Does immune checkpoint inhibitor exhibit limited efficacy against non-viral hepatocellular carcinoma?: A review of clinical trials

Immunotherapy with immune checkpoint inhibitors has been shown to be beneficial for cancers originating from various organs. In May 2020, combination therapy with anti-programmed death-ligand 1 antibody atezolizumab and anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was approved as a novel first-line systemic therapy for hepatocellular carcinoma (HCC). The number of patients with HCC not caused by hepatitis virus infection (non-viral HCC), including non-alcoholic steatohepatitis (NASH)-related HCC, has been increasing in recent years. Recently, Pfister and colleagues reported that immune checkpoint inhibitors may exhibit limited efficacy against NASH-related HCC, based on basic research and clinical data. This review will discuss the mechanism of impaired tumor immune surveillance in NASH and analyze the results of previously published clinical trials of immune checkpoint inhibitors to investigate whether patients with non-viral HCC are less likely to benefit from immunotherapy with immune checkpoint inhibitors. Furthermore, we also discuss the possibility of enhancing the therapeutic effect of immune checkpoint inhibitors for NASH-related HCC by combining anti-VEGF agents.     

Atezolizumab and bevacizumab as first line therapy in advanced hepatocellular carcinoma: Practical considerations in routine clinical practice

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. For advanced HCC, sorafenib was considered the standard of care for more than ten years. Recently the atezolizumab and bevacizumab combination has become standard of care for these patients without contraindications to either immune checkpoint inhibitors or antiangiogenic therapy. We now review the practical aspects of the atezolizumab and bevacizumab combination, including current evidence, indications, contraindications, management of adverse events, sequencing of this combination, areas of current knowledge gaps and future areas of active clinical research of this combination for busy clinicians in clinical practice.     

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.     

Non-alcoholic fatty liver disease-related hepatocellular carcinoma: Is there a role for immunotherapy?

Hepatocellular carcinoma (HCC) is among the most common cancers and it is a major cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD) affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC. The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood. However, metabolic, fibrogenic, oncogenic, inflammatory and immunological pathways seem to be involved. First-line therapy of advanced HCC has recently undergone major changes, since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib. Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy. However, initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease, which seems to be particularly important in NAFLD-related HCC, as these tumors might not benefit from it. This article will review the mechanisms of NAFLD-related hepatocarcinogenesis, with an emphasis on its immune aspects, the efficacy of traditional systemic therapy for advanced NAFLD-related HCC, and the most recent data on the role of immunotherapy for this specific group of patients, showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.     

Immune checkpoint blockade for the treatment of human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers with a high recurrence rate. Currently, tyrosine kinase inhibitors (TKIs) are the first‐line treatment for cases refractory to conventional therapies. However, the acquisition of somatic mutations can result in TKI resistance. Clinical evidence suggests that acquired immunity contributes to the suppression of tumor recurrence, indicating the potential of induced antitumor immune reaction for the treatment of HCC. Recently, immune checkpoint inhibitors have become available for the treatment of malignancies. They are effective regardless of the response to prior therapies and a durable effect can be expected, which should be attributed to an adaptive immunity to HCC components. The results of phase I/II trials of nivolumab, an anti‐programmed cell death‐1 antibody, showed that 20% of patients showed objective response and that nivolumab was effective regardless of prior sorafenib treatment and viral status. Nivolumab received expedited Food and Drug Administration approval in 2017 for the treatment of advanced HCC after failure or intolerance to sorafenib. However, the majority of the patients remain refractory, likely due to the solid immune suppressive status, which involves many stromal cells, humoral mediators, and suppressive checkpoint molecules. Therefore, current clinical trials are focusing on how immunosuppressive conditions in HCC might be overcome using immune checkpoint inhibitors in combination with different types of immune checkpoint blockades, TKIs, and other conventional treatments. The development of immune checkpoint inhibitors is rapidly progressing and these inhibitors are likely to be key agents for HCC treatment in the near feature.     

