World Congress on Gastrointestinal Cancer 14, Barcelona, Spain

CORRECT study data prompts US FDA priority review

Professor Alberto Sobrero – Ospedale SanMartino, Genova, Ital

What have been some of the most recent developments in molecularly-targeted treatment for mCRC?

The major developments can be split into two phases. The first is the year 2000 when we got availability to both the anti-angiogenic bevacizumab as well as the anti-EGFR compounds such as cetuximab and panitumumab. Then this year we have got these two other agents, one is aflibercept that is an anti-angiogenic compound as well, along with regorafenib that is a multi-kinase inhibitor.

What makes regorafenib distinct from other molecularly-targeted agents in mCRC?

It is indeed unique because a) it is a dirty drug, so called dirty meaning that it inhibits multiple pathways so it does not only attack the angiogenesis pathway but it also attacks the stroma as well as the tumour, meaning the capacity of the tumour cells to divide, that’s number one. The second characteristic is that it is the first oral multiple kinase inhibitor that is efficacious in colorectal cancer, all others have failed so far.

You presented the findings from the CORRECT trial, could you remind us about that trial?

Yes, that study is kind of a first in its class because it has a different philosophy as opposed to all the other studies, the philosophy being the fact that its efficacy has been explored in the toughest condition, that is, the patient fully resistant to anything else. So the comparison could only have been done with the best supportive care and that is was what was done. So the trial is a randomised comparison 2:1 on about 700 patients, two patients going into receiving regorafenib and one patient receiving just best supportive care. Of course, the primary endpoint in this setting could not have been anything else but survival.

What are the top-line results from the study?

Certainly the top line results have been the statistically significant difference in overall survival. Now, an issue can be that sometimes what is statistically significant is not so clinically relevant so, in terms of relative figures, the hazard ratio for overall survival was 0.77 which is about a 30% increment as opposed to the control arm. Now, in terms of absolute delta difference, we got only 1.4 months which may sound not as outstanding as expected but in that setting you have to remember that the control arm had only five months life overall survival so extending that by 1.5 months means extending it by 30%. Again, you can judge these results in two ways: that’s too little to be relevant, but if you are really desperate, well, that’s a substantial advancement.

What has been the reaction to these data since their first presentation at ASCO 2012?

Let me articulate this on three levels. The first is that we have been the top accruing centre in the world on this trial so my reaction is relevant because we put more than fifty patients on the trial. We immediately recognised the patients on treatment, as opposed to those not on treatment, because of the very rapid progression of those not receiving the treatment. The second level of comment was how that was perceived at ASCO. That was perceived as a major advancement, both conceptually and in terms of relevance. Again, everybody is very conservative saying yes, we fully agree on the fact that 1.5 months is really so little but in that setting it’s very relevant. The third level is the press release that I heard, well actually the news that I heard from yesterday, that FDA granted fast-track approval process to this, indicating that the three interpretations are coinciding.

Could there be any benefit of using regorafenib earlier in the course of the disease?

Of course we don’t know and we need to run the trial. The problem is that in this disease it has become so difficult to explore the efficacy of new agents in early lines that maybe could be explored, say, as a maintenance agent, something more innovative than just getting going against, say, bevacizumab in first line.

Would there be any benefit of combining regorafenib with other agents?

There it’s really a jump in the dark. Of course it’s something that you want to do whenever you make a step forward, the next step is combination. So one idea could be combining it with oral fluorouracil but again certainly not in first line as opposed to the strong doublet plus bev so, again, plenty of room for development.

Are you now doing other trials with regorafenib?

We have just done… it’s presently running the expanded access programme on the regorafenib and from the accrual I can tell you that in the first fifteen days we have already filled up all the slots, the fifteen slots that were granted to us. So we have asked for extended, just because the people are in need for something.

Are there any other results from the trial that you would like to highlight?

Yes, we have spoken only of overall survival gain but I think that all the other endpoints are very relevant, meaning that, first, the quality of life was not impacted by the use of this agent; second, the spectrum of toxicity is very benign because the major toxicity is fatigue, that is in the range of 20%, and hand foot syndrome, again 20% overall incidence, so not so much impact on quality of life on the subjective type of toxicities. The second aspect that it is worth emphasising is the hazard ratio for PFS, that is a kind of superstar type of hazard ratio, 0.48. So that means a doubling in the chances of not progressing, so that’s nice.

What is your take home message from the CORRECT study?

I could summarise by saying that regorafenib is an incrementalist, it is not a superstar as most of the advancement in this disease, actually as all the advancement in this disease, there is no superstar in this disease. It is so nice to have it.