Hepatocellular carcinoma (HCC)

With approximately 6,000 new cases recorded annually in cancer registries, HCC is the most common malignant tumor of the liver in Germany. About three-quarters of cases occur in men. According to cause-of-death statistics, approximately 4,300 deaths per year have been attributed to HCC in recent years. Age-standardized incidence and mortality rates have recently shown a slight decline among men, whereas they have remained unchanged among women (Figure 1).

The median age at diagnosis is 71 for men and 74 for women. Figure 2 shows the current incidence rates in Germany by age and sex.

The median overall survival (OS) was most recently (2016–2020) 13 months for those under 60, 12 months for those aged 60 to 74, and 8 months for those over 75 years of age. The relative survival rates—which compare the observed OS to survival in the general population of the same age and sex—are 20% at 5 years and 13% at 10 years. The relative 5-year OS has thus increased by about 5% over the past 10 years.

According to epidemiological data from GLOBOCAN, 905,700 new cases of primary liver cancer and 830,200 deaths were recorded worldwide in 2020 [70], with cholangiocarcinomas included in these figures. The incidence has been rising globally in recent years. Up to 80% of global cases emerge in Southeast Asian countries and sub-Saharan African countries. The high incidence of chronic hepatitis B virus infection plays a decisive role here.

Liver cirrhosis is considered the most important risk factor for the development of HCC; in Germany, this is primarily due to excessive alcohol consumption and/or chronic hepatitis C. The annual risk of developing HCC in patients with existing liver cirrhosis is 2.5% per year [12]. However, this rate varies depending on the underlying cause and is 2% for hepatitis B-related cirrhosis and 3–8% for hepatitis C-related cirrhosis. For non-alcoholic steatohepatitis (MASLD, previously referred to as NAFLD) and non-alcoholic steatohepatitis (MASH, previously NASH), rates ranging from 0.004% to 7.6% have been reported [94].

In cases of chronic hepatitis B or C, as well as in MASLD, the risk of developing HCC exists even in the absence of cirrhosis and is 0.12% and 1.3%, respectively.

The underlying risk factors for primary hepatocellular carcinoma vary widely worldwide [31]. For example, alcohol consumption is the cause in 32% of cases in Western Europe, 53% in Eastern Europe, but only 13% in North Africa and the Middle East. In Latin America and West Africa, chronic hepatitis B is the dominant cause, accounting for 45% in each region, while in Western Europe, North Africa, and the Middle East, chronic hepatitis C is the leading cause of HCC, accounting for 44% in each region, and in the Asia-Pacific region, it accounts for as much as 55%. MASH and MASLD are significantly on the rise in Europe, as well as in the United States and China, as causes of liver cirrhosis and HCC [61, 94].

Patients with hemochromatosis have a 1.8-fold increased risk of HCC compared to patients with other forms of chronic liver disease [28].

In addition to nutritional and infection-related causes, genetic polymorphisms in the germline play a role in the risk of developing HCC. For example, the phospholipase PNPLA3 variant rs738409 and the TM6SF2 variant rs58542926 are associated with an increased risk of HCC in patients with alcohol-related liver cirrhosis. In contrast, a polymorphism at locus rs2242652(A) of the telomerase reverse transcriptase TERT is associated with relative protection against the development of HCC [87, 12]. Various polygenic risk scores have been developed to estimate the risk of HCC developing in a MASH/MASLD context [8, 52]; these scores can describe the probability of HCC developing from cirrhosis depending on the etiology of liver damage and the specific population studied (Asian vs. non-Asian).

TP53, TERT, and the activation of the hepatic WNT signaling pathway are considered molecular pathogenic drivers of HCC development [74, 87].

Key measures for reducing HCC risk in Western European countries are listed in Table 1.

For the early detection of HCC, regular screening is recommended for patients with advanced liver fibrosis, such as those with chronic HCV infection or MASLD, as well as for patients with rare predisposing hereditary disorders such as acute intermittent porphyria, hereditary hemochromatosis, glycogen storage disease, Gaucher disease, or tyrosinemia type I [3].

For patients with liver cirrhosis, an HCC screening program involving qualified ultrasound plus AFP measurement every 6 months is recommended. Regular measurement of AFP levels appears appropriate, as AFP levels ≥ 20 ng/ml indicate HCC < 5 cm with a sensitivity of 49–71% and a specificity of 49–86% [80]. For screening patients with alcohol-related liver disease, MASLD, or cirrhosis following cured HCV infection, a lower AFP cutoff of 10 ng/ml has recently been advocated [111]. At the same time, a retrospective Korean analysis of >185,000 HCC patients showed that regular AFP testing improved OS [56]. This effect was particularly pronounced in patients with hepatitis B. However, a prospective phase III study demonstrated that the use of the GALAD score (gender, age, AFP L3, AFP, and Des-γ-carboxyprothrombin) or the GAAD score (excluding AFP L3) instead of AFP measurement alone at 6-month screening intervals significantly improved early HCC detection in patients with cirrhosis [109, 115]. Other complex scores, such as HES-V2, have already been validated in phase III studies in comparison to the GALAD score, among others [101].

Depending on the quality of the available ultrasound, switching to MRI—which generally has a higher sensitivity—is also recommended [102].

A randomized trial demonstrated an improvement in the early detection of HCC, as well as in surgical operability and OS, through screening [95]; these results were confirmed in a meta-analysis of 59 studies involving 145,396 patients [78]. Through structured screening of patients with liver cirrhosis, nearly twice as many patients were detected at an early stage of HCC (hazard ratio [HR] 1.83) and treated with curative intent (HR 1.83). This also had a significant impact on OS (HR 0.67) [78].

In patients with hemochromatosis, HCC can develop even in the absence of cirrhosis; therefore, screening is recommended as soon as the extent of liver fibrosis reaches a certain severity level (METAVIR F3, Ishak Stage 4–5) [24].

Patients with chronic hepatitis B and a non-cirrhotic liver represent a special case. In this group, the PAGE-B score was validated as a prognostic predictor for Caucasian patients [57] (Table 2). A PAGE-B score of <10 had a negative predictive value of 99% for the occurrence of HCC within the next 5 years. For patients with HBsAg-positive hepatitis B and cirrhosis, the AASLD guidelines recommend ultrasound and AFP testing every 6 months.

Diagnostic categories for confirming the diagnosis through imaging using dynamic MRI (preferably with hepatocyte-selective contrast agent [117, 120, 129]) according to the Liver Imaging and Reporting System (LI-RADS) include tumor size, contrast agent kinetics (arterial and washout phases), capsular enhancement, and growth dynamics (≥50% increase in ≤6 months, ≥100% increase in >6 months, new mass ≥10 mm). These criteria result in the LI-RADS categories [38], which are currently applied in their revised version (rLI-RADS) [34].

