Pembrolizumab for the Treatment of Hepatocellular Carcinoma

Kudo, Masatoshi

doi:10.1159/000500143

Cited by 31 publications

(22 citation statements)

References 30 publications

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“…These results paved the way for the US Food and Drug Administration approval of PD1 blockade as a second‐line therapy after progression on sorafenib treatment in September 2017. Similar results were achieved in a phase II study with anti‐PD1 from a different pharmaceutical Company, however recent analysis of results from phase III study Keynote‐240 (NCT02702401) indicated significantly improved OS and PFS that did not reach statistical significance compared to placebo arm according to pre‐specified statistical criteria …”

Section: Introductionsupporting

confidence: 92%

“…Similar results were achieved in a phase II study with anti-PD1 from a different pharmaceutical Company, 124 however recent analysis of results from phase III study Keynote-240 (NCT02702401) indicated significantly improved OS and PFS that did not reach statistical significance compared to placebo arm according to pre-specified statistical criteria. 125 Results of immune checkpoint inhibitors (ICIs) for HCC are promising and ongoing research is focused on strategies to improve therapy success rates. Data are still lacking regarding clinical efficacy of inhibiting checkpoint molecules, other than CTLA4 and PD1 expressed in T cells infiltrating HCC.…”

Section: Targeting Effector Cellsmentioning

confidence: 99%

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Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Cariani

Missale

2019

Liver International

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The development of immunotherapy for solid tumours has boosted interest in the contexture of tumour immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumour cells and TIME components is a key factor for the evolution of hepatocellular carcinoma (HCC) and for the likelihood of response to immunotherapeutics. The availability of high‐resolution methods will be instrumental for a better definition of the complexity and diversity of TIME with the aim of predicting disease outcome, treatment response and possibly new therapeutic targets. Here, we review current knowledge about the immunological mechanisms involved in shaping the clinical course of HCC. Effector cells, regulatory cells and soluble mediators are discussed for their role defining TIME and as targets for immune modulation, together with possible immune signatures for optimization of immunotherapeutic strategies.

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Section: Introductionsupporting

confidence: 92%

Section: Targeting Effector Cellsmentioning

confidence: 99%

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Cariani

Missale

2019

Liver International

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“…The reason why cemiplimab, atezolizumab, avelumab, durvalumab have not been included in the guidelines for the treatment of HCC is that their efficacy and safety is not completely certain, and several trials are still ongoing (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Nivolumab as a first-line treatment option compared with sorafenib is still under research, and nivolumab may become first-line treatment if the result is positive (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23); atezo+bev has potential as a first-line treatment for unresectable HCC; both avelumab and axitinib are known to be safe when administered as monotherapy; cemiplimab and durvalumab have also demonstrated effectiveness in ORR (30,33,35,37,40). With an increase in the number of clinical trails, cemiplimab, atezolizumab, avelumab and durvalumab may be added to the guidelines.…”

Section: Discussionmentioning

confidence: 99%

“…The ORR was 31%, disease control rate (DCR) was 49% and a median duration of response was 17 months ( 22 ). NCCN recommends nivolumab as a subsequent therapy following disease progression in patients with CPA (Child-Pugh class A) or CPB (Child-Pugh class B) disease (a category 2A recommendation) ( 23 ). There are several other ongoing trials of combinations with nivolumab ( Table I ).…”

Section: Listed Drugsmentioning

confidence: 99%

Clinical outcomes and influencing factors of PD‑1/PD‑L1 in hepatocellular carcinoma (Review)

