A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study.

Abou‐Alfa, Ghassan K.; Chan, Stephen L.; Furuse, Junji; Galle, Peter R.; Kelley, Robin Kate; Qin, Shukui; Armstrong, J.; Darilay, Annie; Vlahović, Gordana; Negro, Alejandra; Sangro, Bruno

doi:10.1200/jco.2018.36.15_suppl.tps4144

Cited by 84 publications

(71 citation statements)

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“…23,29 The HIMALAYA Phase 3 study is currently assessing similar combinations of durvalumab and tremelimumab in the first-line setting compared to sorafenib. 30,31 Multiple ongoing trials are evaluating combination therapy of anti-PD-1/PD-L1 or Anti-CTLA-4 antibodies with other modalities such as anti-angiogenesis. Most recently the IMbrave150 study demonstrated the combination of atezolizumab (anti-PD-L1) and bevacizumab which targets vascular endothelial growth factor A (VEGF-A) to be the first combination to increase OS and progression free survival (PFS), the co-primary endpoints of the study, compared to sorafenib in the first-line setting.…”

Section: Immunotherapy In Hcc (Immune Checkpoint Inhibitors)mentioning

confidence: 99%

<p>The Immune Modulation Effect of Locoregional Therapies and Its Potential Synergy with Immunotherapy in Hepatocellular Carcinoma</p>

Singh¹,

Toom²,

Avula³

et al. 2020

JHC

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Locoregional therapies (LRTs) including radiofrequency ablation, surgical resection, and TACE, play a pivotal role in the treatment of early stage/locally advanced hepatocellular carcinoma (HCC). Besides their direct effect on tumor cells, LRTs also play an essential role in the immunomodulation of the tumor microenvironment which is of interest in the current era of cancer immunotherapy. In this review, we describe the HCC immune microenvironment and how it is affected by LRTs as described in multiple pre-clinical and clinical studies and provide the rationale for combining LRTs with immunotherapy.

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Section: Immunotherapy In Hcc (Immune Checkpoint Inhibitors)mentioning

confidence: 99%

<p>The Immune Modulation Effect of Locoregional Therapies and Its Potential Synergy with Immunotherapy in Hepatocellular Carcinoma</p>

Singh¹,

Toom²,

Avula³

et al. 2020

JHC

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“…Preliminary results based only on 40 patients showed a modest ORR of 15% [25] (see Table 3). A large multicenter phase III trial of durvalumab and tremelimumab as first-line treatment in patients with unresectable HCC: HIMALAYA study (NCT03298451) [141] with estimated enrolment of 1310 patients is currently ongoing.…”

Section: Icb and Icb Combinationmentioning

confidence: 99%

Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers

Tai

Choo

Chew

2019

Cancers

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Hepatocellular carcinoma (HCC), the most common type of liver cancer, is derived mostly from a background of chronic inflammation. Multiple immunotherapeutic strategies have been evaluated in HCC, with some degree of success, particularly with immune checkpoint blockade (ICB). Despite the initial enthusiasm, treatment benefit is only appreciated in a modest proportion of patients (response rate to single agent ~20%). Therapy-induced immune-related adverse events (irAEs) and economic impact are pertinent considerations with ICB. It is imperative that a deeper understanding of its mechanisms of action either as monotherapy or in combination with other therapeutic agents is needed. We herein discuss the latest developments in the immunotherapeutic approaches for HCC, the potential predictive biomarkers and the rationale for combination therapies. We also outline promising future immunotherapeutic strategies for HCC patients.

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“…A phase I/II clinical study including combination of Tremelimumab (anti-CTLA4) and Durvalumab (anti-PD-L1) in 40 HCC patients reported a response rate of 25% and manageable toxicity profile [55] . Currently, a phase III study of combination therapy including various dosage regimens of Durvalumab and Tremelimumab versus Sorafenib is ongoing to compare the efficacy of these therapeutic approaches (NCT03298451) [56] . Similar combination therapy of Tremelimumab and Durvalumab is being studied in a phase II trial in HCC patients previously treated with Sorafenib (NCT02519348) [52] .…”

Section: Tremelimumab (Anti-ctla4) + Durvalumab (Anti-pd-l1)mentioning

confidence: 99%

Immune checkpoint blockade therapies for HCC: current status and future implications

Shrestha¹,

Bridle²,

Crawford³

et al. 2019

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Hepatocellular carcinoma (HCC) is the most lethal and common type of liver cancer with limited treatment options at the advanced stage. The use of immune checkpoint inhibitor (ICI) based immunotherapy is exponentially increasing in the treatment of patients with advanced solid tumors. The expression of immune checkpoints on tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape. Checkpoint blockade immunotherapies with antibodies against PD-1, PD-L1 or CTLA-4 are being investigated in clinical trials in HCC patients. ICIs have improved survival in patients with inoperable advanced stage HCC where other curative treatments are not applicable. However, the response rates remain low with only a small subset of patients responding to this therapy. There is an unmet need to identify predictive markers to select those HCC patients who would benefit from ICI therapies. Importantly, epithelial-to-mesenchymal transition (EMT), a major process driving HCC invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state, has been implicated as a resistance mechanism associated with ICI therapies. The role of EMT as a regulator of immune checkpoint molecule in HCC is just emerging. However, the consequence of EMT as a resistance mechanism in HCC patients undergoing ICI treatments remains unexplored. In this review, we summarize the recent clinical studies with ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based on immune and non-immune therapies. We will discuss the ongoing efforts to discover new immune checkpoint molecules in HCC as potential drug targets. We also highlight the role of EMT in facilitating therapy resistance in HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.

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A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study.

Cited by 84 publications

References 0 publications

<p>The Immune Modulation Effect of Locoregional Therapies and Its Potential Synergy with Immunotherapy in Hepatocellular Carcinoma</p>

<p>The Immune Modulation Effect of Locoregional Therapies and Its Potential Synergy with Immunotherapy in Hepatocellular Carcinoma</p>

Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers

Immune checkpoint blockade therapies for HCC: current status and future implications

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