Despite the high diagnostic accuracy, however, approximately 9% of cases result in false-negative assessments when imaging alone is used [18]; therefore, histological confirmation should be performed, particularly in patients who are to receive systemic therapy.

The histopathological classification of HCC should be based on the current WHO classification (most recently updated in 2019) [51], which requires a biopsy. The diagnosis is based on defined histomorphological criteria for hepatocellular differentiation (trabecular growth, bile production, medium- to large-sized cells with round nuclei and prominent nucleoli) and malignancy (architectural disruption with reduction of the reticulin fiber network, nuclear atypia, vascular invasion). Specific subtypes (steatohepatitic, clear-cell, macrotrabecular, cirrhotic, neutrophil-rich, lymphocyte-rich, chromophobic, fibrolamellar) can be identified based on their characteristic morphology, in some cases on molecular alterations (e.g., the DNAJB1-PRKACA fusion in fibrolamellar HCC), and on the appearance of the non-tumorous liver parenchyma. Immunohistochemical expression of arginase-1 and HepPar1 is helpful in distinguishing non-hepatocellular tumors, such as metastases, and in determining the lineage differentiation in combined HCC-cholangiocarcinomas. A particular challenge in biopsy is distinguishing highly differentiated HCC from benign, preinvasive, and early hepatocellular lesions. These include focal nodular hyperplasia (FNH), hepatocellular adenoma, dysplastic nodules, early-stage HCC (<2 cm in diameter, well-differentiated, non-encapsulated), and small, progressive HCC, in which intra- and extrahepatic metastases may occur [35]. In such cases, an immunohistochemical panel using the antibodies glypican-3, HSP70, and glutamine synthetase may be helpful [87]. If ≥2 of these markers are positive, the specificity for an HCC diagnosis is 100% [22, 82]. The detection of mutations in the hTERT promoter also supports the diagnosis of HCC.

The histopathological findings of a resected specimen or explant should include the extent of the tumor (staging) according to the current TNM classification, its type and degree of differentiation (grading), and the presence or absence of tumor tissue at the resection margin (R classification). The template from the International Collaboration on Cancer Reporting (ICCR) is recommended for standardized reporting [58]. Grading has prognostic relevance following resection and transplantation; a three-tiered system is currently recommended.

Molecular testing is not (yet) necessary for the treatment of HCC. However, molecular pathological methods can be used to determine the entity and grade of the tumor. Molecular testing to identify potential therapeutic targets is not standard practice for curably treatable HCC, but may be useful as an individualized therapeutic attempt or for inclusion in clinical trials. Potential targets for molecularly targeted systemic therapies are summarized in Table 4 (according to [54]).

Molecular pathological methods can be used to support tumor typing and grading of hepatocellular tumors.

• In analyses of cell-free DNA from circulating blood, molecular alterations were detected in 92.2% of cases, and potential therapeutic targets (TSC1/-2 18%, BRCA1/-2 8%, and PIK3CA 8%) were identified in 37% of cases [19].

• A specific fusion transcript (DNAJB1-PRKACA) is pathognomonic for fibrolamellar HCC and is also being evaluated as a target for molecularly targeted therapy [4].

Typically, molecular sequencing analyses in HCC reveal a low to moderately increased tumor mutational burden (TMB) with an average of 2.9 mutations per megabase (Mut/Mb), corresponding to approximately 40–60 coding somatic mutations. Recurrent genetic alterations include TERT promoter mutations (50–60%), TP53 alterations (20–40%), CTNNB1 mutations (15–40%), and ARID1A mutations (10–20%) [87]. In HCC of non-viral etiology, EGFR/FGFR/RAS/MAPK alterations are most commonly found [54, 118].

Activation of oncogenic signaling pathways (Wnt-TGFβ, PI3K-AKT-mTOR, RAS-MAPK, MET overexpression, IGF) is frequently detected, as is FGF19/FGFR4 overexpression [42], which potentially allows for the targeted use of FGFR4 inhibitors.

Determination of MSI/MMR status, TMB, or PD-L1 expression has not yet been established as a routine parameter for the initial diagnosis of HCC. The use of immunotherapy regimens is not currently stratified based on these findings (see chapter 6: Treatment). Routine testing for NTRK fusions is also not indicated for primary diagnosis. However, testing for these molecular pathological alterations may be indicated in the context of deciding on systemic therapy after established standard options have been exhausted. In the presence of a (very rare) NTRK fusion or a TMB >10 Mut/Mb, reference can be made to existing tumor-agnostic approvals for entrectinib, larotrectinib, or pembrolizumab.

Testing for germline mutations is not currently recommended as a routine procedure [32, 53].

Staging of HCC should include a contrast-enhanced CT scan of the thorax and abdomen. If the contrast-enhanced MRI provides diagnostic coverage of the entire abdomen, only a native CT scan of the thorax should be performed. With regard to the morphological aspects of the tumor, imaging analysis methods that take vascularity into account should be used [3]. To assess possible vascular infiltration, which is an important prognostic factor, a contrast-enhanced MRI using gadobutrol (Gadovist®) is recommended. In subsequent evaluations, a liver-specific contrast agent is preferred.

Staging serves to determine the TNM classification, the resulting stage assignment (currently according to the AJCC 8th edition, 2017), the tumor grade and degree of fibrosis, as well as to determine the BCLC stage according to the Barcelona criteria [68] (Table 5). To assess treatment options, it is necessary to determine hepatic functional reserve in cases of liver cirrhosis using the Child-Pugh score [62] (Table 6). Focusing solely on the BCLC stage does not reflect current clinical practice when making treatment decisions. Several studies have shown that the decision made by the multidisciplinary tumor board at the respective center regarding the appropriate therapy for the patient may yield better success rates than a decision based solely on the BCLC score [33, 47].

The indication for liver transplantation (LTx) exists provided that macrovascular invasion and extrahepatic tumor manifestations are ruled out and the patient is generally eligible for LTx. The assignment of a match-MELD score via standard exception [48, 88] is based on the Milan criteria [49], whereby tumors smaller than 20 mm are to be surgically resected, and thus the Milan criteria have been replaced by UNOS T2. The static classification serves solely to prioritize patients on the waiting list.

It is becoming increasingly evident that the dynamic selection criteria (biological response, AFP slope, G3, V+) are more suitable than the static ones.

