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

Ovarian cancer developments

Professor Eric Pujade-Lauraine – Hôpital Hôtel-Dieu, Paris, France

Surgery up front, debulking surgery up front, remains standard and neoadjuvant chemotherapy with  interval debulking surgery is only limited to patients with a big burden of disease and felt as inoperable.

Which combination of drugs would you use in that situation if you had somebody who was inoperable?

The standard chemotherapy has not been thoroughly modified for fifteen years and the last Vancouver meeting, consensus conference on ovarian cancer has insisted again that the standard chemotherapy, the combination of carboplatin and paclitaxel every three weeks.

But, of course, the survival curves haven’t changed either and that’s one of the issues of the management of ovarian cancer and that’s why we’re looking for new ways of treating it. So you would go with the gold standard for induction of response in an inoperable patient. Let’s take the more common situation where the patient can get up front surgery, then what’s your practice? What do you think is good quality management?

Today the standard remains six cycles of carboplatin and paclitaxel every three weeks but you get new options. The options could be the weekly paclitaxel combined with carboplatin; the Japanese regimen, which has been found active; if you have been debulked to less than 1 cm you might prefer the option of intraperitoneal therapy. But what is really new is the bevacizumab targeted therapy in combination with carboplatin and paclitaxel and in maintenance.

And that has shifted the survival curve, or it looks like it, is that right? In the ICON study.

There are two positive trials with bevacizumab, one in the US and one in Europe, the GOG218 and the ICON7. Both show the same results in terms of PFS, so there is a significant delay in the relapse, with moderate toxicity, very tolerable toxicity. And what has been shown at the gynaecological session of ASCO is that a subgroup of patients with ovarian cancer benefit from the addition of bevacizumab in overall survival; that means mainly the patients who have residual disease after the first surgery.

And this is not expected, this is counterintuitive. It’s good news for those patients because there is not a great deal else for them.

It’s very good news because they are the high risk patients, so they are the worst, those where we need the most progress. But I fully agree with you, we expected that bevacizumab would prevent the development of micrometastases, thus would be more active in patients without any residual disease than in patients with residual disease but with tumour in place. But in fact I think one explanation is the fact that these patients with residual tumour relapse earlier than the others and the schedule of the bevacizumab administration was limited in time, twelve months in the ICON7 European trial, fifteen months in the US GOG trial, and what has been observed is that as soon as you stop bevacizumab the benefit is decreasing with time.

Well we’ve learnt that. It was predictable, the wise guys say, because all the preclinical stuff suggested that, that you take away the angiogenesis inhibitor and off they go again. So you’re not curing anybody but you’re certainly keeping control.

Exactly, except perhaps this very encouraging overall survival advantage in patients with high risk. So it’s the first time that we have an overall survival benefit, even in a subgroup of ovarian cancer patients in first line since more than fifteen years.

Now when you’re looking at patients who are still doing badly or who relapse, generally speaking you would treat them differently according to whether they were originally platinum sensitive or platinum resistant. My bias for platinum resistant is phase I or phase II; let’s start with platinum sensitive, where is that going and what are the new things there?

The new things in the last few years are that we have demonstrated that the combination with carboplatin is standard and we have several options of platinum combinations. You can use carboplatin and paclitaxel again, or carboplatin gemcitabine or, more recently, the preferred option might be carboplatin and PLD, pegylated liposomal doxorubicin, which has been shown to provide a better benefit risk ratio compared to carboplatin paclitaxel in this situation in CALYPSO.

Obviously less toxicity, that’s clear isn’t it?

But all the cards are again shuffled with the recent disclosure at the ASCO gynaecologic session of the combination of carboplatin, gemcitabine and bevacizumab. And there, this combination provides a highly significant advantage in PFS and some hint for overall survival advantage, compared to the carbo-gem chemotherapy alone arm, with a hazard ratio of 0.48, which has not been encountered in the history of gynaecologic cancer. So it’s remarkable.

And new drugs?

Yes. Another exciting randomised phase II has been disclosed during this gynaecologic session with the anti-PARP olaparib. The olaparib was administered in maintenance after response to a carboplatin combination in platinum sensitive relapse, and the hazard ratio in favour of the olaparib arm is 0.35, so a reduction of 65% of the relapse rate, which is very impressive.

These were selected patients? Based on…?

