Mechanisms of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Patients with Hepatocellular Carcinoma

Lorenzo, Stefania De; Tovoli, Francesco; Trevisani, Franco

doi:10.3390/cancers14194616

Cited by 22 publications

(15 citation statements)

References 92 publications

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“…As a selective inhibitor of VEGFR1-3, FGFR1-4, PDGFR, KIT, and αRET, lenvatinib targets a combination of alternative and common pathways with the immunotherapy treatment. Immune therapy resistance is hypothesized to be related to the modulation of the immune microenvironment, including the tumor mutation burden, MLH expression, and changes in local cytokines [14]. Lenvatinib acts independently of these tumor microenvironment changes which may be responsible for the preserved efficacy after progression on immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study

Palmer,

Gile,

Storandt

et al. 2023

Cancers

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Background: Lenvatinib, a multikinase inhibitor, is an FDA-approved treatment for advanced hepatocellular carcinoma (HCC) in the first-line setting. Recent trial data have established atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab as preferred first-line treatment options for advanced HCC. The role of lenvatinib following progression on immunotherapy in patients with advanced HCC remains unclear. Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at the Mayo Clinic in Minnesota, Arizona, and Florida who received immunotherapy followed by lenvatinib. Median overall survival and progression-free survival analyses were performed using the Kaplan–Meier method, and responses were determined using RECIST 1.1. Adverse events were determined using CTCAE v 4.0. Results: We identified 53 patients with advanced HCC who received lenvatinib following progression on immunotherapy. Forty five (85%) patients had a Child Pugh class A at diagnosis, while 30 (58%) patients were still Child Pugh A at time of lenvatinib initiation. Lenvatinib was administered as a second-line treatment in 85% of the patients. The median PFS was 3.7 months (95% CI: 3.2–6.6), and the median OS from the time of lenvatinib initiation was 12.8 months (95% CI: 6.7–19.5). In patients with Child Pugh class A, the median OS and PFS was 14 and 5.2 months, respectively. Race, gender, and Child Pugh class was associated with OS on multivariate analysis. Discussion: Our study, using real-world data, suggests that patients benefit from treatment with lenvatinib following progression on immunotherapy in advanced HCC. The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown, and these results need to be validated in a clinical trial.

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Section: Discussionmentioning

confidence: 99%

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study

Palmer,

Gile,

Storandt

et al. 2023

Cancers

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“…Unfortunately, according to the RCTs data, only 10–30% of patients with advanced HCC demonstrate an objective response to ICIs ( Table 1 ) and, when the disease control rate (including patients with stable disease) is considered, immunotherapy is effective in only 70% of patients. Therefore, 30–40% of patients do not benefit at all from ICIs, either due to primary (lack of initial response) or secondary resistance (development of resistance to treatment after initial response) [ 10 ]. The identification of biomarkers able to predict the response and resistance to ICIs is urgently needed in order to correctly allocate medical resources and avoid the exposition of non-responder patients to the treatment toxicity.…”

Section: Biomarkers Of Response And/or Resistance To Immune Checkpoin...mentioning

confidence: 99%

“…However, there is still a relevant proportion of patients receiving ICIs who do not benefit from the treatment. Indeed, approximately 40% of HCC patients do not achieve disease control with ICIs due to primary resistance, and a similar proportion will experience disease progression after an initial response (secondary resistance) [ 10 ]. The identification and development of predictive biomarkers capable of accurately identifying patients who will benefit from ICIs (responders) is of the utmost importance to better understand and overcome mechanisms of resistance and, hence, to enable a precision medicine approach in HCC immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Strategies and Biomarkers Predicting Response and/or Resistance

2023

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In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with hepatocellular carcinoma (HCC). Following the positive results of the IMbrave150 trial, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) became the standard of care frontline treatment for patients with advanced stage HCC. Several other trials evaluated immunotherapy in HCC, demonstrating that ICIs-based regimens are currently the most effective treatment strategies and expanding the therapeutic possibilities. Despite the unprecedent rates of objective tumor response, not all patients benefit from treatment with ICIs. Therefore, in order to select the appropriate therapy as well as to correctly allocate medical resources and avoid unnecessary treatment-related toxicities, there is great interest in identifying the predictive biomarkers of response or resistance to immunotherapy-based regimens. Immune classes of HCC, genomic signatures, anti-drug antibodies, and patient-related factors (e.g., etiology of liver disease, gut microbiota diversity) have been associated to the response to ICIs, but none of the proposed biomarkers have been translated into clinical practice so far. Considering the crucial importance of this topic, in this review we aim to summarize the available data on tumor and clinical features associated with the response or resistance of HCC to immunotherapies.

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“…Thus, if immunotherapy might be considered a way to overcome the resistance induced by targeted therapy alone, it must be said that—if administered as a single agent—it fails to be responsive in a major proportion of patients with HCC: in fact, 40% of patients are primarily resistant to immune checkpoint inhibitors (ICIs) [ 13 ]. The mechanisms of resistance to ICIs include different aspects: failure in antigen presentation, heterogeneity in the TME, alterations in the regulatory molecules of ICIs and influence of immune-suppressive cells [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact

Federico¹,

Giunta

Tufo³

et al. 2022

Cancers

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Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new opportunity; however, their use has highlighted other issues: the vascular normalization compared to a vessel pruning to promote the delivery of an active cancer immunotherapy and the development of resistance to immunotherapy which leads to a better selection of patients as candidates for ICIs. Nevertheless, the combination of antiangiogenic therapy plus ICIs represents an intriguing approach with high potential to improve the survival of these patients. Waiting for results from ongoing clinical trials, this review depicts the current knowledge about the resistance to antiangiogenic drugs in HCC. It could also provide updated information to clinicians focusing on the most effective combinations or sequential approaches in this regard, based on molecular mechanisms.

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Mechanisms of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Patients with Hepatocellular Carcinoma

Cited by 22 publications

References 92 publications

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Strategies and Biomarkers Predicting Response and/or Resistance

Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact

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