To determine the appropriate treatment approach, all patients with HCC should be presented at a multidisciplinary tumor board at a center affiliated with a liver transplant center. This requires the participation of qualified specialists from the disciplines of radiology (diagnostic and interventional), radiation oncology, nuclear medicine, pathology, gastroenterology/hepatology, visceral surgery, and hematology/oncology. To make an informed decision, the following information may need to be considered: histopathological findings, radiological findings, infection status (hepatitis), tumor burden (stage and TNM classification according to UICC), BCLC stage, current liver function parameters, AFP level, platelet count, Child-Pugh/ALBI stage in cases of liver cirrhosis, and general condition (Karnofsky or ECOG performance score) may need to be available.

For patients with chronic HBV infection and HCC, guideline-based antiviral therapy is indicated. Tenofovir and entecavir are established as the standard of care in this setting. The indication for antiviral therapy also applies to patients with chronic HCV infection and HCC, adjusted as necessary based on the HCV genotype and the corresponding approval status [59]. In curative-intent treatment, antiviral therapy for HCV infection has been shown to improve OS [13, 59]. This study demonstrates the effectiveness of HBV therapy in reducing late HCC relapses following curative therapy [99].

It is recommended that a liver transplant center be consulted for the initial decision-making process in cases of HCC amenable to curative treatment. This also applies to patients with resectable HCC; however, it is particularly relevant for patients with unresectable HCC and cirrhosis who meet the Milan criteria (BCLC A), but may also apply to patients with surgically resectable or borderline resectable HCC and cirrhosis who meet the Milan criteria [49] [3] (see Table 7). The indication and urgency for a liver transplant must therefore be determined as quickly as possible at a liver transplant center. A transplant may also be indicated outside the UNOS T2 criteria (see Table 7). In Germany, listing based on “Standard Exceptions” (SE) criteria is not possible for these tumors; therefore, other listing options must be evaluated with the respective transplant center (living donation, listing without SE criteria, center-specific offers). This applies in particular to tumors that have responded very well to local and systemic therapy. The level of AFP correlates with transplant outcomes [6], and an AFP level >1,000 ng/ml constitutes a contraindication for liver transplantation [5]. A decrease to < 500 ng/ml (preferably <200 ng/ml) achieved through locoregional or systemic therapy leads to an improved prognosis after transplantation [50].

In patients who are initially ineligible for transplantation but who receive first-line systemic therapy with atezolizumab + bevacizumab, liver transplantation may still be indicated in approximately one-quarter of patients who respond well [133]; in such cases, the patient should be referred back to a liver transplantation center.

When comparing patients who received a liver transplant while meeting the Milan criteria with those who met the Milan criteria only after downstaging, the 10-year OS and the relapse rate are comparable (61.5% vs. 52.1% and 13.3% vs. 20.6%, respectively) [81].

According to the guidelines of the German Medical Association, a de novo HCC may be assumed if the recurrence-free interval exceeds 2 years, which may result in an indication for LTx.

Liver transplantation is not indicated in cases of extrahepatic HCC manifestations and/or macrovascular invasion of the hepatic vessels.

If liver transplantation is indicated, bridging therapy using locoregional treatment (TACE/ablation (see below) or surgical resection) should be pursued. The decision to initiate bridging therapy should always be made in consultation with a transplant center.

Outside of clinical trials, patients with HCC should not receive adjuvant systemic therapy following liver transplantation. This does not preclude the continuation of antiviral therapy for HBV- or HCV-related HCC (see above), which should be decided upon through a multidisciplinary approach.

A prerequisite for primary surgical resection is the possibility of a complete (R0) surgical resection. Portal hypertension (splenomegaly, esophageal varices, ascites, thrombocytopenia) should be ruled out beforehand, if indicated by measuring wedge pressure.

If not all intrahepatic HCC lesions can be completely (R0) surgically resected, a decision should be made prior to treatment regarding the combination with local ablation or embolization procedures (see below) with curative intent.

A retrospective multicenter study from Italy [122] involving 720 patients with early-stage multinodal HCC showed, in a “matched-adjusted” comparison between primary liver resection (n=296), percutaneous RFA (n=240), and TACE (n=184), advantages in 3- and 5-year OS in favor of primary liver resection (3-year OS 71% vs. 65% vs. 49%, 5-year OS 56% vs. 40% vs. 29%).

Liver resection should be performed for a solitary HCC nodule <2 cm in patients with liver cirrhosis who are functionally resectable. For tumors >2 cm, an individualized discussion should take place, in which the tumor’s location, tumor biology, risk of recurrence, and a potential living donor option should be factored into the decision. Liver resection can be performed via open or minimally invasive surgery. If the resection is performed as a bridging procedure to a planned liver transplant, it should be conducted using a minimally invasive approach.

If neoadjuvant or adjuvant systemic therapy is being considered before or after an R0 resection, enrollment in clinical trials is recommended. The current data on this are as follows:

• For adjuvant therapy, the first interim analysis of the treatment with atezolizumab plus bevacizumab in a randomized comparison with follow-up alone (phase III IMbrave 050 trial) demonstrated a significant improvement in progression-free survival (PFS, primary endpoint) [64]; however, this benefit could not be confirmed with longer follow-up. Although the study was not powered for OS, the mature OS data [93] showed no benefit of the treatment compared to follow-up alone; therefore, treatment with atezolizumab plus bevacizumab should not be used as adjuvant therapy.

• Similarly, the adjuvant administration of pembrolizumab in patients with a complete radiological response in the phase III KEYNOTE-937 trial showed no benefit in the primary endpoint of PFS [98].

• Perioperative systemic therapy with nivolumab or nivolumab plus ipilimumab has been shown to be safely feasible; histopathologically, a major pathological response was documented in individual patients following neoadjuvant administration [36]. As of June 2026, there is no EMA approval for this indication.

• In a randomized trial comparing perioperative systemic therapy with camrelizumab plus rivoceranib (also known as apatinib) to surgical therapy alone in 294 patients with Child-Pugh A and primarily resectable HCC, median event-free survival (EFS) improved from 19 to 42 months [124]. There is no EMA approval for this indication; camrelizumab is not yet approved in Germany (as of June 2026).

In the intermediate stage, for unresectable HCC, the indication for intra-arterial therapeutic procedures should first be evaluated. TACE and TARE (or SIRT) are available as locoregional therapeutic options. Both TACE and SIRT/TARE must be administered selectively and in a tumor-targeted manner to preserve the patient’s liver function [107], TACE is typically performed repeatedly, although repeat procedures should be contingent upon evidence of an objective response and the preservation of liver function [11, 86]. This decision should be made by a multidisciplinary tumor board and reevaluated no later than after two treatments. Meta-analyses have found the two procedures to be equivalent in terms of OS; however, TARE was significantly superior to TACE in terms of time to progression [10]. A monocenter, prospective study comparing TARE with TACE in the intermediate stage serves as an example [100]. The superior TTP of TARE compared to TACE (HR 0.36) led to the study’s termination following a planned interim analysis after 72 patients. TACE maintained its superiority in both tolerability and OS. Such consistent data from different studies are particularly important, especially in the bridging phase to transplantation.

