Background & Aims: Programmed cell death protein-1 (PD-1) inhibitors plus tyrosine kinase inhibitor (TKI) has dramatically improved survival of patients with advanced hepatocellular carcinoma (HCC). However, the risk of hepatitis B virus (HBV) reactivation from these antitumor medications remains unclear.Methods: Patients receiving TIK monotherapy (TKI group) or TKI combined with PD-1 inhibitors (combination group) were included. The primary endpoint was HBV reactivation as de ned by an increase in HBV DNA titer by at least 1 log(10-fold) from baseline. The secondary endpoints included tumor progression, overall survival.Results: A total of 499 patients met the inclusion criteria, including 296 patients in the TKI group and 203 patients in the combination group. The 3-month, 6month and 12-month cumulative incidence rates of HBV reactivation in the TKI group vs combination group were 7.8%, 12.8% and 21.3% vs 9.9%,19.2% and 30.0%, respectively (P=0.02). The Cox proportional hazard model indicated that combination therapy (HR 1.41, 95% CI 1.00-1.99, P=0.05), ALT > 40 U/L (HR 1.50, 95% CI, 1.05-2.16, P=0.03), and tumor size > 5 cm (HR 1.58, 95% CI, 1.10-2.28, P=0.01) were independent risk factors for HBV reactivation. Compared with the HBV reactivation group, the progression-free survival and overall survival of patients in the HBV non-reactivation group were signi cantly prolonged (P<0.001 and P=0.001).Conclusions: Patients who received TKI combined with PD-1 inhibitors had a greater risk for HBV reactivation, and those with HBV reactivation had a higher rate of tumor progression and shorter survival time, than those receiving TKI alone.
Hepatocellular carcinoma (HCC) is responsible for roughly 90% of all cases of primary liver cancer, and the cases are on the rise. The treatment of advanced HCC is a serious challenge. Immune checkpoint inhibitor (ICI) therapy has marked a watershed moment in the history of HCC systemic treatment. Atezolizumab in combination with bevacizumab has been approved as a first-line treatment for advanced HCC since 2020; however, the combination therapy is only effective in a limited percentage of patients. Considering that the tumor immune microenvironment (TIME) has a great impact on immunotherapies for HCC, an in-depth understanding of the immune landscape in tumors and the current immunotherapeutic approaches is extremely necessary. We elaborate on the features, functions, and cross talk of the innate and adaptive immune cells in HCC and highlight the benefits and drawbacks of various immunotherapies for advanced HCC, as well as future projections. HCC consists of a heterogeneous group of cancers with distinct etiologies and immune microenvironments. Almost all the components of innate and adaptive immune cells in HCC have altered, showing a decreasing trend in the number of tumor suppressor cells and an increasing trend in the pro-cancer cells, and there is also cross talk between various cell types. Various immunotherapies for HCC have also shown promising efficacy and application prospect. There are multilayered interwoven webs among various immune cell types in HCC, and emerging evidence demonstrates the promising prospect of immunotherapeutic approaches for HCC.
Background: Tyrosine kinase inhibitors (TKI) in combination with programmed cell death-1 (PD-1) inhibitors become the potential treatment modality for patients undergoing unresectable hepatocellular carcinoma (uHCC) in the first-line setting. However, the efficacy and safety of this combination regimen in patients after sorafenib failure remains unclear.Methods: Participants in this study included patients with uHCC after sorafenib failure who received TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center from July 2018 to July 2021. The overall survival (OS) was used to be the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were applied to be secondary endpoints. In addition, the adverse events are recorded and evaluated.Results: Among the 92 patients contained in this work, 50 patients were categorized into the TKI group, while 42 patients were in the combination group. There existed no evident differences between the two groups concerning the ORR (8.0% vs. 9.5%, p = 1.000). However, the DCR in the combined group was better in relative to that in the TKI group (71.4% vs. 50.0%, p = 0.037). In comparison with the TKI group, it was found that the combination group presented notably better median PFS (8.1 months vs. 4.7 months, p = 0.005) and median OS (21.9 months vs. 16.6 months, p = 0.042). According to multivariate analysis, PFS (HR 0.5, 95% CI: 0.3–0.8, p = 0.005) and OS (HR 0.5, 95% CI: 0.3–1.0, p = 0.051) were improved in the combination group in relative to the TKI group after the adjustment for some risk factors. Additionally, the incidence rates of grade ≥1 adverse event in the TKI group and the combination group were 96.0% and 97.6%, respectively. The most normal adverse event in the TKI group was neutropenia (n = 24,48.0%) and the combination group was hypoalbuminemia (n = 23,54.8%). All of these adverse events improved after symptomatic treatment, and no new toxic events were found to occur.Conclusion: TKI combined with PD-1 inhibitors showed better prognosis with manageable toxicity in uHCC patients after sorafenib failure compared with TKI monotherapy.
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