Immunomodulatory Effects of Lenvatinib Plus Anti–Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma

Torrens, Laura; Montironi, Carla; Puigvehí, Marc; Mesropian, Agavni; Leslie, Jack; Haber, Philipp K.; Maeda, Miho; Balaseviciute, Ugne; Willoughby, Catherine E.; Abril-Fornaguera, Jordi; Piqué-Gili, Marta; Torres‐Martín, Miguel; Peix, Judit; Geh, Daniel; Ramon‐Gil, Erik; Saberi, Behnam; Friedman, Scott L.; Mann, Derek A.; Sia, Daniela; Llovet, Josep M.

doi:10.1002/hep.32023

Cited by 99 publications

(67 citation statements)

References 40 publications

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“…In vitro studies have shown that lenvatinib and PD-1 inhibitors can exert synergistic antitumor effects, including activation of effector T cells and depletion of regulatory T cells in the tumor microenvironment, modulation of antigenpresenting cells and dendritic cell maturation, inhibition of immune-suppressive signaling, and normalization of tumor blood vessels (15)(16)(17)(18)(19)(20). Furthermore, a retrospective analysis of first-line lenvatinib plus various PD-1 inhibitors in patients with unresectable HCC demonstrated tumor responses (21).…”

Section: Introductionmentioning

confidence: 99%

Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study

Cao

Yuan

et al. 2022

Front. Oncol.

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BackgroundCombining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC).AimsTo explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC.MethodsThis multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety.ResultsBy March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events.ConclusionFirst-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.

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Section: Introductionmentioning

confidence: 99%

Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study

Cao

Yuan

et al. 2022

Front. Oncol.

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“…LEN significantly decreased the population of tumor-associated macrophages, as well as increased the percentage of activated CD8+ T cells secreting interferon-γ+ and granzyme B ( 24 , 25 ). In addition, LEN significantly reduced the level of tumor programmed death-ligand 1 (PD-L1) and Treg differentiation, improved anti-PD-1 efficacy by blocking FGFR4, and inhibiting TGFß signaling ( 26 , 27 ). The extent to which combination therapies pose clinical safety and tolerability challenges, and whether these challenges will limit their usefulness as an anticancer therapy, have been the focus of an increasing number of studies.…”

Section: Discussionmentioning

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 reliance of lenvatinib on the existence of CD8+ T cells has shed light on combining pembrolizumab or nivolumab with lenvatinib [ 108 , 113 ]. Several animal experiments revealed that the combination of lenvatinib and anti-PD-1 therapy amplified the antitumour effect on HCC, and amplification was presumed to be achieved by exerting immunomodulation through a reduction in TAM infiltration, synergistic modulation on T cells, reversion of immunosuppressive effect caused by anti-PD-1 therapy, and vascular normalization [ 109 , 114 , 115 ]. Long-term administration of PD-1 in patients was reported to increase of VEGF and FGF expression, and lenvatinib exerts a more potent effect on VEGFRs and FGFRs compared to sorafenib as mentioned [ 108 , 114 ].…”

Section: Tkis-induced Tme Remodelingmentioning

confidence: 99%

“…In this context, reversion of the immunosuppressive effect caused by anti-PD-1 was proposed to be achieved by upregulating PD-1, cytotoxic T lymphocyte-associated protein-4, and TIM-3 on T cells, downregulating IFN-γ and granzyme B, and inhibiting T cell cytotoxicity [ 114 ]. The immunomodulation exerted by the combination of lenvatinib and anti-PD-1 was recently proven to be associated with TGF-β inhibition [ 115 ].…”

Section: Tkis-induced Tme Remodelingmentioning

confidence: 99%

Modulation of the tumour microenvironment in hepatocellular carcinoma by tyrosine kinase inhibitors: from modulation to combination therapy targeting the microenvironment

Chen

et al. 2022

Cancer Cell Int

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Tyrosine kinase inhibitors (TKIs) remain the backbone of systematic therapy for advanced hepatocellular carcinoma. Sorafenib and lenvatinib are currently approved as first-line therapeutic drugs, and regorafenib and cabozantinib are applied as second-line treatments. With inhibition of angiogenesis as the main target, TKIs exert a profound effect on the tumour microenvironment (TME). The TME is a complex mixture of cellular and noncellular components surrounding the tumour mass, and is associated with tumour progression partially through the epithelial–mesenchymal transition. Specifically, the TME of HCC is characterized by profound extracellular matrix remodelling and an immunosuppressive microenvironment. The purpose of this review is to provide a summary of TME remodelling mediated by four Food and Drug Administration approved TKIs in HCC and thus summarize the rationale and potential targets for combination therapy. The modulatory effect of TKIs on the TME of HCC was reported to enhance the antitumour effect of TKIs through pyroptosis of macrophages and subsequent natural killer cell activation, T cell activation, regulatory T cell reduction in HCC. Meanwhile, TKIs also induce drug resistance via M2 polarization and accumulation, recruitment of tumour-associated neutrophils, and induction of the epithelial–mesenchymal transition. In conclusion, the effect of TKIs on TME can enhance its antitumour effect, but might also partially contribute to the drug resistance that hinders the progression of TKIs as treatment for HCC. Additionally, the effect of TKIs also provides the rationale for combination therapy, including combining TKIs with immune checkpoint inhibitors, to facilitate increased drug efficacy of TKIs.

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Immunomodulatory Effects of Lenvatinib Plus Anti–Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma

Cited by 99 publications

References 40 publications

Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study

Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study

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

Modulation of the tumour microenvironment in hepatocellular carcinoma by tyrosine kinase inhibitors: from modulation to combination therapy targeting the microenvironment

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