In the results of the EMERALD-1 study, first presented in 2024, a significant advantage of the combination of TACE with durvalumab and bevacizumab compared to TACE alone was observed in 616 HCC patients with Child-Pugh A to B7 in terms of PFS (HR 0.77, 95% CI 0.61–0.98, p=0.032), but no benefit in OS [40], even in the longer-term data analysis [132], so this treatment modality does not represent a new standard of care. Similarly, the randomized comparison of lenvatinib + pembrolizumab + TACE versus placebo + TACE (LEAP-012) in 480 HCC patients with Child-Pugh A in first-line therapy showed a significant PFS benefit for the combination therapy (HR 0.66, 95% CI 0.51–0.84; p=0.0002) [44], but no OS benefit. The EMERALD-3 study (STRIDE + TACE vs. STRIDE + TACE + lenvatinib vs. TACE alone) demonstrates a clear PFS benefit and a potential OS benefit—which has not yet been confirmed—for the combination arms [131]. These data should be discussed with patients in the intermediate stage who have adequate liver function and a good general condition, and may represent a strategy for bridging to a liver transplant (LTx).

Systemic drug therapy using tyrosine kinase inhibitors (TKIs; sorafenib, lenvatinib, regorafenib, or cabozantinib) or immunotherapies (atezolizumab, durvalumab, pembrolizumab, tislelizumab, nivolumab, ipilimumab, tremelimumab) or anti-angiogenic antibodies (bevacizumab, ramucirumab, sometimes in combination therapies) has been established as the standard of care since the publication of the results of the SHARP study [42]. While the SHARP trial compared sorafenib with placebo, subsequent studies compared the new therapeutic approach against sorafenib and/or lenvatinib as the control arm. For ethical reasons, no further randomized comparisons with placebo were conducted; however, no randomized comparisons of newer therapeutic approaches against one another were performed either, which prevents a nuanced assessment of the benefits of the numerous newer treatment options.

In principle, for patients for whom the liver transplant center does not consider a curative treatment option to be available, treatment with atezolizumab plus bevacizumab, durvalumab with or without tremelimumab, nivolumab with ipilimumab, as well as with sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab is possible. For patients who are initially ineligible for transplantation and who are treated with first-line systemic therapy consisting of atezolizumab plus bevacizumab, liver transplantation may still be indicated in approximately one-quarter of patients who show a good response [133]; in such cases, the patient should be referred back to a liver transplant center.

For Child-Pugh stage B, data are available from observational studies for sorafenib and from smaller phase II studies for ICI. A meta-analysis of previously published reports on PD-1 antibodies in patients at this stage confirmed an acceptable overall safety profile for these agents, although with higher associated morbidity than in patients with Child-Pugh A cirrhosis [89]. Similarly, in a retrospective analysis of 343 patients with Child-Pugh B (EU, USA, Asia) from 2017–2022, treatment with atezolizumab plus bevacizumab or nivolumab resulted in a significant improvement in median OS from 4 to 7.5 months compared to best supportive care (HR 0.59, p<0.001) [106]. Focusing on patients with Child-Pugh B7 (see Table 6), it was reported that the subgroup of patients with slightly increased bilirubin, moderately reduced albumin, mild ascites, and no hepatic encephalopathy can achieve a clinical outcome comparable to that of Child-Pugh A patients when treated with atezolizumab and bevacizumab [112]. Accordingly, systemic therapy may also be considered for selected patients with Child-Pugh B7 who are in good general condition (ECOG PS≤1) [3, 32, 107]. In patients with Child-Pugh C cirrhosis, systemic drug therapy for HCC is not indicated.

Systemic therapy should not be continued beyond the point at which treatment failure is confirmed; however, following a decision by a multidisciplinary tumor board, it should be switched to another systemic therapy if indicated.

If a patient with HCC that is not initially amenable to curative treatment, but without distant metastases, shows a very good response to systemic anticancer therapy, it is recommended that this case be presented again to the tumor board to discuss the possibility of secondary, potentially curative therapy [3].

The currently available study results on the above-mentioned agents for first-line systemic therapy in HCC can be summarized as follows:

• In the combination of atezolizumab plus bevacizumab versus sorafenib, an overall response rate of 27.3% versus 11.9% was observed, along with a PFS of 6.8 versus 4.3 months (HR 0.66; p<0.001), and a 1-year OS of 67.2% vs. 54.6% [26]. Longer follow-up revealed a median OS of 19.2 vs. 13.4 months (HR 0.65; p<0.001) [69]. These results were also replicated under practical “real-world” conditions [29].

• In a phase Ib/II study involving 59 patients with Child-Pugh A an improvement in response rate, PFS, and OS compared to atezolizumab-bevacizumab [104]; however, the prospective randomized IMbrave152/SKYSCRAPER-14 study showed no benefit compared to atezolizumab/bevacizumab alone [105].

• Adding ipilimumab to the atezolizumab/bevacizumab combination did not result in an improvement in response in a randomized comparison with atezolizumab/bevacizumab (“TRIPLET HCC”) [116].

• The combination of tremelimumab and durvalumab (“STRIDE” regimen) (HIMALAYA study) versus sorafenib yielded a response rate of 20.1% versus 5.1% (for the STRIDE regimen), a PFS of 3.8 versus 4.1 months (for sorafenib) (HR 0.90 for STRIDE) and an OS of 16.4 vs. 13.8 months (HR 0.76; p=0.0008) [1]. The analysis of patient-reported outcomes (PROs) showed an improvement in clinical symptom burden and quality of life for patients receiving tremelimumab plus durvalumab compared with sorafenib [119].

• The combination of nivolumab plus ipilimumab (CheckMate-9DW study), tested against lenvatinib or sorafenib, showed a response rate of 36% vs. 13% in 668 patients, a PFS of 7.5 vs. 7.5 months (HR 0.72) and an OS of 23.7 vs. 20.6 months (HR 0.79; p=0.018) [21].

• In the CARES-310 trial, camrelizumab plus rivoceranib (also known as apatinib) versus sorafenib achieved an improved PFS of 5.6 vs. 3.7 months (HR 0.52; p<0.0001) and significantly longer OS of 22.1 vs. 15.2 months (HR 0.62; p<0.0001). Overall, treatment-related toxicity was increased with this combination, although no negative impact on patients’ quality of life was observed [63].