Targeted and immune therapies for hepatocellular carcinoma:Predictions for 2019 and beyond

Systemic therapy for hepatocellular carcinoma(HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However,development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1 st line and 2 nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed.On the other hand, clinical trials of 4 agents(regorafenib, lenvatinib,cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible(regorafenib and lenvatinib) or underway(cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization(TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib(TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early,intermediate and advanced stage, is expected to be changed drastically in the very near future.     

Angiogenesis and immune checkpoint dual blockade: Opportunities and challenges for hepatocellular carcinoma therapy

The disease burden related to hepatocellular carcinoma (HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors (ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase III clinical trial IMBrave150 [atezolizumab (anti-programmed cell death ligand 1 antibody) combined with bevacizumab (anti-vascular endothelial growth factor monoclonal antibody)], showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of anti-angiogenics and ICIs, and point out the existing challenges of the combination therapy.     

Sequencing of systemic treatment for hepatocellular carcinoma:Second line competitors

During the last decades, further knowledge of hepatocellular carcinoma(HCC)molecular mechanisms has led to development of effective systemic treatments including tyrosine kinase inhibitors(TKIs) and immunotherapy. In this review,we describe first and second line systemic treatment options for advanced HCC.Several trials have evaluated new drugs for the treatment of HCC patients: In first line, lenvatinib resulted non-inferior to sorafenib and it can be used as alternative, even in the lack of evidence for sequential treatment options in second line after lenvatinib. Recently, atezolizumab plus bevacizumab have shown superiority over sorafenib in first-line. Sorafenib-regorafenib sequential administration in selected patients has opened a new paradigm of treatment in advanced HCC with a life expectancy exceeding two years. Other TKIs for second line treatment include cabozantinib and ramucirumab(specifically for patients with Alpha-fetoprotein values ≥ 400 ng/mL). The combination of TKIs with immunotherapy may represent a big step forward for these patients in the near future.     

Selection of first-line systemic therapies for advanced hepatocellular carcinoma: A network meta-analysis of randomized controlled trials

BACKGROUNDThe majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma (HCC) used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.AIMTo systematically review and compare response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma.METHODSWe searched PubMed, Science Direct, the Cochrane Database, Excerpta Medica Database, and abstracts from the American Society of Clinical Oncology 2020 annual congress. Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC. Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments.RESULTSIn total, 1398 articles were screened and 27 included. Treatments compared were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. For overall response rate, lenvatinib ranked 1/19, followed by atezolizumab plus bevacizumab and nivolumab. For progression-free survival (PFS), atezolizumab + bevacizumab was ranked 1/15, followed by lenvatinib. With the exception of atezolizumab + bevacizumab [hazard ratios (HR)_PFS = 0.90; 95% confidence interval (CI): 0.64-1.25], the estimated HRs for PFS for all included treatments vs lenvatinib were > 1; however, the associated 95%CI passed through unity for bevacizumab plus erlotinib, linifanib, and FOLFOX4. For overall survival, atezolizumab plus bevacizumab was ranked 1/25, followed by vandetanib 100 mg/d and donafinib, with lenvatinib ranked 6/25. Atezolizumab + bevacizumab was associated with a lower risk of death vs lenvatinib (HR_os = 0.63; 95%CI: 0.44-0.89), while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity. Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13, respectively, for the lowest incidence of treatment terminations due to adverse events, followed by sorafenib (5/13), lenvatinib (10/13), and atezolizumab + bevacizumab (13/13).CONCLUSIONThere is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals.     

