Hepatocellular carcinoma (HCC) accounts for nearly 90% of primary liver cancers, and in 2020, approximately 905,700 people worldwide were diagnosed with liver cancer, of which 830,200 died. Although chronic viral hepatitis, alcohol consumption, and aflatoxin exposure remain major triggers, cases of HCC due to fatty liver disease (MASLD) associated with metabolic disorders are on the rise, which is associated with factors such as obesity and diabetes.
The increasing and still high mortality rate of HCCs underscores the urgent need for innovative** approaches. Patients are often diagnosed at an advanced stage, and traditional** such as surgery has become impractical. In addition, HCCs have shown resistance to standard chemotherapy, prompting a shift to advanced** such as targeted and immune** to improve survival and improve patient quality of life. This article will present an update on the first-line system** approach to HCC and will discuss how to select the appropriate first-line strategy for individual patients.
Currently approved first-line**
For more than a decade, the only system** that has demonstrated efficacy in advanced hepatocellular carcinoma is sorafenib, a multi-targeted tyrosine kinase inhibitor approved since 2007. Sorafenib is the first effective system approved based on the results of the SHARP trial** with an overall survival (OS) of 107 months, compared to 79 months (hr is 0.)69, ci is 055 to 087，p < 0.001), and the time to radiological progression was prolonged (55 vs. 2.8 months, p < 0001）。The main ones include diarrhoea, weight loss, and hand-foot reactions.
In 2018, Kudo et al. conducted a phase III REFLECT trial to demonstrate the non-inferiority of the tyrosine kinase inhibitor lenvatinib compared with sorafenib in prolonging OS. Lenvatinib demonstrated better results in progression, disease-free survival (PFS) and overall response rate (ORR). The main main*** of lenvatinib include high blood pressure, proteinuria, and diarrhea. However, the study only included patients with advanced HCC who had no hepatic portal vein invasion or bile duct invasion and whose tumor burden was less than 50% of the total liver volume.
Finally, the efficacy of atezolizumab + bevacizumab as a first-line non-operable HCC** has been evaluated by the phase III randomized trial IMBR**E150, which compared 336 patients receiving atezolizumab + bevacizumab** to 165 patients receiving sorafenib**. The study showed that atezolizumab + bevacizumab compared with sorafenib showed significant performance at 12 months in OS (672%（95% ci，61.3–73.1）vs 54.6%（95% ci，45.2–64.0)) and PFS (68 months (95% CI, 5.)7–8.3）vs 4.3 months (95% CI, 4.)0-5.6)).
In the following 15In an updated analysis after a median follow-up of 6 months, atezolizumab + bevacizumab in combination with ** was significantly significantly improved in OS (192 months vs 13 of sorafenib4 months) and PFS (69 months vs 43 months). With regard to safety, the incidence of adverse events was higher in the combined group;The most common event was hypertension, consistent with the known safety profile of bevacizumab. However, patients in the sorafenib group experienced adverse events such as diarrhoea, anorexia, and palmoplantar erythema, resulting in a poorer quality of life.
Recently, the phase III randomized controlled trial Himalaya compared the CTLA+4 inhibitor tremelimumab in combination with the PD+L1 inhibitor durvalumab**, the STRIDE regimen, with sorafenib in patients who had not yet received systemic **. Tremelimumab + durvalumab was superior to sorafenib in terms of OS (HR 0.).78；96% ci，0.65–0.92；p = 0.0035）。At the data cut-off, the median OS for the STRIDE group was 1643 months, compared to 13 in the sorafenib group77 months. In addition, major bleeding events due to esophageal varices were rare at follow-up in the STRIDE group (026%）。
Based on the four-year OS update data, the efficacy and safety of STRIDE were consistent with the preliminary analysis, in particular the OS hazard ratio of STRIDE compared to sorafenib was 078（95% ci，0.67–0.92), and the OS rate at 36 and 48 months in the STRIDE group was 307% and 252% compared to 19 in the sorafenib group8% and 151%。Based on these data, durvalumab + tremelimumab in combination with ** has been approved by the FDA, and the EMA may also approve it as a first-line alternative to atezolizumab + bevacizumab in the near future.
Factors in choosing DYXnets**
As previously stated, atezolizumab + bevacizumab showed better OS than sorafenib in patients with unsurgically resected HCC, particularly in patients who had not received prior system**;As a result, it is seen as the preferred first line**. However, there are no randomized clinical trials that directly compare atezolizumab + bevacizumab with lenvatinib. Recent network meta-analyses have shown that atezolizumab + bevacizumab is superior to lenvatinib, nivolumab, and sorafenib in terms of OS and PFS. However, in clinical practice, there are a number of circumstances that limit the prescribing of atezolizumab + bevacizumab. For example, patients with autoimmune diseases or those requiring chronic immunosuppression are not candidates for immune checkpoint inhibitors, so tyrosine kinase inhibitors (TKIS) are a more appropriate option in these cases. When selecting these two classes of agents, it is also important to consider their toxicity profile and the patient's specific condition.
In addition, the FDA recently approved durvalumab + tremelimumab as a first-line**, but there are currently no randomized clinical trials directly comparing it with atezolizumab + bevacizumab. Therefore, when choosing between the two, it is necessary to consider their efficacy and safety in a comprehensive manner.
*: International Hepatobiliary Information.