Wang

Tang

et al. 2021

Oncol Lett

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Hepatocellular carcinoma (HCC) has an increasing incidence worldwide, and the global 5-year survival rate ranges from 5-30%. In China, HCC seriously threatens the nation's health; the incidence of HCC ranks fourth among all theriomas, and the mortality rate is the third highest worldwide. The main therapies for HCC are surgical treatment or liver transplantation; however, most patients with HCC will experience postoperative recurrence or metastasis, eventually resulting in mortality. As for advanced or unresectable HCC, the current appropriate treatment strategy is transarterial chemoembolization; however, limited therapeutic effect and natural or acquired drug resistance affect the efficacy of this approach. Previous studies have demonstrated that PD-L1 expression on host cells and myeloid cells plays an important role in PD-L1 blocked-mediated tumor regression. Thus, further research on programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is required. Countries including the United States, France, Britain and China have developed PD-1/PD-L1 blockers, including nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, toripalimab, sintilimab and camrelizumab. Notably, all of these blockers have therapeutic effect and influencing factors in HCC. Factors that influence the clinical outcome of PD-1 have also been discovered, such as inflammatory genes, specific receptors and signaling pathways. The discovery of these factors will help to identify novel methods, such as combination treatment, to decrease the influence of other factors on the efficacy of PD-1/PD-L1. Sorafenib and lenvatinib have been approved for first-line treatment for patients with advanced HCC. When first-line treatment frequently fails, pembrolizumab and ipilimumab plus nivolumab are used following sorafenib (but not lenvatinib) treatment in advanced HCC. Thus, tumor immunotherapy using PD-1/PD-L1 blockers exhibits promising outcomes for the treatment of HCC, and more novel PD-1/PD-L1 inhibitors are being developed to fight against this disease. The present review discusses the clinical results and influencing factors of PD-1/PD-L1 inhibitors in HCC to provide insight into the development and optimization of PD-1/PD-L1 inhibitors in the treatment of HCC. Contents 1. Introduction 2. Listed drugs 3. Listed drugs in China 4. Influencing factors 5. Discussion 6. Conclusions

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“…2) include not only those with inherently low immunogenicity, but also those with WNT/β-catenin mutations, as described by Sia, Llovet and colleagues [8, 9]; thus, they are not infiltrated by CD8-positive cells. Therefore, anti-VEGF antibody or TKI therapy may work in such Teng type II tumors [14, 15] without immune cell infiltration by increasing immunogenicity through direct antitumor and necrotic effects on HCC. Harding et al [16] demonstrated this effect in patients with HCC; they found that all patients (10/10) with WNT/β-catenin mutations showed PD, whereas in the 17 patients without mutations, ICI therapy resulted in a disease control rate of 71% [16] (Table 2).…”

Section: Effects Of Ici Monotherapy and Combination Therapy In Patienmentioning

confidence: 99%

Limited Impact of Anti-PD-1/PD-L1 Monotherapy for Hepatocellular Carcinoma

Kudo¹

2020

Liver Cancer

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Two ICIs are approved by the United States Food and Drug Administration (FDA) for HCC: nivolumab as second-line therapy following progression on sorafenib (based on the results of the phase I/II CheckMate 040 study) [3], and pembrolizumab as second-line therapy (based on the phase I/II KEYNOTE-224 study) [4]. However, the confirmatory phase III CheckMate 459 study [5] (nivolumab vs. sorafenib) and the second-line phase III KEYNOTE-240 study [6] (pembrolizumab vs. placebo) both failed; therefore, approval of nivolumab and pembrolizumab was withheld in most countries. The results from the first interim analysis of a study published in the New England Journal of Medicine show that combination therapy with atezolizumab plus bevacizumab is markedly superior to sorafenib as the current standard for all endpoints (overall survival, progressionfree survival, objective response rate, quality of life, and adverse events) [7]. The regimen was already approved by the FDA followed by approval in many countries, including Japan. The success of first-line combination therapy with atezolizumab and bevacizumab is thus surprising considering the failure of first-and second-line monotherapy with ICIs. This editorial explores the limitations of ICIs as monotherapy.

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Pembrolizumab for the Treatment of Hepatocellular Carcinoma

Cited by 31 publications

References 30 publications

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Clinical outcomes and influencing factors of PD‑1/PD‑L1 in hepatocellular carcinoma (Review)

Limited Impact of Anti-PD-1/PD-L1 Monotherapy for Hepatocellular Carcinoma

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