Interventional treatment for unresectable hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the sixth most common cancer and third leading cause of cancer-related death in the world. The Barcelona clinic liver cancer classification is the current standard classification system for the clinical management of patients with HCC and suggests that patients with intermediate-stage HCC benefit from transcatheter arterial chemoembolization(TACE). Interventional treatments such as TACE, balloon-occluded TACE, drug-eluting bead embolization, radioembolization, and combined therapies including TACE and radiofrequency ablation, continue to evolve, resulting in improved patient prognosis. However, patients with advanced-stage HCC typically receive only chemotherapy with sorafenib, a multi-kinase inhibitor, or palliative and conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidatesfor systemic therapy. However, these patients require therapy that is more effective than sorafenib or conservative treatment. Several researchers try to perform more effective therapies, such as combined therapies(TACE with radiotherapy and sorafenib with TACE), modified TACE for HCC with arterioportal or arteriohepatic vein shunts, TACE based on hepatic hemodynamics, and isolated hepatic perfusion. This review summarizes the published data and data on important ongoing studies concerning interventional treatments for unresectable HCC and discusses the technical improvements in these interventions, particularly for advanced-stage HCC.     

Current status of systemic therapy in hepatocellular cancer

Hepatocellular cancer (HCC) is a common cancer and an important cause of cancer-related death globally. Although surgery is the primary curative treatment, most patients at diagnosis are not surgical candidates and are treated with liver-directed therapy and or systemic therapy. Over the past decade, the systemic treatment options for patients with advanced HCC have evolved. This paper reviews recent progress in systemic therapy and the results of major clinical trials involving novel compounds in patients with HCC. A literature search was performed using keywords related to HCC and systemic therapy. The evidence shows that at the present time an effective adjuvant systemic therapy is not available for patients with early-stage HCC following surgery. In patients with advanced HCC, in addition to sorafenib at least four other targeted agents and several immune checkpoint inhibitors, alone or in combination have been shown to be associated with improved progression-free and overall survival. The optimal sequence of agents, is currently not known, and is determined by patient characteristics, toxicities profile, patients and physicians preference. The future identification of novel active agents and predictive biomarkers are vital to personalize systemic therapy in HCC.     

Argentinian clinical practice guideline for surveillance,diagnosis, staging and treatment of hepatocellular carcinoma

The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.     

Sirolimus plus sorafenib in treating HCC recurrence after liver transplantation: a case report

A case of hepatocellular carcinoma (HCC) with pulmonary recurrence after liver transplantation for HCC is presented in this report. The patient showed disease progression on sorafenib therapy demonstrated by computed tomography scans as well as serial serum α-fetoprotein (AFP) elevation. After his immunosuppression therapy was successfully transitioned to sirolimus and a continuation of sorafenib, he achieved partial remission based on RECIST criteria and normalization of AFP. Mammalian target of rapamycin inhibitors including sirolimus alone or in conjunction with sorafenib may be useful in the treatment of post transplant HCC.     

分子靶向药物与免疫抑制剂联合治疗及其他联合治疗在肝细胞癌中的应用

肝细胞癌(HCC)是最常见的恶性肿瘤之一,发病隐匿,发展迅速,高复发的特点导致HCC患者长期生存面临巨大挑战。分子靶向药物与免疫抑制剂在HCC治疗中成为研究的热点,大量临床试验发现,联合治疗取得了不错的疗效。主要介绍了分子靶向药物与免疫抑制剂联合治疗及其他联合治疗在HCC中的应用,指出当前HCC治疗的最新研究热点在于系统治疗或局部治疗相关的联合治疗。     

Argon plasma coagulation with atezolizumab and chemoradiation in lung pleomorphic cancer showed a remarkable response: Case report

Rationale:Lung pleomorphic carcinoma (LPC) is generally resistant to chemotherapy or radiotherapy. However, a combination of immune checkpoint inhibitors and radiotherapy has a remarkable efficacy against LPC.Patient Concerns and Diagnoses:Here, we report the case of a 50-year old man diagnosed with progressive LPC. The tumor invaded the carina and predominantly obstructed the right main bronchus; therefore, a combination of palliative chemoradiotherapy and atezolizumab was initiated. However the trachea was gradually obstructed.Intervention and Outcome:Argon plasma coagulation (APC) was performed to prevent tumor invasion. After three APC sessions, the tumor showed a necrotic change and was easily excised using biopsy forceps.Lessons:A combination of chemoradiotherapy, atezolizumab, and APC showed a good efficacy, and the patient had a good response to atezolizumab maintenance therapy. Multidisciplinary treatments, such as a combination of immune checkpoint inhibitors and APC, could have synergistic efficacy in lung cancer.     

