You are here

The Which: Clinical Evidence and Ongoing Trials in Anti-Angiogenic Treatments - Hepatocellular Carcinoma

L. Bolondi (Italy)

Luigi Bolondi talks about liver cancer, introducing some of its characteristics, such as abnormal arterial vascularization. The presentation then considers phase III clinical trials and looks to the future of treatment beyond sorafenib.


Florian Lordick:  Now it’s time for Professor Luigi Bolondi, who is a Professor of Medicine and Gastroenterology at the University of Bologna treating a lot of patients with hepatocellular carcinoma, so Luigi, what is the role of anti-angiogenic treatment in HCC?

Full transcription

Full transcription


Florian Lordick:  Now it’s time for Professor Luigi Bolondi, who is a Professor of Medicine and Gastroenterology at the University of Bologna treating a lot of patients with hepatocellular carcinoma, so Luigi, what is the role of anti-angiogenic treatment in HCC?

Disclosure statement

Luigi Bolondi :  Thank you, Florian and dear colleagues.  As you know, I am a gastroenterologist and not an oncologist, but as many gastroenterologists and hepatologists we are involved in the treatment of liver cancer because, as you know, primary hepatocellular carcinoma develops in the great majority of cases, over 90% of cases, on the background of chronic liver disease and especially liver cirrhosis.

Vascularization of liver nodules changes during hepatocarcinogenesis: arterial enhancement

The peculiar aspect of hepatocellular carcinoma during its development, during the process of hepatocarcinogenesis is the abnormal arterial vascularisation.  Liver cirrhosis is characterised by the development of regenerative nodules.  These regenerative nodules may increase in size.  Normally they are 3mm in size and they can reach the size of 8mm, 9mm, 10mm and during this increase there is a change in the vascularisation of these nodules with a decrease of portal venous supply.  Normally the liver lobule is supplied by two-thirds from the portal flow and one-third from the arterial flow.

As you know from this slide, there is a progressive decrease in the portal flow and the development of an increased abnormal arterial supply.

At the level of well differentiated hepatocellular carcinoma, there is a great majority of abnormal arterial supply and this is the key factor for the diagnosis of hepatocellular carcinoma because hepatocellular carcinoma is probably the unique cancer where we can reach a definite diagnosis without biopsy, only on the basis of the pattern, the typical vascular pattern at contrast enhanced ultrasound, dynamic CT scan and MRI. This is acknowledged by all the guidelines, but this abnormal arterial supply is also the key factor for a targeted therapy.

Sorafenib consistently increased overall survival in different global patient populations

In fact, in 2007 there results of the SHARP trial demonstrated that sorafenib which is an anti-angiogenic drug as you know, but it has also an anti-proliferative effect, this drug has been demonstrated to be effective in prolonging the overall survival in a large Phase III, multi-centre trial.

These results were also confirmed by another trial in a different population, the Asia-Pacific trial and as you can see from this slide, the hazard ratio of the two studies is quite similar, 0.69 for the SHARP trial and 0.68 for the Asia-Pacific trial. These studies were published in 2008 and 2009.

Sorafenib was expected to open the way to a long list of first-line drugs, but this has not been the case to date

At the moment, sorafenib is the only drug with a demonstrated efficacy on prolonging survival.

But this drug was expected to open the way to a long list of first-line drugs, but this has not been the case until now.

Mostly negative results: phase III clinical trials testing molecular targeted therapies in advanced HCC

You see here a list of trials where the results were negative for brivanib, linifanib, erlotinib.  The trial with regorafenib which is a second-line trial is still ongoing.  The trial on everolimus with a different target, the mTOR, was a negative one and recently the trial of ramucirumab which is a second-line trial was negative.

There are other trials with different targets, the refametinib with the RAS target and the tivantinib with the MET target which are still ongoing.

When sorafenib fails due to progression or intolerance: perspectives for second-line treatment

When sorafenib fails due to the progression or intolerance, the perspectives for a second-line treatment are still ongoing because we don’t have a second-line treatment for this cancer.

REACH: a phase III trial of second-line ramucirumab vs placebo in patients with advanced HCC following first-line therapy with sorafenib

But it is important to analyse the results of the REACH trial because this trial demonstrated that there is an increase of survival.  In the treated arm the survival was 9.2 months in comparison to 7.6, but the p-value of the difference was negative.

REACH: patients with high levels of AFP at baseline show increased OS on ramucirumab compared with those treated with placebo

But if we go into a subgroup analysis differentiating patients with elevated alpha-fetoprotein, more than 400ng of alpha-fetoproteins and below this level, you can see that the difference in the survival is significant with a hazard ratio quite significant of 0.67, similar to the hazard ratio we met in the SHARP trial for sorafenib.

There is no difference in the survival curves of patients below this level of alpha-fetoprotein, below 400ng.

REACH: conclusions

So the second-line treatment with ramucirumab showed improvements in PFS, time to tumour progression and objective response but did not improve the median overall survival in patients with advanced HCC in comparison with placebo.

But patients with a baseline AFP over 400ng showed an improvement in overall survival and this finding is hypothesis-generating only and requires confirmation by prospective studies.

RESOURCE: a phase III trial of regorafenib vs placebo in sorafenib-relapsed HCC patients

There are other ongoing trials, as I told you.  In the RESOURCE phase III trial of regorafenib versus placebo in sorafenib-relapsed HCC patients, there is a randomisation two to one.

What is important to know is that all these trials are performed in patients with good liver function, Child-Pugh A Class and these patients represent only a minority of patients because the majority of these patients with advanced hepatocellular carcinoma are in Child-Pugh B Class, so these patients in Child-Pugh B Class still represent an orphan population.

Phase III: ADI-PEG 20 vs placebo for advanced HCC failing prior systemic treatment

Another trial with a different target is the ADI-PEG Phase III trial.  The ADI-PEG is arginine deiminase inhibitor.  This is a protein inhibiting the synthesis of arginine which is very important for the tumour growth.  Also this trial is carried out in patients with Child-Pugh Grade A+ but also B7, but this is still ongoing.

Tivantinib (ARQ 197)

Another trial with a definite target, the MET target is still ongoing. 

OS is significantly greater in MET-high patients treated with tivantinib compared with those receiving placebo

It has been demonstrated in a Phase II trial that the patient with high MET treated with this drug has a significant improvement in the overall survival with a hazard ratio of 0.38 which is very important.  There is a great difference.

Phase II tivantinib vs placebo in MET-high patients with inoperable HCC after prior systemic treatment

On the basis of this Phase II trial, the Phase III trial has been established and this is the Phase III trial again in Child-Pugh A patients without important systemic symptoms.

What does the future hold beyond sorafenib?

There are some ongoing trials in Phase III especially for the second-line treatment.  The first-line treatment still remains sorafenib for patients with advanced HCC who cannot be treated with other treatments such as surgery, liver transplantation.  HCC is the only cancer which can be treated by liver transplantation and also by other local treatments such as thermal ablation and arterial chemoembolisation, but for advanced cancer, the first-line treatment still remains sorafenib.

We have some perspectives and this represents the first attempt to perform a personalised treatment of HCC.  The MET-high patient could be treated, if the trial will be positive with tivantinib, RAS-high with refametinib, the MET-low with regorafenib, the AFP-high patients with ramucirumab.  These are the perspectives.

Thank you! BLOG – Bolondi unit

Thank you for your attention.