Checkpoint Inhibitors for the Treatment of Advanced Hepatocellular Carcinoma
Laura A. Huppert M.D.
John D. Gordan M.D., Ph.D.
Robin Kate Kelley M.D.
First published: 26 March 2020 https://doi.org/10.1002/cld.879
Potential conflict of interest: J.D.G. advises Genentech. R.K.K. advises Genentech and Roche.
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Abbreviations
APC
antigen‐presenting cell
ASCO
American Society of Clinical Oncology
BSC
best supportive care
CPI
checkpoint inhibitor
CTLA‐4
cytotoxic T lymphocyte–associated protein 4
FDA
US Food and Drug Administration
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
IRAE
immune‐related adverse event
MHC
major histocompatibility complex
MKI
multikinase inhibitor
ORR
objective response rate
OS
overall survival
PD‐1
programmed cell death protein 1
PD‐L1
programmed death‐ligand 1
PFS
progression‐free survival
TACE
transarterial chemoembolization
VEGFR
vascular endothelial growth factor receptor
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer‐related deaths worldwide.1 In the United States, HCC is the fastest rising cause of cancer death, owing in part to the obesity epidemic.2 The high rate of mortality has been attributed to an aggressive tumor biology, comorbid underlying liver disease in a majority of patients, late stage of disease at diagnosis in many cases, and a lack of effective systemic therapy options. For more than a decade, the multikinase inhibitor (MKI) sorafenib has been the only systemic therapy to improve survival in advanced HCC, although median survival prolongation from sorafenib is less than 3 months and fewer than 5% of patients achieve objective response rate (ORR) in the pivotal sorafenib trials.3, 4 Since 2017, multiple new drugs, including lenvatinib, regorafenib, and cabozantinib, have demonstrated noninferiority to sorafenib in the treatment of advanced HCC, leading to regulatory approvals and dramatically expanding the treatment landscape for advanced HCC. Despite these advances, the median overall survival (OS) remains only about 1 year after the start of systemic therapy, the duration of treatment response is limited, and new treatment strategies are still urgently needed.
Cancer immunotherapy with checkpoint inhibitors (CPIs) is an exciting and rapidly evolving area of oncology that has dramatically increased survival in patients with many types of cancer.5 HCC arises in the setting of proinflammatory conditions, such as hepatitis B/C infections and liver cirrhosis, and demonstrates an immunosuppressive microenvironment. These features are associated with response to immunotherapy in other cancer types, suggesting that CPI may have potential benefit in HCC as well. In this review, we will first discuss the basic principles of cancer immunology and mechanisms of immunotherapy. Then, we will highlight key clinical trials that demonstrate the therapeutic potential of immunotherapy in the treatment of advanced HCC. Finally, we will comment on challenges and future directions in this field.
Conclusion
Immune CPIs have established the potential for durable, robust, and meaningful responses across agents and subgroups of patients with advanced HCC. Ongoing clinical trial biomarker analyses aim to define features associated with response to CPI monotherapy. In addition, combination approaches are underway to determine whether the addition of tyrosine kinase inhibition, the anti–vascular endothelial growth factor antibody bevacizumab, or additional immune CPIs can augment the proportion of patients with response to PD‐1 or PD‐L1 inhibition. The unprecedented activity of CPI in patients with advanced stage HCC has prompted a new generation of clinical trials in early and intermediate stages of disease in hopes of improving the proportion of patients who achieve disease cure. 作者: StephenW 时间: 2020-3-28 20:45