ASCO 2012, Chicago, USA

Regorafenib effective for GISTs that progress due to resistance to approved targeted therapies

Dr George Demetri – Dana-Farber Cancer Institute, Boston, USA

George, great to have you here for ecancer.tv. Regorafenib has actually performed very well, now this is an alternative now for patients with GIST.

It’s not yet, we have to get it approved by the regulators but our data should support that.

So what do you have? Tell me about the study you’ve just presented here at ASCO.

The study we did was based off an academic screening study where we saw regorafenib control the disease in patients even after Gleevec or imatinib and Sutent, sunitinib, had failed in those patients, patients who were progressing, had a median progression free survival of about ten months. My colleague, Suzanne George, was the first author and JCO 2012 just got published. On the basis of that screening study we proposed to Bayer a phase III worldwide study to really prove the point – does this drug do something unique even after Gleevec and Sutent have failed?

And what actually is it doing mechanically?

What it does, actually it goes back to some basic science we did with the kit receptor, it has a very different way of binding to the kit receptor. It looks like it can actually bind to mutant forms of the kit receptor with very different kinetics. So that gave us a scientific rationale, we took it into our GIST pre-clinical models and it looked good there and so Bayer was a wonderful collaborator, they said, ‘Absolutely, let’s do this.’ We got the worldwide GIST community together. So between January and July 2011 we finished this study worldwide. My collaborators across the world, Europe, Asia, US and what came out of that study were the results we presented here at ASCO 2012 which is a much longer progression free survival in the group initially randomised to regorafenib, about 5 months, compared to less than a month for those patients who initially were randomised to placebo. A hazard ratio of 0.27, 73% reduction in risk of progression in death, so highly statistically significant.

What might this mean, then, in terms of practical medicine?

What this means practically is once we get this drug approved we believe it will set a new standard of care for patients who had had imatinib and failed, had sunitinib and had that fail to control their disease, now this gives them a third option. For researchers and doctors it actually also raises a vexing question – where should a drug this powerful fit? Should it stay in the third line, should it move earlier? I think that’s going to be an interesting question for clinicians in future clinical research to work on. Also, might this drug combine with other interesting drugs that target different pathways? We know that GIST can be controlled, sometimes very long term, by shutting down the kit or PDGF receptor kinases but we’re not curing these patients. How can we continue to push towards cure and might regorafenib give us a new tool to do that?

It seems you’ve made out a case for fast tracking this agent which you sort of have already.

Absolutely. The first GIST patient in the world got this drug in 2010 in an academic study and by March 2012 we have enough data to go to worldwide regulators and say, ‘We think this is a new standard.’

Is there a downside, though, of using this agent?

The downside is simply one of learning to use it like many of the multi kinase inhibitors. Remember, regorafenib hits the VEGF receptor pathway so it’s a little bit more like Sutent than Gleevec so it absolutely is a VEGF receptor inhibitor. Because of that it has certain known and expected side effects – high blood pressure, hand-foot syndrome, some more diarrhoea. So these things in our trial were highly manageable, very few patients, less than 7%, had to come off study because of adverse events but the doctors were very skilled in doing dose modification. So I think the one downside is that it takes some skill, takes a bit of a learning curve, but then once you’re used to working with regorafenib, as our team is, it’s actually a very easy drug to work with.

Now imatinib and sunitinib initially made a massive difference to patients with GIST, this is making another difference, how do you see the future of this disease shaping up?

I see it like many other cancers, many other solid tumours. We make a difference for patients, we gain some years of benefit and survival, then we add another drug incrementally. We might add another year, add another drug, maybe another year. I think it’s the way cancer medicine goes – we make incremental advances and before long we will find some combination that will make the next dramatic event. I think this gives us an important new tool to really do those sorts of combination studies.

And the take home message for doctors?

The take home message is be optimistic, screen patients, enrol in clinical trials and then good things happen. Our patients will benefit from this research. The other thing is that GIST is still a relatively rare disease and yet even in a relatively rare disease, because our community worldwide of doctors and nurses work together with the patients and with a very supportive pharmaceutical company that actually allowed us to do the research that was rigorous, we’re going to have data in remarkably rapid time. Two years from first patient to a registration packet is, I think, a new world record. So we’re happy about that as a collaborative team.

George Demetri, great to have you with us, thank you.

Thanks for inviting me. Thank you.