WIN 2012

The WINTHER Study

Professor Razelle Kurzrock – MD Anderson Cancer Center, Houston, USA



Dr Kurzrock, we’re here in WIN 2012 in Paris; it’s been an exciting year for WIN. You’re going to talk to us a little bit about the WINTHER trial which is a very new trial that you’ve been behind, you’re instigation designing. So, can you talk a little bit?

Sure, it’s my pleasure to talk about the WINTHER trial. I believe that the WINTHER trial is one of the most forward thinking trials that I’ve seen. It incorporates very comprehensive molecular analysis to identify which patients should get which drugs. It has two arms, an arm A and an arm B; the arm A includes next generation sequencing which is an integrated approach to looking at DNA for mutations and other abnormalities but we know that these types of abnormalities, even with this advanced technology, are only found in up to 50% of patients. So it incorporated a second arm where we look at RNA analysis and other similar types of testing so that even patients that don’t have molecular abnormalities identified at the DNA levels can have interrogation of their tumours and a signature found to match them with appropriate drugs.

So it’s a trial that’s going to be carried out in four continents and it’s going to be different types of tumours.

That’s correct. So it will include any type of tumour and the reason for that is we now believe that different types of tumours may have more in common if they indeed have the same molecular signature than even the same type of tumour that has different molecular signatures.

So the trial involves… you have somebody doing the… the foundation medicine are doing the…

Next generation sequencing, yes.

So the trial is in collaboration with a company that are doing the next generation sequencing. How will this work?

The next generation sequencing is arm A and the IGR in France will be integral to arm B. So we will be doing a biopsy on each patient before they start the trial and there’s something unique about the types of biopsies that we’re going to be doing because we’re biopsying not just the tumour but also the normal tissue. This is something that has been missing from previous analyses because if you just biopsy the tumour you may get many signals that are irrelevant so it makes sense to compare it to normal tissue and subtract the signals from the normal tissue and then you can get the best information. So we will do the analyses for arm A and arm B simultaneously. The patient will come in, get biopsy of tumour, get biopsy of normal tissue, the tissue will then be sent to different places, one to do the next generation sequencing, and that’s a very comprehensive analysis of DNA for mutations, rearrangements and so forth, and the other part of the tissue to be sent for RNA analysis and to look for other signatures, other pathways that may be activated and can point to a drug that might be effective.

So how are you going to select patients?

We’re going to select patients that we believe are eligible for many of our trials. We’re going to take patients that have advanced cancer and that are currently undergoing therapy. While they’re undergoing therapy we will get their consent, of course, and we will let them know that this is in planning for future therapy in case the current therapy doesn’t work. And, of course, that’s a big problem for many patients with cancer, especially patients with metastatic disease, that their therapy that we give them may not work or it may work temporarily. That’s the most common type of scenario. So patients come in, they have advanced cancer, they’re getting therapy, we will do the biopsies and start planning for the next therapy.

But is there a risk that the genetic signature of the patient taken at the beginning of the trial could change as a result of the therapy they’ve undergone?

That might be a risk for RNA analysis, I think it’s much less of a risk for DNA analysis. It will be one of the confounding factors that we will have to take into consideration. I think what’s really important to remember with this trial is that it’s a pilot trial, it’s very forward thinking, but we’re not going to presume that we’re going to have all the answers. We have to construct a trial that’s doable logistically and if we wait until after the patient finishes therapy patients just cannot wait for the answers that long. So we have to do the analysis while they’re on their previous therapy otherwise the patient, if there is a gap in therapy that’s too long, the patient will become ill or die.

So it’s just that it’s a pilot trial and it’s involving just 200 patients initially.

It’s 200 patients will be treated on it. I think there’s going to be an immense amount of information that comes from these 200 patients but we’re also going to learn about feasibility, about the challenges. If nobody has done trial like this before and what I know from experience is you can try to figure out all the challenges before you do a trial but once you start doing it there are unexpected circumstances that come up and you learn from doing the trial. So we think that in the future all patients will be tested in this way but this is the first trial with this comprehensive analysis doing normal tissue, doing tumour tissue, doing all sorts of different molecular testing with the most advanced technology and the most advanced scoring systems available. So yes, it will be 200 patients to start but this can be a foundation for a further trial that could be 10,000 patients if this is successful. But we have to start with the smaller group.

And so what is the main endpoint?

The main endpoint is looking at how long it takes for the patient to progress on the therapy to which they’re matched compared to how long it took them to progress on the previous therapy. So in general for cancer patients, every time you get a new therapy we know that the time that you do well is shorter. So if you’re on your third therapy it’s going to be better than your fourth therapy and your fourth is going to be better than your fifth because the cancer develops resistance. What we believe is, with the matching, the therapy we give with the matching will be better than the prior therapy and that’s what we’re going to test. Each patient will be their own control.

But in analysing these patients, if you come across a lot of patients that you just cannot find a signature that you can treat, will you keep going until you get to the 200? How will it work?

We’re going to have 200 treated patients, not 200 total patients.

OK.

So the idea is I’m sure we’re going to have many patients that don’t end up being treated and it may be because they refuse treatment or because they become ill with time or other logistic reasons that they can’t actually get treatment. But we want to have 200 that get treated according to this matching system.

Thank you. So we’ll catch up with you in two years and we’ll see the results of this very, very novel type of trial. Thank you.

We’re looking forward to it, thank you.