Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?

Brizzi, Maria Pia; Pignataro, Daniele; Tampellini, Marco; Scagliotti, Giorgio Vittorio; Maïo, Massimo Di

doi:10.1080/14737140.2016.1227706

Cited by 15 publications

(8 citation statements)

References 51 publications

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“…Advanced HCC still is a medical unmet need; for over a decade, sorafenib had been the only approved treatment in this setting, with several drugs failing to show a benefit both in first- and second-line setting in RCTs 61. Trials conducted in the last decade have been generally characterized by an underestimation of driving mechanisms of HCC pathogenesis and progression; thus, many studies enrolled a heterogeneous population regardless of potential biomarkers of response.…”

Section: Discussionmentioning

confidence: 99%

Second-line treatment options in hepatocellular carcinoma

Marino¹,

Zichi²,

Audisio³

et al. 2019

DIC

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For many years, sorafenib has been the only approved systemic treatment for advanced hepatocellular carcinoma (HCC). For over a decade, randomized controlled trials exploring the efficacy of new drugs both in first- and second-line treatment have failed to prove any survival benefit. However, in the past few years, several advances have been made especially in pretreated patients; phase III trials of regorafenib, cabozantinib, and ramucirumab in patients with elevated α-fetoprotein have demonstrated efficacy in patients progressing after or intolerant to sorafenib. In addition, early phase I and II trials have shown promising results of immunotherapy alone or in combination with tyrosine-kinase inhibitors or monoclonal antibodies in the same setting of patients. In this review, we will discuss the evidence on second-line options for HCC, focusing on the latest results that are currently refining the treatment scenario.

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Section: Discussionmentioning

confidence: 99%

Second-line treatment options in hepatocellular carcinoma

Marino¹,

Zichi²,

Audisio³

et al. 2019

DIC

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“…In detail, several phase III trials conducted after the approval of sorafenib, testing new drugs both as first-line compared to sorafenib or as second-line for patients who have failed sorafenib, yielded dismal results, and for almost a decade, sorafenib remained the only available treatment for advanced HCC patients. 14,[18][19][20][21][22][23][24][25][26][27] Luckily, in the past 3 years, several phase III trials have positively changed the therapeutic scenario.…”

Section: Clinical Evidence Of Ramucirumab Use In Hccmentioning

confidence: 99%

<p>Ramucirumab, A Second-Line Option For Patients With Hepatocellular Carcinoma: A Review Of The Evidence</p>

Luca¹,

Marino²,

Maïo³

2020

CMAR

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Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and predominantly develops in patients with liver cirrhosis. In patients with advanced disease, such as extra-hepatic extension or portal vein involvement, and with intermediate disease unsuitable for locoregional therapies, systemic therapy is recommended, if liver function and performance status are adequate. Following a decade of negative Phase III trials since the approval of sorafenib, more recently several drugs have proven efficacy both in first line versus sorafenib (lenvatinib) or in second line versus placebo (regorafenib, cabozantinib, ramucirumab). In this review, we summarize the preclinical and clinical evidence supporting the use of ramucirumab, a recombinant IgG1 monoclonal antibody that specifically binds to Vascular Endothelial Growth Factor receptor 2 (VEGFR-2), in HCC. Following the results of the REACH trial, that was negative in the overall study population but identified a subgroup that could benefit from ramucirumab treatment, the REACH-2 trial was a randomized, placebo-controlled trial, designed to assess ramucirumab as second line in patients with alpha-fetoprotein (AFP) ≥400 ng/mL. The results of REACH-2 were published in February 2019, leading to Food and Drug Administration and European Medicines Agency approval of the drug as second-line agent for advanced HCC (after sorafenib) in patients with AFP ≥400 ng/mL. For the first time in the history of systemic treatments for HCC, a predictive factor of efficacy was identified. In this review, we also discuss the potential clinical development of systemic treatments in HCC, focusing on combination therapies with immunotherapy (following the recent results of the combination of atezolizumab and bevacizumab in the IMbrave 150 clinical trial) and treatment sequences as a way to maximize survival benefit.

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“…The most important causes of those negative results are: (1) the heterogeneity among the HCC patients recruited and the lack of selection criteria based on molecular patterns; and (2) the imbalance between adverse events and tolerable dosage vs anticancer efficiency and drug potency of the tested agents. Current advances in medicine and biology will improve our knowledge regarding the different and complex molecular mechanisms and driving mutations involved in this vast heterogeneity of this unique and multidimensional type of cancer and will guide us towards the right direction of conducting successful trials in the near future [104]. …”

Section: Sorafenib and Other Chemotherapeutic Drugsmentioning

confidence: 99%

Evolving role of Sorafenib in the management of hepatocellular carcinoma

Ziogas

Tsoulfas

2017

WJCO

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Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality. Although there is a broad spectrum of treatment options to choose from, only a few patients are eligible candidates to receive a curative therapy according to their stage of disease, and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer. Sorafenib, a multikinase inhibitor, is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease. It has been shown to improve the overall survival, but with various side effects, while its cost is not negligible. Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy. Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection, liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents. In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies.

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Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?

Cited by 15 publications

References 51 publications

Second-line treatment options in hepatocellular carcinoma

Second-line treatment options in hepatocellular carcinoma

<p>Ramucirumab, A Second-Line Option For Patients With Hepatocellular Carcinoma: A Review Of The Evidence</p>

Evolving role of Sorafenib in the management of hepatocellular carcinoma

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