Combination of molecularly targeted therapies and immune checkpoint inhibitors in the new era of unresectable hepatocellular carcinoma treatment

Liu, Ze-Long; Liu, Jinghua; Staiculescu, Daniel; Jiang, Chen

doi:10.1177/17588359211018026

Cited by 15 publications

(11 citation statements)

References 218 publications

(314 reference statements)

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“…Based on the survival efficacy from the results of phase II clinical trials, anti-PD1 inhibitors nivolumab and pembrolizumab were approved as the subsequent-line treatment for unresectable HCC ( 14 , 15 ). However, the overall response rate (ORR) of nivolumab or pembrolizumab for advanced HCC was 15-20% ( 16 ). In order to improve the therapeutic effect of ICIs for HCC, a large number of register clinical trials on the combination treatment with ICIs are being carried out.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: Monotherapies and Combined Therapies

2022

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Hepatocellular carcinoma (HCC) is an important cause of cancer death and is considered the 3rd most lethal around the world. Hepatectomy, liver transplantation, and ablation therapy are considered curative treatments for early-stage HCC. Transarterial chemoembolization is the preferred therapy for intermediate stage HCC. Ssystemic therapy is recommended for advanced HCC. For more than a decade, sorafenib and lenvatinib were used as the first-line treatment for the advanced HCC. For the great success of immunotherapy in melanoma and lung cancer, some immune-based treatments, such as immune checkpoint inhibitors (ICIs), have been applied in the treatment of HCC. The anti-programmed cell death protein 1 (PD1) antibodies, including nivolumab and pembrolizumab, have been approved by the Food and Drug Administration for sorafenib-pretreated patients. Moreover, due to the results of durable antitumor responses attained from the phase 3 trials, atezolizumab in combination with bevacizumab is now the standard therapy for advanced HCC. Recently, there are a lot of clinical trials involving the ICIs, as monotherapy or combination therapy, with tyrosine kinase inhibitors, antiangiogenic drugs, cytotoxic agents, and locoregional treatments, providing a promising outcome for advanced HCC. Thus, this review summarized the role of ICIs for HCC patients with monotherapy or combination therapy. The success and failures of monotherapy and combination therapy involving ICIs have provided advanced insights into HCC treatment and led to novel avenues to improve therapy efficacy in HCC.

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Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: Monotherapies and Combined Therapies

2022

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“…In addition, in the dose-expansion phase, a total of 214 advanced HCC patients were enrolled into 4 cohorts, including uninfected sorafenib refractory (n = 57), uninfected sorafenib intolerance (n = 56), HCV infected (n = 50), and HBV infected (n = 51). The ORR was 20% (95% CI [15][16][17][18][19][20][21][22][23][24][25][26], the DCR was reported as 64% (95% CI, 50-71), and the median PFS was 4.0 months (95% CI, 2.9-5.4). The OS was not reached.…”

Section: Icis In Hccmentioning

confidence: 99%

“…Immune checkpoint inhibitors (ICIs) prevent the inactivation of T cells by blocking interactions between checkpoint proteins and their ligands, such as those mediated by programmed cell death-1 (PD-1)/ programmed cell death ligand 1 (PD-L1), cytotoxic Tlymphoc yte-associated p rot ein 4 (CTLA4), T-ce ll immunoglobulin, mucin domain containing-3 (TIM3), and lymphocyte-activation gene 3 (LAG3), thereby exerting antitumor effects (20,21). However, not all patients (especially in the era of pre-liver transplantation) with HCC respond to immunotherapy, and more importantly, the ORR is low, and OS does not significantly improve with single-agent immunotherapy (22,23). Given these data, more effective combination therapies for the treatment of HCC are explored, including ICIs combined with other ICIs, TKIs, anti-VEGFs, and other agents (24).…”

Section: Introductionmentioning

confidence: 99%

Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma

Chen

Yuan

et al. 2022

Front. Immunol.

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Hepatocellular carcinoma (HCC) is usually diagnosed in an advanced stage and has become the second deadliest type of cancer worldwide. The systemic treatment of advanced HCC has been a challenge, and for decades was limited to treatment with tyrosine kinase inhibitors (TKIs) until the application of immune checkpoint inhibitors (ICIs) became available. Due to drug resistance and unsatisfactory therapeutic effects of monotherapy with TKIs or ICIs, multi-ICIs, or the combination of ICIs with antiangiogenic drugs has become a novel strategy to treat advanced HCC. Antiangiogenic drugs mostly include TKIs (sorafenib, lenvatinib, regorafenib, cabozantinib and so on) and anti-vascular endothelial growth factor (VEGF), such as bevacizumab. Common ICIs include anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1), including nivolumab, pembrolizumab, durvalumab, and atezolizumab, and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumab and ipilimumab. Combination therapies involving antiangiogenic drugs and ICIs or two ICIs may have a synergistic action and have shown greater efficacy in advanced HCC. In this review, we present an overview of the current knowledge and recent clinical developments in ICI-based combination therapies for advanced HCC and we provide an outlook on future prospects.

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“…Intrahepatic tumor recurrent HCC (rHCC) is the major cause of treatment failure in HCC (2,3). In patients with rHCC, multikinase inhibitors, molecularly targeted therapies, and immune checkpoint inhibitors are administered as secondline systemic therapy (4,5). Transarterial Chemoembolization (TACE) (2,6), Transarterial radioembolization (7), radiotherapy (3), and thermal ablation (8) are used as alternative locoregional therapy for rHCC.…”

Section: Introductionmentioning

confidence: 99%

Clinical Outcome of CT-Guided Iodine-125 Radioactive Seed Implantation for Intrahepatic Recurrent Hepatocellular Carcinoma: A Retrospective, Multicenter Study

Yuan

et al. 2022

Front. Oncol.

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The efficacy and safety of CT-Guided Iodine-125 Radioactive Seed Implantation (RSI) for the treatment of intrahepatic recurrent hepatocellular carcinoma (rHCC) were analyzed in this multicenter retrospective study. We reviewed the medical records of patients with rHCC treated with I-125 seed implantation at four different hospitals in China from December 2011 and January 2021. The local progression-free survival (LPFS),liver PFS, and overall survival (OS) were calculated, and the short-term efficacy and treatment-related toxicities were evaluated. A total of 82 patients were enrolled; the median follow-up time was 46 months (range, 3–80 months). The 1-, 3- and 5-year LPFS rates were 63.8%, 27.1%, and 7.9%, respectively, and the corresponding OS rates were 74.8%, 32.9%, and 12.6%, respectively. Univariate analysis showed that factors influencing LPFS included the maximum lesion diameter, Barcelona Clinic Liver Cancer (BCLC) stage, interval between treatment and recurrence, and D90. Multivariate analyses revealed that the BCLC stage, interval between treatment and recurrence, and D90 were independent factors influencing LPFS, whereas BCLC stage, D90, and short-term efficacy were independent factors influencing OS. In summary, I-125 seed implantation is a safe and effective treatment for rHCC. The BCLC stage, interval, and D90 were found to influence the local control. A larger, prospective study is required to confirm the dose-response curve for Iodine-125 RSI of rHCC.

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Combination of molecularly targeted therapies and immune checkpoint inhibitors in the new era of unresectable hepatocellular carcinoma treatment

Cited by 15 publications

References 218 publications

Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: Monotherapies and Combined Therapies

Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: Monotherapies and Combined Therapies

Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma

Clinical Outcome of CT-Guided Iodine-125 Radioactive Seed Implantation for Intrahepatic Recurrent Hepatocellular Carcinoma: A Retrospective, Multicenter Study

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