aim is to describe the randomized trials recently conducted in HCC patients, in order to understand the main reasons potentially related to the failures of many drugs. In addition, we briefly describe the main ongoing trials, that could potentially change the scenario of HCC treatment in the next years. Expert commentary: Heterogeneity of study populations, lack of understanding of critical drivers of tumor progression, risk of liver toxicity associated with experimental agents, ﬂaws in trial design and marginal antitumoral potency can be considered the main reasons for failure of phase III clinical trials in HCC. Most ongoing trials are conducted without any molecular selection criteria, although many drugs could be probably better tested in a molecularly selected population. The knowledge of potential predictive factors for drug efficacy in patients with advanced HCC could improve the chance of obtaining positive results in clinical trials.
authors.affiliation: a Division of Medical Oncology, Department of Oncology , University of Turin, San Luigi Gonzaga Hospital , Turin , Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Brizzi
authors.affiliation: a Division of Medical Oncology, Department of Oncology , University of Turin, San Luigi Gonzaga Hospital , Turin , Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Pignataro
authors.affiliation: a Division of Medical Oncology, Department of Oncology , University of Turin, San Luigi Gonzaga Hospital , Turin , Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tampellini
authors.affiliation: a Division of Medical Oncology, Department of Oncology , University of Turin, San Luigi Gonzaga Hospital , Turin , Italy.
authors.forename: Giorgio Vittorio
authors.initials: GV
authors.lastname: Scagliotti
authors.affiliation: b Division of Medical Oncology, Department of Oncology , University of Turin, Mauriziano Hospital , Turin , Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D015195:Drug Design; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D018579:Patient Selection; D010671:Phenylurea Compounds / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012107:Research Design; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: Hepatocellular carcinoma; cabozantinib; clinical trials; nivolumab; ramucirumab; regorafenib