The safety and efficacy of lenvatinib combined with immune checkpoint inhibitors therapy for advanced hepatocellular carcinoma

Wang, Yun; Jiang, Man; Zhu, Junmin; Qu, Jing; Qin, Kang; Zhao, Delong; Wang, Li; Dong, Lei; Zhang, Xiaochun

doi:10.1016/j.biopha.2020.110797

Cited by 35 publications

(25 citation statements)

References 72 publications

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“…Several clinical trials demonstrated that lenvatinib could significantly prolong the median OS of patients with HCC, and it even showed better clinical efficacy than sorafenib 8,25,26 . Moreover, as reported, when combined with immune checkpoint therapy, the prognosis of patients with HCC had been greatly improved 11,12,27 . In addition, pervious research demonstrated that lenvatinib monotherapy could increase tumor‐infiltrating macrophages and CD8 + T cells through mice model in anaplastic thyroid cancer 28 .…”

Section: Discussionmentioning

confidence: 92%

“… 10 On the other hand, immune modulatory effects also played a vital role in tumor development. Several research had already showed that when combined with immune‐checkpoint inhibitors, lenvatinib could greatly enhance its antitumor effect 11 , 12 ; other reports indicated lenvatinib itself has ability to alleviate the immune suppression 13 and further affects the immune cells 14 so as to improve the prognosis of patients with tumor burden. However, there is no relevant research explains how lenvatinib regulates the immune status of HCC patients.…”

Section: Introductionmentioning

confidence: 99%

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The immunomodulatory activity of lenvatinib prompts the survival of patients with advanced hepatocellular carcinoma

et al. 2021

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Background Lenvatinib is a novel multiple receptor tyrosine kinase inhibitor used for hepatocellular carcinoma (HCC) treatment. Although its main function is to suppress VEGFR and FGFR pathway, its immunomodulatory activity in HCC is not elucidated. Thus, this study aimed to investigate the immunomodulatory capability of lenvatinib in HCC. Material and methods Totally 47 patients with HCC were enrolled in this study, and the immune cells and serum cytokine profiles before initiation of treatment and after 1 and 3 months were measured. The immune checkpoint receptors on the immune cells were also evaluated. Kaplan–Meier survival estimate and log rank tests were used to assess the prognostic value. Result The frequency of T helper (Th) cells and T regulatory (Treg) cells reduced after lenvatinib treatment, while cytotoxic T lymphocyte (CTL) cells increased significantly. The cytokine profiles showed IL‐2, IL‐5, IFN‐γ increased; other cytokines including IL‐6, IL‐10, TNF‐ α and TNF‐ β decreased with lenvatinib therapy. Furthermore, the PD‐1 and TIM‐3 expressed on CTL had greatly decreased; the expression of TIM‐3 and CTLA‐4 was reduced on Treg cells as well. Besides, the new index CTL/Treg ratio was created, and low ratio was associated with the unfavorable outcome of HCC patients. Conclusion Our results confirmed that lenvatinib is capable of improving patients’ immune status, saving the effector cells from exhaustion status and inhibiting the number and function of immunosuppressive cells. The novel index CTL/Treg ratio qualifies as a predictor for the outcome of patients with lenvatinib therapy.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

The immunomodulatory activity of lenvatinib prompts the survival of patients with advanced hepatocellular carcinoma

et al. 2021

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“…Several tyrosine kinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, have been approved for the treatment of advanced HCC [ 25 , 26 ]. Therefore, the development of the abovementioned tyrosine kinase inhibitors may offer therapeutic benefits for patients with HCC.…”

Section: Discussionmentioning

confidence: 99%

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

Chen

Hsu

Chen

et al. 2021

Cancers

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While regorafenib was approved for the treatment of advanced HCC in 2017, with a partial response and survival benefit; other combination agents to facilitate the efficacy of regorafenib still need to be explored. Magnolol is a potential natural anti-tumor compound for many types of cancers. Combination indexes calculated on the basis of both in vitro and in vivo models have indicated a synergistic effect of the combination of regorafenib and magnolol. The overexpression of the VEGF-A protein significantly diminished regorafenib’s inhibition of cell viability, while the transient knockdown of VEGF-A by siRNA effectively sensitized HCC cells to regorafenib. In addition, the inhibition of MCL-1 by siRNA combined with regorafenib allowed for a significantly greater inhibition of cell growth, compared to regorafenib alone. A lower protein expression level for VEGF-A and MCL-1 was found for the combination treatment of HCC in vitro and in vivo. A superior metastasis inhibition was also found in the combination group, as compared to the single-treatment groups, using a transwell assay, wound healing assay, and Western blotting. The caspase-dependent and -independent and DNA damage effects, as determined by flow cytometry and a comet assay, were increased by the combination therapy. Taken together, magnolol sensitized HCC to regorafenib, which was correlated with the reduction of VEGF-A and MCL-1 and the induction of apoptosis.

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“…Furthermore, the benefits remain limited and novel treatment strategies for patients with advanced HCC are urgently required. Numerous studies are examining treatment concepts using combinations of LEN with immune checkpoint inhibitors (ICIs), with preliminary results showing that the combinations were well-tolerated and encouraging (13)(14)(15). In 104 patients enrolled in the phase Ib trial of LEN plus pembrolizumab, the confirmed objective response rate (ORR) was 46% and median OS was 22 months (13).…”

Section: Introductionmentioning

confidence: 99%

Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study

Huang

et al. 2021

Front. Oncol.

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BackgroundNivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC.MethodBetween June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed.ResultsAll the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis.ConclusionThe combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.

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The safety and efficacy of lenvatinib combined with immune checkpoint inhibitors therapy for advanced hepatocellular carcinoma

Cited by 35 publications

References 72 publications

The immunomodulatory activity of lenvatinib prompts the survival of patients with advanced hepatocellular carcinoma

The immunomodulatory activity of lenvatinib prompts the survival of patients with advanced hepatocellular carcinoma

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study

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