Favorable response to second-line atezolizumab and bevacizumab following progression on nivolumab in advanced hepatocellular carcinoma: A case report demonstrating that anti-VEGF therapy overcomes resistance to checkpoint inhibition

Rationale:Advanced hepatocellular carcinoma (HCC) remains a deadly disease in part due to decades of limited therapeutic options. With recent advances in our understanding of the tumor biology, several promising treatment strategies involving targeted and immunotherapies have emerged. However, enhancing their modest efficacy in HCC and other gastrointestinal malignancies is essential to improving survival.Patient concerns:A man in his late 50s with a history of type 2 diabetes mellitus and morbid obesity initially presented with progressive abdominal pain and anorexia prompting an abdominal computed tomography scan that revealed a large solitary liver mass with extensive local involvement.Diagnoses:Although there were features consistent with a primary gastric tumor on subsequent endoscopic evaluation leading to early diagnostic uncertainty, his clinical picture, including a dominant liver mass, immunohistochemical staining profile, and significantly elevated alpha fetoprotein ultimately favored HCC.Interventions:The patient received palliative systemic therapy with infusional fluorouracil for a presumed gastric primary, however restaging scans after 3 cycles demonstrated disease progression. The consensus from a multidisciplinary discussion was that his pathology was more consistent with primary HCC. He was subsequently started on nivolumab with a partial response, although after 5 months, he progressed prompting initiation of second-line atezolizumab and bevacizumab with a favorable response.Outcomes:The addition of atezolizumab and bevacizumab led to a sustained biochemical and radiographic response that appeared to overcome the resistance to nivolumab monotherapy. Aside from several mild immune-related adverse effects, his quality of life has greatly improved and he has tolerated treatment well to date.Lessons:Our findings suggest that vascular endothelial growth factor inhibition can overcome resistance to checkpoint inhibition in advanced HCC by resulting in a unique synergy that has never before been described in patients. The biological rationale for this response is likely attributable to the immunomodulatory effects of antiangiogenic agents, promoting an immunostimulatory microenvironment that can be exploited by immune checkpoint inhibitors for more effective antitumor activity. Given the considerable benefit patients may derive following progression on first-line treatment, it is important to consider this strategic combination of therapies which can ultimately lead to improved patient outcomes.     

Advanced hepatocellular carcinoma with response to lenvatinib after atezolizumab plus bevacizumab

Rationale:Various treatments are available for treating hepatocellular carcinoma (HCC). The immune checkpoint inhibitor combination of atezolizumab plus bevacizumab was recently approved for the treatment of unresectable HCC, but there are few reports on the failure of the combination treatment. Here, we present a case of unresectable HCC with adrenal metastasis that was eventually operated on after lenvatinib (LEN) treatment that followed failed treatment with atezolizumab plus bevacizumab.Patient concerns:A 68-year-old man was diagnosed with non-alcoholic steatohepatitis-based HCC with adrenal metastasis.Diagnosis:Cirrhosis was classified as Child-Pugh score of 5. HCC was diagnosed as Barcelona Clinic Liver Cancer stage C.Interventions:We initiated treatment with atezolizumab plus bevacizumab. Liver dysfunction appeared 2 days after the first administration but was improved by intravenous rehydration and did not appear after the second course. The HCC shrank, but the adrenal metastasis grew bigger after the fourth course, so we changed the therapy to LEN. After HCC and adrenal metastasis were necrotic by LEN, conversion surgery was performed.Outcomes:After successful conversion therapy, the general condition of the patient was good, and has been carefully followed for 4 months to date without any evidence of further recurrences.Lessons:This case showed that even if atezolizumab plus bevacizumab is not effective, multidisciplinary treatment such as LEN and conversion surgery is possible. Given the efficacy of LEN after atezolizumab plus bevacizumab, it is important to consider that there is a possibility of cure even when first-line treatment is not effective for a patient with unresectable HCC.     