• Compared with sorafenib, lenvatinib demonstrated a PFS of 7.4 vs. 3.7 months and an OS of 13.6 vs. 12.3 months (HR 0.92) [39]. Similar to sorafenib, more recent phase III studies with lenvatinib achieved an OS of up to 20 months.

• Compared with placebo, sorafenib demonstrated a response rate of 2.3%, progression-free survival (PFS) of 4.9 vs. 4.1 months, and a significantly improved OS of 10.7 vs. 7.9 months (HR 0.69; p<0.001) [42]. In recent phase III trials in which sorafenib served as the control arm, an OS of 13–15 months was achieved, which is likely attributable primarily to the use of evidence-based second-line therapies.

• The combination of lenvatinib with pembrolizumab versus lenvatinib plus placebo in first-line therapy among 794 patients with Child-Pugh A (LEAP-002) did not result in a significant improvement in OS or PFS with the combination therapy [114].

• In a comparison of the immunotherapy/TKI combination of atezolizumab plus cabozantinib with sorafenib, the COSMIC study showed a significantly prolonged PFS of 6.9 vs. 4.3 months (HR 0.63; p=0.0012), but comparable OS of 16.5 vs. 15.5 months (HR 0.90; p=0.44) [91].

• Another option for first-line systemic therapy, toripalimab plus bevacizumab, was randomized against sorafenib in the phase III HEPATORCH trial. In 326 Asian patients with Child-Pugh A, the combination of the PD-1 antibody with bevacizumab resulted in a significant improvement in PFS and OS [121]. Toripalimab is approved in the EU for the treatment of nasopharyngeal and esophageal carcinoma.

• Despite differences in study results—which are likely due primarily to study-specific selection criteria—meta-analyses show no significant difference between the various combination therapies tested [15, 30, 113].

• Based on current data, first-line therapy with an ICI as monotherapy is not superior to sorafenib:

  • Durvalumab vs. sorafenib [1]—however, due to its non-inferiority to sorafenib, durvalumab is approved by the EMA as monotherapy for first-line treatment of HCC.

  • Tislelizumab vs. sorafenib [66]

  • Nivolumab vs. sorafenib [91]

    • The FDA’s previously granted accelerated approval of nivolumab for this indication was revoked in July 2021.

• In a randomized phase III trial from China, the combination of lenvatinib with TACE demonstrated a significant improvement in OS (17.8 vs. 11.5 months) and PFS (10.6 vs. 6.4 months), as well as a better response rate according to mRECIST (54.1% vs. 25.0%) in patients with advanced-stage disease [60]. However, the use of local therapies for BCLC C is not considered an accepted standard of care [3] and should only be performed following a multidisciplinary discussion in the tumor board.

• The combination of camrelizumab and rivoceranib (also known as apatinib) with TACE resulted in a significant improvement in PFS (3.2 vs. 10.8 months) compared to camrelizumab and rivoceranib alone in a randomized phase II trial (n=200 patients). OS was positively influenced by the combination therapy; however, the follow-up period is still too short and fewer than 50% of OS events have occurred, so a definitive assessment cannot yet be made [130]

• In intermediate-risk patients with relapse following prior primary resection, a randomized phase III trial comparing local ablation with TACE alone versus a combination of sorafenib and TACE demonstrated a significant prolongation of median OS from 15 to 22 months (HR 0.55, p<0.001) was achieved with the combination therapy [103].

• According to the results of the CATCH-IT study, treatment with ICI can be used in patients with HIV infection with comparable efficacy and safety to that observed in HIV-negative patients [23].

Consequently, for first-line systemic therapy in patients who cannot be treated curatively with Child-Pugh stage A cirrhosis (5–6 points; see Table 6) and no contraindications, the combination of atezolizumab plus bevacizumab, or durvalumab plus tremelimumab, or nivolumab plus ipilimumab should be used until radiologically detectable tumor progression occurs. Extending this recommendation to individual patients in Child-Pugh stage B7 requires a decision by the multidisciplinary tumor board on a case-by-case basis.

For patients with contraindications or intolerance to these agents, lenvatinib (or sorafenib) should be used as first-line monotherapy (see figure 5).

Following failure of first-line systemic therapy, second-line therapy should be initiated. Phase III studies have demonstrated the efficacy of regorafenib, cabozantinib, and ramucirumab following failure of sorafenib therapy. For patients who have not been treated with sorafenib, no formal phase III data are currently available; however, treatment with the approved agents is recommended, particularly for patients with well-preserved liver function. To date, no randomized comparisons between the TKIs have been conducted for this indication. The addition of the PD-L1 checkpoint inhibitor atezolizumab to second-line therapy with lenvatinib or sorafenib did not demonstrate an OS benefit (primary endpoint) in the IMbrave251 study [123].

None of the aforementioned immunotherapies (atezolizumab, pembrolizumab, durvalumab, nivolumab, ipilimumab, tremelimumab) are approved for second-line therapy following TKI failure. If a patient did not receive immunotherapy-based treatment in the first-line setting (e.g., due to relative contraindications), this option may be considered in the treatment sequence. Studies conducted to date have yielded the following results:

• In the Checkmate-040 study, the combination of nivolumab plus ipilimumab following prior treatment with sorafenib demonstrated a response rate of approximately 30% [90].

• Pembrolizumab monotherapy, in a randomized comparison with placebo, resulted in a PFS of 3.0 vs. 2.8 months and an OS of 13.9 vs. 10.6 months [27].

• In Asian patients who had previously received sorafenib or oxaliplatin-based chemotherapy, pembrolizumab monotherapy resulted in a response rate of 12.7% vs. 1.3%, a PFS of 2.6 vs. 2.3 months, and an OS of 14.6 vs. 13.0 months compared with placebo [65].

However, the VEGFR2 inhibitor ramucirumab is approved as monotherapy following sorafenib pretreatment for patients with an AFP level of ≥400 ng/mL. While no significant benefit was observed in this indication among unselected patients compared with placebo [97], a follow-up study demonstrated a significant OS benefit (8.5 vs. 7.3 months) in patients with a baseline AFP level of ≥400 ng/mL. PFS was also significantly prolonged, at 2.8 vs. 1.6 months [96].

The available TKIs (following failure of sorafenib) include lenvatinib and cabozantinib, regorafenib and ramucirumab (for AFP ≥400 ng/mL), and (following failure of lenvatinib) sorafenib and cabozantinib (see Figure 6). Lenvatinib is not approved for second-line therapy following sorafenib failure.