Based on histology, high grade serous ovarian cancer and based on the platinum sensitivity because they should have been twice platinum sensitive.

And some people have said that that’s BRCAness, it’s BRCA similar to BRCA mutations etc. I’m not personally particularly happy with the histopathological description of this. It’s a very important number of patients too, isn’t it? I mean it’s about 50% of them have this situation but to say that they look like a BRCA mutated thing, I think we have to do better than that, particularly given that sort of degree of important benefit.

Yes, the selection of the patients is a talent; trying to find a signature has been already attempted with a limited success. But everybody is working hard to find the BRCAness phenotype.

It’s just a matter of time, it’s bound to come out. So that’s very exciting indeed and that is another impressive hazard ratio. What about the other kids on the block?

For now the question is what shall we do when we come back from ASCO in platinum sensitive disease. Because carbo-gemcitabine is perhaps not the optimal combination for chemotherapy in platinum sensitive disease and we were very impressed by the combination with bevacizumab, but should we combine bevacizumab with carbo-PLD, that is a question in the future to try to solve because at the poster session there was a phase II study of triple combination carboplatin PLD bevacizumab which showed that it was active and well tolerated. So that is, of course, one question and the other question, how shall we combine or how shall we manage patients with, on one side bevacizumab, and on the other side olaparib? Shall we combine both, but there is, of course, a price issue? Shall we select the patients, but how? It’s all the questions which are addressed.

It’s slightly easier in terms of the olaparib because we will get a BRCAness marker shortly. We’re still struggling to find a marker for bevacizumab.

Very much.

In terms of which patients should get this drug.

So at the ASCO meeting this year, a Scottish team has shown that there are, in the high grade serous subtype, there are four different populations and one is the immune microenvironment dependent subtype. So this split of the disease, of epithelial ovarian cancer, in today seven or eight different diseases, we really think that we will find a subpopulation which is much more sensitive to bevacizumab than the others.

But it’s not happened yet. Any other new drugs? Somebody was talking about trabectedin, has that been in randomised trials or is that phase II un-randomised?

Trabectedin is a very interesting drug or so, with a unique mechanism of action.

A Spanish drug, as I recall.

It’s a Spanish drug coming from the sea, so it’s quite unique. It has been shown to be very active combined with pegylated liposomal doxorubicin, with PLD, at least much more active than PLD alone. And it has been shown during this ASCO meeting that there is a benefit also in overall survival for patients treated by the combination of trabectedin plus PLD compared to PLD alone. There is obviously a place in the armamentarium of ovarian cancer for trabectedin and PLD, a non-platinum combination, particularly in the 6-12 month category that is what we call the partially platinum sensitive disease.

And immunotherapy? You’ve mentioned ipilimumab, there has to be something break there in ovarian in the next couple of years, surely? All the early monoclonal antibodies were probably the wrong antigen or probably given the wrong way and so on, but I’ve always had this feeling that immunotherapy has been overlooked for too long.

I fully agree with you. We always say if you want to cure a patient with ovarian cancer you need a good surgeon, a good medical oncologist and good T-cells. So T-cells within the tumour is highly prognostic in ovarian cancer, so we are all passionate that we should do more in immunotherapy but unfortunately a very big trial of more than 800 patients has been run and the results have been shown during this session. It was the MIMOSA trial with a monoclonal anti-idiotype antibody against CA125 and the abagovomab and unfortunately the results were negative. But, you know, we have still to try.

I’m encouraged by the ipilimumab data last year at ASCO in melanoma, this year in primary treatment of melanoma. It just has to be tested in a variety of areas in other cancers. It’s not an anti-cancer antibody. I suppose people expect an anti-CA125 to be therapeutic, there’s not a lot of data to suggest that it would be toxic but now we’ve got the data so we can move on to something else. Have you got any other little snippets that attracted your attention as you were walking the corridors of ASCO?

Well I think that’s already a fantastic year for gynaecologic cancer. Of course we hope that we will have always new drugs but how to combine, how to play them in the strategy…

The number of questions has grown.

Exactly, the more you do trials, the more you have questions.

Which is very good. Well we’ll get some answers maybe, I hope you’ll come to Milan in December for the European Society for Gynaecological Oncology, we’re proud to be the hosts and we hope that it will be fun and we’ll get some more answers. Thank you very much indeed, Eric, I appreciate it.