Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study

Lee, Michael S.; Hsu, Chih Hung; Numata, Kazushi; Verret, Wendy; Hack, Stephen P.; Spahn, Jessica; Liu, Bo; Abdullah, Heba; Wang, Yulei; He, Aiwu Ruth; Lee, Kyung Hun; Bang, Yeonghak; Bendell, Johanna C.; Chao, Yee; Chen, J. S.; Chung, Hyun Cheol; Davis, S. Lindsey; Dev, Atul; Gane, Edward; George, Ben; He, Aiwu Ruth; Hochster, Howard S.; Hsu, Chiun; Ikeda, Masafumi; Lee, J.; Lee, M.; Mahipal, Amit; Manji, Gulam A.; Morimoto, Manabu; Pishvaian, Michael J.; Qin, Shukui; Ryan, David P.; Ryoo, Baek Yeol; Sasahira, Naoki; Stein, Stacey; Strickler, John H.; Tebbutt, N. C.

doi:10.1016/s1470-2045(20)30156-x

Cited by 444 publications

(413 citation statements)

References 31 publications

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“…A recent phase 1b study showed that the objective response rate (ORR; according to RECIST version 1.1) of atezolizumab plus bevacizumab (arm A) was 36% [40], which was markedly higher than the ORR (RECIST version 1.1) of nivolumab monotherapy and pembrolizumab monotherapy (15-18.3%) [20,21]. This is attributed to the fact that anti-VEGF therapy improves the recruitment of DC, the activation of CD8 + T cells, and trafficking and infiltration of CD8 + T cells into the tumor tissue and improves immunosuppressive TME in the immune moderate subclass [39] (Fig.…”

Section: Possible Treatment Strategy For the Immune Subclass Includinmentioning

confidence: 99%

Gd-EOB-DTPA-MRI Could Predict WNT/β-Catenin Mutation and Resistance to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma

Kudo

2020

Liver Cancer

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Section: Possible Treatment Strategy For the Immune Subclass Includinmentioning

confidence: 99%

Gd-EOB-DTPA-MRI Could Predict WNT/β-Catenin Mutation and Resistance to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma

Kudo

2020

Liver Cancer

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“…34 Given the high response rate, tolerability and durability of response in the trial of tivozanib, a trial of tivozanib and PD-L1 inhibitor durvalumab is now underway (NCT03970616).The proof of concept of anti-VEGF and checkpoint inhibition in HCC was recently confirmed in a large phase 3 study with atezolizumab and bevacizumab. 32,33 In summary, our studies provide an important insight into 'off-target' effect of tivozanib in the targeted therapy of HCC as reflected by its beneficial effect on reduction of immunosuppressive phenotypes. Importantly of clinical relevance, reduction in Tregs after tivozanib therapy significantly improved OS of the patients.…”

Section: Discussionmentioning

confidence: 85%

“…24 Additionally, recent clinical trials that reported improvement in OS and PFS of unresectable HCC patients treated with atezolizumab in combination with bevacizumab corroborates with our findings. 32,33 Furthermore, by performing a comparative study of biomarker effect on survival benefit, we report for the first time the significant association of elevated CD4 + T cells: Tregs ratio with OS of patients treated with tivozanib as compared to patients treated with sorafenib. Better antititumor efficacy, particularly significant improvement in progression-free survival reported in advanced renal cell carcinoma patients treated with tivozanib versus those patients treated with sorafenib, is supportive of our results in HCC patients.…”

Section: Discussionmentioning

confidence: 95%

Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients

et al. 2020

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The immune modulatory effect of tivozanib, a tyrosine kinase inhibitor, and the underlying immune mechanisms impacting survival of HCC patients have not been investigated. Pre-clinical studies have shown that tivozanib reduces Tregs and MDSCs accumulation through inhibition of c-Kit/SCF axis. We rationalized that c-Kit/SCF axis antagonism by tivozanib may reverse tumor-induced immune suppression in HCC patients. The frequency of circulating Tregs, MDSCs, CTLA-4 + Tregs, PD-1 + T cells, c-Kit + pERK-2 + Tregs, and c-Kit + pERK-2 + MDSCs were quantified in HCC patients at baseline and two time points during tivozanib treatment. We report for the first time that reduction in Tregs after tivozanib treatment and increased levels of baseline CD4 + PD-1 + T cells correlated with significant improvement in overall survival (OS) of the patients and these signatures may be potential biomarkers of prognostic significance. This immune modulation resulted from tivozanib-mediated blockade of c-Kit/SCF signaling, impacting ERK2 phosphorylation on Tregs and MDSCs. Low pre-treatment CD4 + T cells: Treg ratio and reduction in the frequencies of Foxp3 + c-Kit + pERK + Tregs after tivozanib treatment correlated significantly with progression free survival. In a comparative analysis of tivozanib vs sorafenib treatment in HCC patients, we demonstrate that decrease in the baseline numbers or frequencies of Foxp3 + Tregs, MDSCs and exhausted T cells was significantly greater following tivozanib treatment. Additionally, greater increase in CD4 + T cell: Treg ratio after tivozanib treatment was associated with significant improvement in OS compared to sorafenib treatment, highlighting the greater efficacy of tivozanib. These insights may help identify patients who likely would benefit from c-Kit/SCF antagonism and inform efforts to improve the efficacy of tivozanib in combination with immunotherapy.

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“…For diseases refractory or unamenable to transarterial chemoembolization, combined targeted therapy and immunotherapy can produce an objective response rate of approximately 30% [2][3][4][5], which leaves much room for improvement. Moreover, patients who fail rst-line systemic therapy exhibit poor prognosis [6].…”

Section: Introductionmentioning

confidence: 99%

Role of Eg5 in Prognosis Prediction and Treatment of Hepatocellular Carcinoma

Shao

Sun

Jeng

et al. 2020

Preprint

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Background: The kinesin Eg5, a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of Eg5 in HCC.Methods: HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. Eg5 expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific Eg5 inhibitor, was tested in HCC cell lines. In vivo efficacy of Eg5 inhibition was investigated in a xenograft model.Results: A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low Eg5 expression levels. OS of patients with low Eg5 expression was better than that of patients with medium and high Eg5 expression (median, 155.6 vs. 75.3 vs. 57.7 months, p = 0.002). DFS of patients with low Eg5 expression was also better than that of patients with medium and high Eg5 expression (median, 126.3 vs. 46.2 vs. 39.4 months, p = 0.001). In multivariate analyses, the associations between Eg5 expression and OS (p < 0.001) or DFS remained (p < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than the control.Conclusion: High Eg5 expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that Eg5 may be a reasonable therapeutic target for HCC.

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Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study

Cited by 444 publications

References 31 publications

Gd-EOB-DTPA-MRI Could Predict WNT/β-Catenin Mutation and Resistance to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma

Gd-EOB-DTPA-MRI Could Predict WNT/β-Catenin Mutation and Resistance to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma

Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients

Role of Eg5 in Prognosis Prediction and Treatment of Hepatocellular Carcinoma

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