Second-line therapies are also generally restricted to patients with adequate general health (ECOG ≤1) and Child-Pugh A cirrhosis; such therapy may be considered for Child-Pugh B7 (7 points according to Table 6) only in selected individual cases.

Experimental treatment options that can be derived from molecular pathology findings—such as dostarlimab for MSI-H/dMMR, selpercatinib upon detection of a RET fusion, larotrectinib or entrectinib upon (extremely rare) detection of an NTRK fusion, or pembrolizumab or nivolumab plus ipilimumab in cases of increased tumor mutation burden [53]—provided that ICI has not been used previously—are case-by-case decisions outside established treatment standards that may be recommended by a molecular tumor board.

Atezolizumab is a humanized IgG1 antibody targeting PD-L1 and belongs to the class of ICIs. It is approved for the treatment of HCC [27] in combination with bevacizumab, as well as for a broad spectrum of other malignant neoplasms. For use in HCC, evidence of PD-L1 expression is not required. As with other ICI targeting PD-1 or PD-L1, immune-mediated adverse effects such as hepatitis, pneumonitis, colitis, endocrinopathies, or skin reactions have been documented in clinical trials, as well as fatigue, which can be severe in some cases. There is a risk of exacerbation of a pre-existing autoimmune disease. No clinically significant pharmacological interactions with other active substances have been reported; however, the efficacy of atezolizumab is expected to be impaired following prior administration of immunosuppressive medications.

See Chapter 7.13 Rivoceranib.

Bevacizumab is a monoclonal, antiangiogenic antibody directed against the vascular endothelial growth factor (VEGF). The prescribing information for atezolizumab indicates approval in combination with bevacizumab for first-line treatment of HCC, whereas this indication is absent from the prescribing information for the various bevacizumab formulations. Adverse reactions (grade 3 or 4) that occurred in more than 5% of patients in the registration studies were hypertension and proteinuria. Rarer critical complications include arterial thromboembolic events and gastrointestinal perforations. The note in the guidelines regarding the risk of bleeding in the presence of esophageal varices must be observed.

Bevacizumab is proteolytically degraded in the body. It is not eliminated via the kidneys or the liver. Therefore, it is unlikely that other drugs will have a significant pharmacokinetic effect on the action of bevacizumab. Cases of microangiopathic hemolytic anemia have been reported in patients receiving combination therapy with bevacizumab and sunitinib; this is also noted in the prescribing information for bevacizumab.

Cabozantinib is a multikinase inhibitor. In addition to the VEGFR1, VEGFR2, and VEGFR3 kinases, it also inhibits AXL and MET. Cabozantinib is approved for second-line treatment following failure of sorafenib in hepatocellular carcinoma (prolonged OS compared to placebo) as well as in renal cell carcinoma and differentiated thyroid carcinoma. In first-line therapy, no improvement in OS was observed when used in combination with atezolizumab compared to sorafenib [92]. The most commonly reported adverse effects in larger clinical trials of cabozantinib monotherapy were palmar-plantar erythrodysesthesia (17%), hypertension (16%), diarrhea (10%), and fatigue (10%).

Cabozantinib exhibits very high plasma protein binding. As a result, it can displace other drugs that are strongly bound to plasma proteins from their plasma protein binding sites. In the case of drugs with a narrow therapeutic index, this can lead to an increase in both desired and undesired effects if their metabolic and excretion pathways are simultaneously impaired. When cabozantinib is taken with a very high-fat meal, its oral bioavailability is increased by 57% compared to when taken on an empty stomach. Cabozantinib is metabolized primarily by CYP3A4. Concomitant treatment with cabozantinib and strong CYP3A4 inducers may reduce the systemic availability of cabozantinib and thus its clinical efficacy. Concomitant treatment with cabozantinib and strong CYP3A4 inhibitors may increase the incidence of adverse effects. Concomitant use of cabozantinib with drugs that are strong CYP3A4 inducers or CYP3A4 inhibitors should be avoided. Throughout the entire duration of treatment with cabozantinib, patients should avoid consuming grapefruit, grapefruit-like fruits (e.g., pomelo, bitter orange), and preparations containing them. Myelosuppression caused by cabozantinib, which occurs very frequently, may be exacerbated by the concomitant use of other myelosuppressive drugs. Since electrolyte disturbances have been observed very frequently during therapy with cabozantinib, concomitant treatment with cabozantinib and drugs that prolong the QTc interval may increase the risk of polymorphic ventricular arrhythmias, known as “torsade de pointes.” During treatment with cabozantinib, attention should be paid to a possible decrease in the levels of individual or all blood cell lines. Appropriate measures should be taken as necessary. Concomitant treatment with cabozantinib and drugs that prolong the QTc interval should be avoided. If this is not possible, care should be taken to maintain electrolyte balance, and the QTc interval should be monitored regularly. Taking cabozantinib may lead to bleeding, which can sometimes be severe. This risk is increased by the concomitant administration of cabozantinib with anticoagulants. During concomitant treatment with cabozantinib and anticoagulants, coagulation-related laboratory parameters should be monitored regularly. Cases of gastrointestinal perforation have been reported in clinical trials. This risk may be increased by the concomitant use of cabozantinib with substances known to carry a risk of gastrointestinal perforation. Concomitant treatment with cabozantinib and drugs associated with a risk of gastrointestinal perforation should be avoided.

Camrelizumab is a humanized IgG4 monoclonal antibody targeting PD-1 that belongs to the class of ICIs. It has not yet been approved in the EU. Camrelizumab was evaluated in combination with rivoceranib (also known as apatinib) for first-line treatment of HCC compared to sorafenib in the CARES-310 study [63], where it demonstrated a benefit in OS. In early August 2024, the EMA granted “Orphan Drug” designation to this combination for first-line treatment of HCC. In monotherapy for HCC, the main treatment-related adverse effects reported were vascular skin reactions (up to 70%), proteinuria (23%), elevated transaminases and bilirubin (15–20%), and thrombocytopenia (15%).

Serious pharmacological interactions are not expected due to the properties of camrelizumab; no reliable data are currently available on this topic.

Durvalumab is a humanized IgG1 monoclonal antibody against PD-L1 and belongs to the class of ICIs. It is approved for the treatment of small-cell and non-small-cell lung cancer, as well as hepatocellular and biliary carcinomas. For HCC, it is approved as monotherapy and in combination with tremelimumab for first-line therapy. When used as monotherapy for HCC, severe treatment-related adverse events were reported in 8.2% of patients [1]. As with other ICIs, immune-mediated adverse events such as pneumonitis, colitis, endocrinopathies, skin reactions, hepatitis, pancreatitis, and others have been documented with the use of durvalumab. There is a risk of exacerbation of pre-existing autoimmune diseases. In addition, fatigue and gastrointestinal side effects are frequently reported. No clinically relevant pharmacological interactions with other active substances have been identified; however, the efficacy of durvalumab is expected to be impaired following prior administration of immunosuppressive medications.

