G&H Why were guidelines recently released by the Asian Pacific Association for the Study of the Liver on systemic therapy for patients with hepatocellular carcinoma?
GL Hepatocellular carcinoma (HCC) has a large disease burden in the Asia-Pacific region despite methods for reducing risk factors via low-cost screening and therapy for hepatitis B and hepatitis C as well as recommendations for surveillance. Unfortunately, most HCCs are already in an advanced stage upon presentation and many patients die. Just in China, around 380,000 people die from HCC each year. There are now new methods for dealing with the deadly disease of advanced HCC with systemic therapies in terms of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Once in an advanced stage, HCC is beyond resection and locoregional therapy, and survival is very low. Based on large-scale phase 3 clinical trials, numerous systemic therapies have recently been made available to improve the overall survival of patients with advanced HCC. As the premier liver society in the Asia-Pacific region, the Asian Pacific Association for the Study of the Liver (APASL) decided to write guidelines to help provide our colleagues with the most updated knowledge for their clinical practice when managing patients with HCC.
G&H How were these guidelines developed?
GL Development of the guidelines was initiated approximately 3 years ago by the APASL steering committee, and an expert panel with key opinion leaders was formed. Relevant clinical questions were defined and responses were obtained from the expert panel through questionnaires and meetings. Recommendations were then drafted and presented at last year’s APASL annual meeting, which was held in Kyoto and attracted 6000 participants. Modifications were made based on the comments that were obtained. The clinical practice guidelines were written by myself, the other chairs, and key expert panel members, and were published in Hepatology International, the official journal of our society.
G&H According to these guidelines, which patients with HCC should be considered for systemic therapy and what are the recommended first-line options?
GL The guidelines recommend that systemic therapy be offered to patients with unresectable HCC who are not eligible for locoregional therapy and have good performance status (0-1 on the Eastern Cooperative Oncology Group scale) and fairly good liver function (Child-Pugh score of A or B), including those with portal vein thrombosis. Recommendations for systemic therapies are based on recent positive phase 3 data from the following studies: REFLECT (lenvatinib [Lenvima, Eisai]), ZGDH3 (donafenib), IMbrave150 (atezolizumab [Tecentriq, Genentech] plus bevacizumab), ORIENT-32 (sintilimab plus IBI305), CARES-310 (camrelizumab plus rivoceranib), RATIONALE-310 (tislelizumab), HIMALAYA (for which I am the lead investigator; tremelimumab plus durvalumab [Imfinzi, AstraZeneca]), and CheckMate-9DW (nivolumab [Opdivo, Bristol Myers Squibb] plus ipilimumab [Yervoy, Bristol Myers Squibb]). The guidelines recommend that the first choice for systemic HCC therapy be anti–vascular endothelial growth factor (VEGF) plus anti–programmed death 1 (PD-1)/anti–programmed death ligand 1 (PD-L1) therapies in patients without risk of bleeding (ie, atezolizumab plus bevacizumab, camrelizumab plus rivoceranib, or sintilimab plus IBI305) or dual ICIs with anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and anti–PD-1/anti–PD-L1 or anti–PD-1/anti–PD-L1 therapies. If patients have limited resources or contraindications to immunotherapy, the guidelines recommend considering lenvatinib or sorafenib.
G&H Which systemic therapies are recommended for second-line treatment?
GL The guidelines recommend considering second-line therapy when HCC progresses following 8 to 12 weeks of first-line therapy. After failure of anti-VEGF plus anti–PD-1/anti–PD-L1 therapies, dual ICIs with anti–CTLA-4 and anti–PD-1/anti–PD-L1 therapies or lenvatinib should be considered. Following failure of dual ICIs with anti–CTLA-4 or anti–PD-1/anti–PD-L1 therapies, the guidelines now recommend considering anti-VEGF plus anti–PD-1/anti–PD-L1 therapies or lenvatinib. After failure of first- and second-line therapies, third-line therapy should include regorafenib or cabozantinib (Cabometyx, Exelixis) or, if patients have an alpha-fetoprotein level greater than or equal to 400 ng/mL, ramucirumab (Cyramza, Lilly).
G&H Could you discuss the key recommendations regarding immune-related adverse events?
GL Providers are seeing an array of immune-related adverse events associated with the use of ICIs, which are becoming the backbone of first-line systemic therapy. The organs affected by immune checkpoint blockades vary in different patients. Unfortunately, at this point we do not know the patterns regarding which patients will develop which type of adverse events with which therapy. The adverse events could include encephalitis, uveitis, thyroiditis, pneumonitis, thrombocytopenia, rash, vitiligo, myocarditis, pancreatitis, colitis, enteritis, adrenal insufficiency, nephritis, vasculitis, neuropathy, or arthralgia. The guidelines recommend that patients with unresectable HCC should be monitored 1 to 2 times a week for immune-related adverse event toxicity when dual ICIs (anti–CTLA-4 and anti–PD-1/anti–PD-L1 therapies) are used and 2 to 4 times a week if only anti–PD-1/anti–PD-L1 therapy is used. The diagnosis of these adverse events should be made only after other differential diagnoses are ruled out. Grading immune-related adverse events is very important, and the guidelines recommend using the 6th version of the National Cancer Institute Common Terminology Criteria for Adverse Events and classifying the severity of events according to Version 26.2 of the Medical Dictionary for Regulatory Activities.
G&H What are the key recommendations for using systemic therapy with ablation or transarterial chemoembolization?