Efficacy of iron chelator deferoxamine for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma patients refractory to current treatments

The prognosis of advanced hepatocellular carcinoma (HCC) remains poor. For patients with advanced HCC, the multikinase inhibitor sorafenib is recommended as the current standard of care. In contrast, hepatic arterial infusion chemotherapy (HAIC) is one of the recommended treatments in Japan. However, in Japan, the use of sorafenib versus hepatic arterial infusion chemotherapy for first-line treatment remains unclear, because there have been no randomized controlled trials comparing HAIC with sorafenib. HAIC can substantially prolong survival in patients with complete and partial response, while non-responders may be suitable candidates for sorafenib therapy. Nonetheless, HAIC non-responders with deteriorated liver function currently have no treatment options. We have shown the efficacy of an alternative therapy, the iron chelator deferoxamine, for advanced HCC patients with deteriorated liver function. Iron chelators may have future therapeutic possibilities in this patient population.     

Targeted systemic therapies for hepatocellular carcinoma: clinical perspectives, challenges and implications

Hepatocellular carcinoma(HCC) is a lethal disease in most patients,due to its aggressive course and a lack of effective systemic therapies for advanced disease.Surgical resection and liver transplantation remain the only curative options for a small subset of patients.Few patients with HCC are diagnosed early enough to be eligible for curative treatment.Angiogenesis inhibition is a natural therapeutic target for all solid tumors,but particularly for the highly vascularized HCC tumors.With the approval of the targeted agent sorafenib,there are now additional options for patients with HCC.Although sorafenib does produce some improvement in survival in HCC patients,the responses are not durable.In addition,there are significant dermatologic,gastrointestinal,and metabolic toxicities,and,as importantly,there is still limited knowledge of its usefulness in special subpopulations with HCC.Other angiogenesis inhibitors are in development to treat HCC both in the first-line setting and for use following sorafenib failure;the furthest in development is brivanib,a dual fibroblast growth factor pathway and vascular endothelial growth factor receptor inhibitor.Additional agents with antiangiogenic properties also in phase Ⅱ and Ⅲ development for the treatment of patients with HCC include bevacizumab,ramucirumab,ABT-869,everolimus and ARQ 197.     

Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Sorafenib and lenvatinib are approved for first‐line treatment of patients with advanced hepatocellular carcinoma (HCC), and the efficacy of atezolizumab plus bevacizumab has been demonstrated versus sorafenib. Over time, first‐line treatment frequently fails, and regorafenib, cabozantinib, ramucirumab (for patients with alpha fetoprotein ≥400 ng/mL), nivolumab, pembrolizumab and ipilimumab plus nivolumab are approved for use after sorafenib (but not lenvatinib) treatment in advanced HCC. Given the considerable complexity in the therapeutic landscape, the objective of this review was to summarize the clinical evidence for second‐line agents and provide practical guidance for selecting the best sequential treatment approach. The timing and sequencing of treatment switches are key to optimizing patient outcomes in advanced HCC, and decisions should be informed by reasons for discontinuation of previous therapy and disease progression. It is important not to switch too soon, because sequential treatment benefit may then be lost, nor should switching be delayed too long. Effectiveness, safety and tolerability, patient quality of life, route of administration, dosing regimen, drug class, molecular target and individual patients’ characteristics, including comorbidities, inform the selection of second‐line systemic treatment, independently of the aetiology of HCC, tumour stage and the response to previous treatment. Biomarkers predictive of treatment effectiveness are of great value, but currently biomarker‐driven patient selection is possible only in the case of ramucirumab. The approval of new combination therapies for advanced HCC in the first‐line setting will further increase the complexity of decision‐making. However, the important factors will remain the individual patient’s characteristics and preferences.