Entrectinib is a potent inhibitor of neurotrophic tropomyosin receptor kinases (NTRK) A, B, and C and is approved for the treatment of NTRK-fusion-positive tumors as well as ROS1-mutated non-small cell lung cancer. Across three cross-entity studies, the following adverse effects were reported: taste disturbances, constipation, diarrhea, fatigue, confusion, elevated serum creatinine, dysesthesia, nausea, vomiting, arthralgia, myalgia, and weight gain, as well as isolated cases of severe neurotoxicity. QT prolongation may also occur.

Concomitant use of strong or moderate CYP3A inhibitors (e.g., ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, grapefruit, or bitter orange) should be avoided; if unavoidable, the dose of entrectinib should be reduced in accordance with the prescribing information. Concomitant use of strong CYP3A4/PGP inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John’s wort, apalutamide, ritonavir) should be avoided. Entrectinib may inhibit P-glycoprotein; however, no clinically relevant effects, e.g., on digitoxin, have been observed.

Ipilimumab is a medication belonging to the class of ICIs. It blocks the inhibitory T-cell regulator CTLA-4, thereby enhancing the body’s own immune response. It is approved for first-line treatment of HCC, as well as for the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, malignant pleural mesothelioma, squamous cell carcinoma of the esophagus, and colorectal cancer. Except for melanoma, this approval is contingent upon combination with nivolumab. In the phase I/II CheckMate 040 study on HCC treatment in combination with nivolumab [90], treatment-related adverse events were reported in 70–94% of patients across three different dosage regimens. The most common events included skin reactions, gastrointestinal symptoms such as diarrhea, and immune-mediated inflammatory reactions or organ dysfunction. Interstitial pneumonitis occurred in 10% of patients.

No clinically relevant pharmacological interactions with other active substances were observed; however, administration of immunosuppressive medications prior to the start of ipilimumab therapy is expected to impair the efficacy of ipilimumab.

Larotrectinib is a selective NTRK inhibitor approved for the treatment of NTRK-fusion-positive tumors. Clinical trials have reported the following side effects: fatigue, elevated liver enzymes, confusion/dizziness, constipation, nausea/vomiting, and constipation; in addition, less common side effects include muscle and joint pain, edema, headache, weight gain, hyperglycemia, and peripheral neuropathy.

Pharmacological interactions have been reported with inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, or grapefruit) as well as CYP3A and P-glycoprotein inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, or St. John’s wort). The prescribing information notes that if concomitant administration with a potent CYP3A4 inhibitor is necessary, the larotrectinib dose should be reduced by 50%.

Lenvatinib is a multi-tyrosine kinase inhibitor that inhibits VEGFR1–3, FGFR1–4, PDGFR alpha, PDGF, KIT, and RET. It is approved for the treatment of renal cell carcinoma. From the phase III study comparing it with sorafenib in first-line treatment of HCC [39], the following adverse events were primarily reported: cutaneous erythrodysesthesia on the palms and soles, hypertension, gastrointestinal symptoms (e.g., diarrhea, constipation, nausea/vomiting, loss of appetite, and weight loss), hypothyroidism, and elevated liver enzymes. According to the prescribing information, proteinuria, aneurysms, aortic dissections, renal failure, CNS toxicity, fistulas/perforations, bleeding, arterial thromboembolism, impaired wound healing, osteonecrosis of the jaw, and cardiac dysfunction such as QT interval prolongation may also occur.

Myelosuppression caused by lenvatinib may be exacerbated by the concomitant use of other myelosuppressive drugs. Since prolongations of ventricular repolarization have been observed during treatment with lenvatinib, the concomitant administration of lenvatinib with drugs that prolong the QTc interval may increase the risk of polymorphic ventricular arrhythmias, known as “torsade de pointes.” Concomitant treatment with lenvatinib and drugs that prolong the QTc interval should be avoided. If this is not possible, electrolyte balance should be maintained, and the QTc interval should be monitored regularly. Bleeding also occurs very frequently with the use of lenvatinib. Concomitant treatment with lenvatinib and anticoagulants may further increase the risk of bleeding. When lenvatinib is used concomitantly with anticoagulants, coagulation-related laboratory parameters should be monitored regularly. Renal dysfunction, particularly acute renal failure, frequently occurs during treatment with lenvatinib. Concomitant administration of lenvatinib and drugs that interfere with the renin-angiotensin-aldosterone system (RAAS) may be associated with an increased risk of acute renal failure. When lenvatinib is administered concomitantly with drugs that affect the RAAS, renal function should be monitored regularly. The administration of corticosteroids or NSAIDs during therapy with lenvatinib should be avoided.

Gastrointestinal perforations have been observed during treatment with lenvatinib. The risk of this may increase with the concomitant use of lenvatinib and drugs that interfere with prostaglandin metabolism (e.g., NSAIDs, corticosteroids).

Lenvatinib is primarily metabolized via oxidation by aldehyde oxidase. N-demethylation via CYP3A4 and glutathione conjugation represent minor metabolic pathways. Therefore, neither CYP3A4 inhibitors nor CYP3A4 inducers have a significant effect on the systemic availability of lenvatinib.

Nivolumab is a monoclonal anti-PD-1 antibody and belongs to the class of ICIs. It is approved in combination with ipilimumab for first-line treatment of HCC, as well as for use as monotherapy or combination therapy for the treatment of a broad spectrum of malignant neoplasms. In a phase III study comparing first-line treatment of HCC with nivolumab versus sorafenib [91], the most commonly reported treatment-related adverse effects of nivolumab were fatigue, skin reactions, gastrointestinal symptoms (diarrhea, nausea, loss of appetite), and elevated transaminases. Other possible adverse effects include, among others, anemia, hypoalbuminemia, hyperkalemia, elevated liver enzymes, heart failure, elevated serum amylase, hyponatremia, elevated creatine phosphokinase, and renal dysfunction, as well as sometimes severe fever and interstitial pneumonia (immune-mediated pneumonitis), and immune-mediated liver or kidney inflammation and endocrinopathies.

As with other humanized monoclonal antibodies, there is no pharmacological interaction with the cytochrome P450 isoenzyme system or other drug-metabolizing enzymes. If immunosuppressive medications have been administered previously, the efficacy of nivolumab is expected to be impaired.

