Immunotherapy for the Treatment of Hepatocellular Carcinoma

Publication Date: September 7, 2023
Last Updated: September 29, 2023

Assessment and Diagnosis

  • A multidisciplinary tumor board review of liver lesions is recommended for HCC diagnosis and the development of a management plan.
  • Notwithstanding that LI-RADS-5 is nearly 100% specific for HCC (LE: 1), histologic confirmation is recommended for patients with unresectable disease particularly prior to the initiation of systemic therapy. Histologic diagnosis is mandatory for non-cirrhotic patients.
  • Despite the controversy regarding the scoring and staging systems that could be used, before initiation of systemic therapy, an evaluation of liver function, including aspartate transaminase (AST)/alanine aminotransferase (ALT), bilirubin, prothrombin time (PT)/international normalized ratio (INR), albumin, plus platelets, is critical (LE: 2).
  • For patients being considered for immunotherapy, an HCC-specific staging system incorporating liver function assessment is suggested (LE: 2).
  • To evaluate patients prior to receiving immunotherapy, Child-Pugh classification would be the most appropriate to date (LE: 1) to measure liver function.


  • In 2022, the ICI combination of durvalumab (anti-PD-L1) with tremelimumab (anti-CTLA-4) was also approved for the treatment of unresectable HCC. Additional trials are ongoing and the therapeutic landscape continues to evolve and expand.
  • For first-line treatment of patients with advanced Child-Pugh A HCC, atezolizumab plus bevacizumab (LE:2) or tremelimumab plus durvalumab (LE:2) are recommended, unless any medications are contraindicated.
  • General contraindications to bevacizumab include high risk of cardiac disease, stroke, hemorrhage, hemoptysis, gastrointestinal perforation, or non-healing wounds (LE: 1). (For contraindications to immunotherapy, see the Patient selection and management section). Consideration should be given to timing of prior events. Additional contraindications specifically relevant to HCC include untreated or incompletely treated gastroesophageal varices at risk for bleeding (LE: 2).
  • For patients with contraindications to an ICI-containing combination therapy (ie, atezolizumab plus bevacizumab or tremelimumab plus durvalumab), lenvatinib or sorafenib should be considered as standard first-line therapy (LE:2).
  • Nivolumab monotherapy has demonstrated activity in Child-Pugh B7-B8 HCC for both first-line treatment of sorafenib-na├»ve patients and for second-line treatment of patients who were intolerant to or progressed on sorafenib (LE: 3).
  • For patients with good performance status who have progressed on first-line therapy and have not received prior immunotherapy, other non FDA-approved or conditionally approved anti-PD-1 checkpoint inhibitors may be considered as immunotherapeutic options (LE: 3).
  • Clinicians should encourage patients' participation in clinical trials.
  • Future biomarker development might help to select a subgroup of patients benefitting from single-agent nivolumab treatment. Designing a biomarker strategy based on pretreatment and on-treatment tissue and blood samples to assess immune cell changes and other correlatives is critical to elucidate mechanisms of response or resistance to immunotherapy in combination with local therapy in early-stage HCC.
  • Studies evaluating combinations of other immunotherapies with ICIs should be based on solid scientific rationale.
  • Future randomized studies to compare local therapy alone to local therapy combined with immunotherapy are essential to assess the expected synergy and favorable treatment outcome of the combination strategy.



Immunotherapy for the Treatment of Hepatocellular Carcinoma

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