GL APASL is the first society to recommend against using ICIs in patients after local ablation or surgical resection to prevent HCC recurrence. When we wrote the guidelines, interim results of the IMbrave150 study suggested that recurrence-free survival was reduced in HCC patients with a high risk of recurrence after surgery who were given ICI plus anti-VEGF therapy. However, the survival curves start to collapse when looking at the data very carefully. I think we are correct in not recommending the use of ICI plus anti-VEGF therapy in patients who have undergone resection for HCC to prevent disease recurrence. Subsequent longer-term follow-up research has shown no difference in overall survival. The American Association for the Study of Liver Diseases recently released an update to its practice guidelines on the prevention, diagnosis, and treatment of HCC and also advised against the use of new adjuvant systemic therapies in patients undergoing liver resection or local ablation.
A recent study randomized patients who received transarterial chemoembolization (TACE) as a locoregional therapy with durvalumab plus bevacizumab vs placebo. Median progression-free survival improved by 6.8 months in those who received durvalumab plus bevacizumab with TACE vs placebo plus TACE. Therefore, the APASL guidelines recommend considering durvalumab plus bevacizumab therapy in patients with unresectable HCC who are eligible for embolization such as TACE.
G&H How do the guidelines recommend using systemic therapy pre– and post–liver transplant?
GL One important clinical question is whether the size of the HCC can be reduced or maintained so that it can meet transplant criteria. Because ICI therapy is becoming the backbone of systemic HCC therapy, it might be possible to reduce or control HCC size and satisfy transplant criteria, and the risk of rejection after liver transplant would not be increased. Hence, it is of paramount importance to know the optimal washout window for the last dose of ICI-based therapy prior to transplant. There are not a lot of data in this area. Based on case reports on the use of ICI-based therapy in pre–liver transplant patients with HCC, as well as the expert opinions of panel members, the guidelines recommend using ICI-based therapy in the pretransplant setting, and the procedure can be performed after 6 weeks of washout for patients who meet local transplant criteria.
HCC recurrence after liver transplant is another important issue. Although patients have to meet criteria for liver transplant, there is still a risk for HCC recurrence after the procedure. Patients need to receive immunosuppressive therapy post–liver transplant, but can they be treated with ICI therapy if they have liver cancer recurrence? Unfortunately, the data in this area are very scattered. For the APASL guidelines, we searched the literature and found only 32 case reports on what happens in patients who have HCC recurrence after liver transplant, including whether they received ICI-based therapy and whether there is an increased incidence of rejection with such therapy. The rejection rates were summarized to be around 18% to 19%. Based on these data as well as expert opinions, the guidelines recommend the use of TKIs (ie, sorafenib or lenvatinib) to treat HCC recurrence following liver transplant. After weighing the patient’s immunologic risks and oncologic benefits, ICIs can be used cautiously as salvage therapy for HCC recurrence in patients who have undergone liver transplant. After all, with the costs of liver transplant and scarcity of organs, we try to do as much as we can to save patients.
G&H Would you like to highlight any other recommendations from the guidelines?
GL One of the most important recommendations emphasizes using a multidisciplinary approach for the treatment of patients with HCC, especially those with advanced HCC who are receiving systemic therapy. Quite a lot of randomized evidence suggests that such an approach helps prolong overall survival of patients. Therefore, our guidelines encourage the use of a multidisciplinary team, which should include experienced hepatologists, oncologists, radiologists (diagnostic and interventional), oncology nurses, surgeons (transplant and hepatobiliary), pathologists, molecular biologists, and palliative care specialists.
G&H What are future directions in this area?
GL Artificial intelligence with machine and deep learning is of great importance to understand the complexities of different treatment modalities and diversity in tumor responses using data recorded in real life by electronic health care records, imaging modalities, histopathology, and biomarkers. If these data are collected correctly, we will be able to improve selection of therapy to enhance patient survival and quality of life. Digitalization of data, not just laboratory data but imaging, histopathology, and biomarker data, should enable providers to be more precise regarding which patients should be given which therapy, when to switch, how to predict risk-benefit ratios in terms of immune-related adverse events, and whether patients should receive liver transplant.
Research is also needed to elucidate the mechanisms of immune-related adverse events in order to develop more precise treatments. There are many possible mechanisms, but too little work is being performed regarding what is responsible for different types of adverse events in different patients. Some immune-related adverse events can be very mild and some can be very severe, and it is not clear whether those being witnessed in HCC are similar to those in other cancers being treated with ICI therapy. This is an uncharted area that needs attention, and APASL is committed to staying alert and providing updated clinical practice guidance to aid our fellow colleagues and the global community in the management of HCC.
Disclosures
Professor Lau has no relevant conflicts of interest to disclose.
Suggested Reading
Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070.
Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862-873.
Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905.
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173.
Lau G, Abou-Alfa GK, Cheng AL, et al. Outcomes in the Asian subgroup of the phase III randomised HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. J Hepatol. 2025;82(2):258-267.
Lau G, Obi S, Zhou J, et al. APASL clinical practice guidelines on systemic therapy for hepatocellular carcinoma-2024. Hepatol Int. 2024;18(6):1661-1683.
Qin S, Bi F, Gu S, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase II-III trial. J Clin Oncol. 2021;39(27):3002-3011.
Qin S, Chan SL, Gu S, et al; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402(10408):1133-1146.
Qin S, Kudo M, Meyer T, et al. Tislelizumab vs sorafenib as first-line treatment for unresectable hepatocellular carcinoma: a phase 3 randomized clinical trial. JAMA Oncol. 2023;9(12):1651-1659.
Ren Z, Xu J, Bai Y, et al; ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021;22(7):977-990.