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Emerging role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standardcare for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results inan alternative first-line treatment for the Chineseclinical oncology guidelines. Moreover,nivolumab and pembrolizumab,two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approvedfor subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessmentof new ICIs-based combinatory approaches.

SUBMITTER: Longo V

PROVIDER: S-EPMC6843273 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Project description:Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade, and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago. FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI-based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance. IMPLICATIONS FOR PRACTICE: Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)-based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus-related HCC, especially hepatitis B virus-related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease.

Project description:Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI's, combinations of CPI's and combinations of CPI's with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15-20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.

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Emerging role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

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