Latest in hepatocellular carcinoma treatments
Dr Ghassan Abou-Alfa - Memorial Sloan Kettering Cancer Center, New York, USA
I have a couple of presentations, I actually am talking about the results of the CALGB-80802 study which is the doxorubicin plus sorafenib versus sorafenib, a phase III clinical trial for first line in hepatocellular carcinoma. This will be at the oral presentation session for the non-colorectal GI on Monday morning. This will be followed by the arginine deaminase, ADI-peg20, versus placebo, a phase III trial again in second line in HCC as well.
Can we talk some more about the sorafenib trial first?
The story of the sorafenib doxorubicin is really as old as sorafenib itself. Actually from the first day when sorafenib was launched, or rather the sorafenib study, the SHARP trial, was launched, versus placebo in first line we launched a study of doxorubicin plus sorafenib versus doxorubicin plus placebo at that time because understandably there was no sorafenib data and at this point in time it was the understanding, at least, that doxorubicin is a standard of care. This emanated from phase I data that showed in this combination there could be actually some potential benefit for the combination in HCC specific added to at least three, if not four, mechanism of action that really would enhance that combination. As such we embarked on that study, this was reported already in The Journal of the American Medical Association, or JAMA. In an exploratory analysis where we compared the two arms, the study was not powered, it is a randomised phase II study, but we compared the two arms of doxorubicin plus sorafenib versus doxorubicin plus placebo and we found a critical improvement in survival for the doxorubicin plus sorafenib arm – 13.7 months versus doxorubicin plus placebo 6.5 months. Obviously clinically and statistically significant.
Now, you can imagine what the question would be – is this really the combination or is it really sorfenib on its own? We really didn’t know at that time, nonetheless the appropriate second step will be to do the study of doxorubicin and sorafenib versus sorafenib. That’s really what led to that study which is under the umbrella of the Alliance now, which is the Alliance for Clinical Trials or previously CALGB plus other co-operative groups, a multi-co-operative group run by all the co-operative groups under the umbrella of the CTEP and the NCI. That’s a very important study because it’s the first historical ever phase III trial in HCC run by the US government NCI. So really why this is important, yes, it’s nice historically but also it’s critical because it shows that HCC is unfortunately a disease that’s abundant in the US and accrual to that study is very feasible and possible. So that’s a very important conclusion, regardless of what the data shows.
When it comes to the results of sorafenib by itself or in combination, what is the best combination, the best course there?
Unfortunately the data did not pan out as the data is reported at this meeting. Doxorubicin plus sorafenib did show a median survival of about close to 9 months and for the sorafenib close to 10 months which is the classic what we see with sorafenib alone anyway. There was no clinical or statistical significance. So, in addition to that we found that, of course, the added toxicity from the doxorubicin was noticeable, we’re adding a chemotherapeutic agent, and as such I would say this is not a combination that I would recommend for further use in the first line setting and the only piece missing still in our part of the puzzle is a lot of correlative work that we’re hoping will come out and maybe we’ll learn more from.
Then moving on to the ADI trial, could you tell us more about that?
The ADI is really a different story all together and it’s a fascinating story. Arginine deamination is actually a mainstay and the powerhouse for the treatment of leukaemia, as we know. Our bodies depend on arginine to survive and our cells need arginine as an essential amino acid. Of course you can deplete arginine and kill the cells but the body is smarter than that. If anything, when you deplete the arginine through ADI-peg20 it turns it into citrulline. Citrulline abundance in the cell will turn citrulline back into arginine through two enzymes, one of them is called argininosuccinate synthetase or ASS and the argininosuccinate lyase, ASL. The beauty of that experiment is not the drug itself because the depletion of the arginine is one story but along with it we have found that actually primary liver cancer or HCC lacks ASS and, as such, your ability after depleting arginine to replete it through citrulline is not there and, as such, the cells die.
With this all said, a couple or at least three phase II clinical trials have been reported in the literature that showed an improvement in outcome in the second line setting as well as in the first line setting for patients who are receiving ADI-peg20 which is the pegylated form of arginine deamination. As such, a phase III trial was a totally appropriate next step so a randomised phase III trial in the second line setting randomising patients to ADI-peg20 versus placebo, and this is the data we are reporting. Unfortunately again this data did not pan out, the median survival was really across the two arms very similar, like not different at all but we are showing at the meeting a fascinating piece of data where if you show the arginine depletion that will last more than seven weeks corrected for the number of treatments, of course we don’t want to say that we treated more that’s why people do better, but if you correct for the number of treatments and you correct for the baseline arginine level and you show that the depletion went before seven weeks then the two curves will open up like magic and there is a clear improvement in survival for that subpopulation.
The other thing we learned along the way also, that our population in that study is very heavy on sorafenib pre-treatment, in other words they all either received sorafenib and they failed on it or they received sorafenib and they did not tolerate it, close to about 80%. We discovered that actually if you pre-treat with sorafenib in cell lines, and this data we did not know at that time, if you pre-treat with sorafenib cell lines with HCC cell lines ASS goes up. As such we have already sadly created for ourselves a phenomenon of resistance without knowing it. Interestingly again we have the 20% population which is very small but if you look at that population no statistical significance and this is a look that we did despite being part of the subgroup of analyses that were planned and the stratification that’s planned. Nonetheless we see that the two curves again open up. So this study is still negative in regard to proving that ADI-peg20 does not work in the second line setting at the dose of 80mg/m2, because we have some question about the dosing as well.
However it opens a question with regard to future development from the perspective of how much arginine depletion you want, number two is how you mitigate the resistance to the ASS elevation and number three dosing and probably also some form of a new generation of ADI-peg20 because also one thing we’ve found is that because it’s pegylated the body will develop antibodies and something to medicate as well.
So a lot of learning that hopefully will follow on in this world of metabolomics.