Ramucirumab is a human IgG1 antibody that specifically binds to the vascular endothelial growth factor (VEGF) receptor-2. It is approved for second-line therapy following failure of sorafenib in patients with HCC and a serum AFP level of ≥400 ng/ml, as well as for adenocarcinomas of the stomach or the gastroesophageal junction, colorectal carcinomas, and non-small-cell lung carcinomas. In the placebo-controlled phase III REACH-2 trial evaluating second-line therapy for HCC [96], the most commonly reported treatment-related adverse events in the ramucirumab arm were fatigue, nausea/vomiting, loss of appetite, proteinuria, hypertension, bleeding tendency, peripheral edema, and diarrhea or constipation. To prevent infusion-related adverse reactions, premedication with an H1 antagonist is recommended.

Clinically relevant pharmacological interactions with other active substances are not described in the prescribing information and, as with other humanized monoclonal antibodies, are not expected.

Rivoceranib is a VEGFR2-targeted tyrosine kinase inhibitor that has not yet been approved in the U.S. or the EU. It was evaluated in combination with camrelizumab for first-line treatment of HCC compared with sorafenib in the CARES-310 study [63], where it demonstrated an advantage in OS. In early August 2024, the EMA granted “Orphan Drug” designation to this combination for first-line treatment of HCC (https://elevartherapeutics.com/2024/08/01/elevar-therapeutics-granted-orphan-designation/). Side effects reported from monotherapy studies primarily include hypertension, gastrointestinal symptoms such as nausea and vomiting, fatigue, hand-foot syndrome, and skin reactions.

The primary metabolic pathway is CYP3A4, so relevant pharmacological interactions with CYP3A4 inhibitors such as itraconazole or voriconazole and CYP3A4 inducers such as rifampicin or St. John’s wort are to be expected. A prescribing information document is not yet available in the EU.

Selpercatinib is a highly selective RET kinase inhibitor. It is approved across tumor types for the treatment of RET-fusion-positive tumors as well as for RET-mutated thyroid carcinomas. The main adverse effects in the tumor-agnostic phase I/phase II study were hypertension and elevated liver enzymes, along with fatigue, proteinuria, and abdominal discomfort. Severe treatment-related adverse events were reported in 40% of patients. The prescribing information also lists the following as common adverse events: pneumonia, hypersensitivity reactions, headache, QT prolongation, bleeding, interstitial pneumonitis, gastrointestinal symptoms such as nausea, vomiting, diarrhea, or constipation, edema, and myelosuppression. For patients with a known QT prolongation, specific cardiac evaluations are recommended prior to the use of selpercatinib (see prescribing information). Due to its metabolism via CYP3A4 and P-glycoprotein, as well as its effect on CYP2C8, selpercatinib has numerous drug interactions with other medications and active ingredients (St. John’s wort, azole antifungals, grapefruit juice, phenytoin, rifampicin, rifabutin, carbamazepine, HIV antivirals, and many others for CYP3A4, as well as cerivastatin, enzalutamide, paclitaxel, repaglinide, torasemide, sorafenib, rosiglitazone, buprenorphine, selexipag, dasabuvir, or montelukast for CYP2C8) and its absorption following oral administration is affected by proton pump inhibitors (PPIs). Please refer to the prescribing information for detailed information on this.

Sorafenib is a tyrosine kinase inhibitor that targets PDGFR-beta, VEGF receptors 2 and 3, BRAF, CRAF, FLT3, and c-KIT; it is approved for the treatment of HCC, as well as renal cell carcinoma and differentiated thyroid carcinoma. In the pivotal trial for the treatment of HCC, the most commonly reported treatment-related adverse effects of sorafenib compared to placebo were diarrhea, weight loss, palmo-plantar erythrodysesthesia (hand-foot syndrome), and hypophosphatemia. The prescribing information lists numerous other potential sorafenib-associated adverse effects that should be taken into account.

Sorafenib is primarily metabolized in the liver via oxidative degradation by CYP3A4 as well as by UGT1A9-mediated glucuronidation. According to the prescribing information, the group of CYP3A4 inducers (rifampicin, St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) is of particular clinical relevance, as their concurrent administration can lead to a reduction in sorafenib concentrations.

Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, which was specifically developed to minimize binding to FcγR on macrophages. The binding site of tislelizumab on PD-1 largely overlaps with that of PD-L1, resulting in complete blockade of the PD-1/PD-L1 interaction. Tislelizumab belongs to the class of ICIs. It is approved for the treatment of non-small cell lung cancer and esophageal cancer. In first-line treatment of HCC, tislelizumab did not demonstrate significant superiority in a randomized comparison with sorafenib (RATIONALE-301) [66]. The most commonly reported tislelizumab-associated adverse effects were elevations in transaminases and bilirubin, skin reactions, thrombocytopenia, and gastrointestinal symptoms (diarrhea, loss of appetite, weight loss). Immune-mediated adverse effects (pneumonitis, hepatitis, colitis, endocrinopathy, etc.) occurred in 18.3% of patients.

Tislelizumab is removed from the bloodstream through catabolic degradation. No formal pharmacokinetic interaction studies have been conducted. Since monoclonal antibodies are not metabolized by cytochrome P450 enzymes or other drug-metabolizing enzymes, inhibition or induction of these enzymes by concomitantly administered drugs is not expected to affect the pharmacokinetics of tislelizumab (prescribing information). The use of systemic corticosteroids and other immunosuppressants prior to the start of treatment with tislelizumab should be avoided, with the exception of physiological doses of systemic corticosteroids (10 mg/day of prednisone or an equivalent), due to their potential to affect pharmacodynamic activity and efficacy (prescribing information).

Tremelimumab is a human IgG2a monoclonal antibody directed against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and belongs to the class of ICIs. It is approved for first-line treatment of HCC in combination with durvalumab, as well as for non-small cell lung cancer.

When tremelimumab is used in combination with durvalumab to treat HCC, immune-mediated adverse effects such as pneumonitis, colitis, endocrinopathies, skin reactions, hepatitis, pancreatitis, and others have been documented. There is a risk of exacerbation of pre-existing autoimmune diseases. In addition, fatigue and gastrointestinal side effects are frequently reported. From previous monotherapy studies for the treatment of melanoma, the most commonly reported side effects with tremelimumab included fatigue, nausea/vomiting, diarrhea/colitis, skin reactions, and endocrinopathies, as well as numerous other treatment-related side effects.

No clinically relevant pharmacological interactions with other active substances have been identified; however, if immunosuppressive medications are administered prior to the start of ipilimumab therapy, a reduction in the efficacy of tremelimumab is to be expected.