ASCO 2011 Annual Meeting, 3—7 June 2011, Chicago

Standard of care for ovarian cancer

Professor Stan Kaye - Royal Marsden Hospital, Surrey, UK

Tell us how you at the Royal Marsden Hospital in London manage your ovarian cancer practice now. What’s the standard of play to which you should all be working? Surgery up front is unchallenged?

No, I think actually there’s an increasing move towards this notion of neoadjuvant chemotherapy first and surgery after three courses of chemotherapy, and we’re individualising that according…

Based on what, based on which individual parameters?

Patients who present with really quite advanced disease, The EORTC study, which Vergote headed up, indicated that in those bad patients there is nothing to be lost by starting the chemotherapy first. So actually the surgeons are encouraging us to do that, partly because it gives them a bit more time to plan their operating time, which is an increasing problem. So we’re kind of moving towards that. Actually that gives us an interesting opportunity, because if patients are going to get interval debulking surgery after three courses of chemotherapy, it gives us an opportunity to ask another question. So what will happen in the next…

You can get two lots of tissue?

Yes exactly, so that’s really important. So that interval debulking, if a patient gets optimal debulking, which is what we want to achieve, we’re just opening the intraperitoneal trial. We’re not sold on intraperitoneal chemotherapy at all, nowhere should it be a standard of care; but it is possible that you can insert a catheter after three courses, and get a benefit from intraperitoneal chemotherapy at that point. So that’s a new trial started, PETROP it’s called, it’s going to be a UK study for patients: optimal interval debulking.

It lightens my heart, having dedicated fifteen years of my life to intraperitoneal chemotherapy.

It’s a fiddle, though, it has to be. I think it’s wrong to do it in any other setting. But the other part, of course, is that if patients do not get an optimal debulking after three courses, or they’ve had a relatively poor response to the first three they’re really in trouble. They’ve had three courses of Taxol carboplatin and it hasn’t gone well enough. Now what we’re going to do then is, within a structure that we’ve got, is to add Avastin.

Right, bevacizumab

Bevacizumab. And the reason for adding bevacizumab in that context is perhaps for us to get more experience with it, but to take advantage of one of the things perhaps that was first shown at ESMO last year, but confirmed at ASCO this year, which is that in the sub-group of ICON7, the first line trial, patients that look as if they’re having a survival benefit are the sub-optimal patients in ICON7, the ones who had sub-optimal surgery. So you could argue, well those are the patients who might have the most to gain by adding bevacizumab to chemotherapy in the first line.

That’s a very nice result, to get out of that study. It was quite unexpected; we teach our students that the poor prognosis patients do poorly, and that nothing much salvages them, but here the ICON7 data is bucking that. And I think there is some supportive evidence from the American study, GOG218, too, isn’t there. It’s not as mature yet. Tell us about the ICON7 trial presented today, and it seems to be essentially consolidating the story that we heard earlier.

The ICON7 yes, essentially it was… what people had been wanting to say was that they’re not prepared to use bevacizumab as part of a maintenance strategy in the first line, simply on progression-free survival, they want overall survival data. I’m actually not sold on that, to be honest, I think that there’s so much that can happen after patients progress that overall survival, for me, is not the holy grail. But it’s always nice to see it, of course, and that’s what was seen in that subgroup analysis, strengthening the case. Now the key thing, of course, is that in ICON7, those patients stopped bevacizumab at 12 months, so this is really what has… The other study that was presented just the other day was the OCEANS study, which is now the second line of Avastin/ bevacizumab maintenance trial but in that trial, it was continued to  progression. And that was a bigger hazard ratio of benefit than in the other maintenance studies.

And that makes sense.

Yes. So for me, although the only difference there, of course, it was still a higher dose, it was the 15 mg/kg, ICON7 was 7.5, GOG218 was 15 as well. But I think it’s kind of beginning to make people feel that if they’re going to use bevacizumab as a maintenance treatment in ovarian cancer, they’re going to continue with it until disease progression, and that’s what we would do.

And you could probably get away with 7.5 mg.

I think so, yes.

And then on disease progression?

Well it’s a good question I think. Actually the disease progression isn’t all that easy to pick up because it’s much more gradual. I think probably we don’t know this yet, but my hunch is that they perhaps should then move to another kind of angiogenesis inhibition. Of course we’re not going to know the answer to that for a couple of years. The ICON6, which is the trial with cediranib, the AstraZeneca small-molecule VEGF, does allow patients to enter that who have had previous Avastin. And the kind of experimental data would suggest that you do need to move to a slightly different angiogenesis, antiangiogenic strategy.

There’s not cross-resistance? Or not total?

No, there doesn’t seem to be. We’ve certainly seen that you can respond to cediranib having previously had bevacizumab, but there are other… it’s getting very crowded now.

Are there cytotoxics?

The other bit that’s getting crowded is the PARP inhibitor of course, and that was the presentation with the stunning hazard ratio of 0.35, which is in sporadic ovarian cancer. So I think we’ve got a real issue now, all of a sudden we’ve got maintenance treatments that look as if they work, and I think that in the next couple of years people are going to ask the question about on progression of Avastin maybe they should move to a PARP inhibitor, or should they think about using them together? At least in second relapse, in first relapse.

Is there much data on combination of bevacizumab and PARP inhibitors?

Not yet, not yet.

The data on combination with platinum is added toxicity, I’m led to believe?

Yes, exactly. And there was a study presented that I think turns out not to be with a PARP inhibitor, the iniparib study, and that is the combination with gemcitabine and carboplatin, but that didn’t have extra myelosuppression, because it probably isn’t a genuine PARP inhibitor, it’s doing something else. For sure we know that the PARP inhibitor is going to have a role as a single agent in maintenance. I think probably with chemotherapy you can do it with reduced doses but we need to see. There’s going to be a study presented at the end of this year, which will be the first randomised study of chemotherapy with and without PARP inhibitor, then we’ll know.

I’ve seen a couple of abstracts, one on pegylated doxorubicin, liposomal doxorubicin, which looked to be cutting down toxicity; and then trabectedin. What are you views on those two?

I think they’re both drugs, we’ve used a lot of pegylated doxorubicin, I think that’s basically standard of care for relapsed disease. I think one of the questions is when patients relapse between six and twelve months, what is the standard of care? And that’s actually a difficult area, because they’re not completely resistant and they’re not completely sensitive. And one of the hypotheses is that it’s better, in that group, to keep the platinum up your sleeve until later. So then the question is, well if you’re not going to give platinum, should you give doxyl by itself, or should you give it with something else. And that was where trabectedin looks interesting, because the study that was done actually combined trabectedin with doxyl, this was a randomised trial we presented last year, and across the board the sub-group that looks as though it was the best was that six to twelve sub-group, which is now showing an overall survival benefit, which kind of suggests that maybe the strategy is correct, of trying to maximise the platinum-free interval, and maybe getting a survival benefit by what you get afterwards, which will be platinum. So that’s going to be tested, that’s going to be a new trial, that has already started, where trabectedin doxyl will be compared with carboplatin doxyl in that six to twelve month group. So I think trabectidin as a partner for doxyl in that context is interesting.

Any other drugs coming on? No immunotherapy in this area?

Not yet.

You haven’t got ipiluminab data, for instance?

That’s a good question, and there is a story that that drug might actually… there is a discussion about testing that in ovarian cancer for various reasons. We might see that actually, and that would be good.

I’ve always fancied ipiluminab intraperitoneally, ever since I heard that it worked.

Well I think that intraperitoneal treatment in ovarian cancer in relapsed disease, the abdomen’s quite complicated. It’s okay in the first line, but we tend to find more problems later. I’m think in terms of other cytotoxics, there is a novel form of camptothecin, MKTR it’s called, which is looking quite promising.  And the other final thing, we’ve been interested in the folate receptor a lot. It’s highly expressed in most ovary actually. Endocyte have got this drug, EC45, which is a folate conjugate with vinblastin analogue, and it really looks very interesting, combined with doxyl. It doubles the progression-free survival in that six to twelve month space, interestingly. And actually that’s potentially going to go forward for a registration trial. So, lots to do.

Next year, ASCO 2012, what do you expect in the ovarian field? Do you get mature data on the North American trial with bevacizumab?

Yes. I think what we need most of all, actually, maybe at AACR, actually, is a really proper biomarker for a PARP inhibitor. Because there’s no point giving that drug to anybody that doesn’t have a DNA deficiency and it’s not rocket science to work out a biomarker. And that will be really helpful, because that’s nearly half of all ovarian cancer.

Well, some people say that the histopathology is enough, and why go wasting money trying to find something sophisticated when you’ve got a pathologist who looks down their microscope and has a look at it. And of course before next year’s ASCO we’ve got ESCO in Milan, and we’re looking forward to very much to seeing you there.

I will be there.

You will be there, fantastic, we’ll carry on the conversation. Thanks very much indeed Professor Kaye.

Thank you.