COMMENTARY

Bevacizumab: The Sleeping Giant in Ovarian Cancer

Maurie Markman, MD; Gini Fleming, MD

Disclosures

June 13, 2011

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Introduction

Hello. I'm Maurie Markman, Vice President of Patient Oncology Services and National Director for Medical Oncology at Cancer Treatment Centers of America in Philadelphia, Pennsylvania. Welcome to Medscape Oncology Insights on Gynecologic Cancer. Joining me today is Dr. Gini Fleming, Professor of Medicine and Director of Medical Gynecologic Oncology at the University of Chicago in Chicago, Illinois.

Olaparib: Streams of Positive Data

Welcome, Gini. The meeting so far, and actually gynecology sessions are over, has been very exciting. There were a number of very interesting presentations that certainly have the opportunity to change the way we treat patients with gynecologic malignancies. The first abstract I would like to ask you about is the data on the PARP [poly ADP ribose polymerase] inhibitor, olaparib.[1] What do you think?

Gini Fleming, MD: I think that we continue not having a PARP inhibitor available for our patients despite continued streams of positive data. This was an indubitably positive trial. Patients with platinum-sensitive serous ovarian cancer had a doubling of progression-free survival when the drug was used in maintenance, and interestingly, that seemed to be regardless of the BRCA mutation status, although the numbers were very small. As one physician got up and asked, "When are we going to have these commercially available?" It's not clear yet.

Use in "BRCA-ness" patients.

Maurie Markman, MD: There is a biology associated with why serous tumors might be relevant even though you don't necessarily know if there are BRCA 1 or BRCA 2 abnormalities present. There are also the original data, of course, specifically focused on the population with these abnormalities where very impressive single-agent activity was seen. What is your take on the switch from a specific focus on genetic abnormality to the more general approach of the serous cancers, where there is perhaps a high percentage of somatic mutations but not necessarily documented?

Dr. Fleming: This idea of BRCA-ness is that these act as though they had the same type of tumors that BRCA mutations carriers had -- being more platinum sensitive and living longer. The hope is that a larger group of women will benefit from [olaparib] and that if it is tested in the broad group of women and if approval can be gained for a broad group, that is better than trying to figure out how to define BRCA-ness. I haven't heard. I don't know if you have heard anything more about some tests that you can do on the tumors of women who are not BRCA mutation carriers to prove that they have this BRCA somatic mutation. There are probably multiple mechanisms by which the gene can be repressed. At this point, it doesn't appear that the companies who are developing these drugs are taking the tack of trying to get approval just for mutation carriers.

Dr. Markman: It is going to be interesting to see how this develops. It certainly might turn out that a trial is done along the lines that we saw in the general population, but the oncology community or certainly many doctors may then elect to use the drug perhaps specifically in a population where the genetic abnormality is present. The other interesting follow-up is your comment about the fact that there is not a test. Certainly, there was a lot of discussion at the meeting about the revolution in genetic testing in looking at these. It may be available in the relatively near future just as in other cancer types. It might be [that] in ovarian cancer we will be able to look at this genetic profile on all patients when they come in and perhaps select the population based on some profile, even though that may not be the intent today in the trials. We may in the future be able to select patients more specifically based on a profile to get a drug where it may make sense. We'll see.

Are toxicities a problem? One of the other questions that comes up and many people have talked about is clearly the concept that maintenance therapy makes sense. On the other hand, the PARP inhibitors almost by definition are drugs that interfere with a repair mechanism and we have a lot of experience in oncology that interfering with repair mechanisms that are a normal part of our physiology may have some downsides. Any thoughts on those concerns?

Dr. Fleming: There were no leukemias or preleukemic syndromes reported in this particular trial, which is something that we are always looking for with this type of compound as well as other side effects. Once you start using a drug in maintenance, that is in people who by definition at that time don't generally have a lot of evidence of disease or symptoms from their disease, who could be taking this drug a very long time, there is always a lot of concern about long-term toxicity that doesn't necessarily exist when you're treating for a shorter period of time and giving the drug to somebody who has symptoms. We continue to worry but there wasn't anything particularly worrisome in this presentation. It sounded like the drug was well tolerated and [patients] had anemia, interestingly, and fatigue but not much else.

BRCA Mutation Screening

Dr. Markman: There was one other study from Australia[2] that specifically looked at BRCA mutations, with a provocative conclusion about routine screening. Do you want to comment on that?

Dr. Fleming: Most physicians at this point think of BRCA mutation carriers as the patients who will most benefit from PARP inhibitors. There is an increasing trend to want to test more and more people because there might be benefit for the patients themselves and not merely for their heirs and relatives and knowing that they have a BRCA mutation. The Australians screened an unselected-by-family-history population. They excluded patients with mucinous tumors and found that slightly more than 13% of the patients had a BRCA mutation and that only half of these had a family history, the idea being that if you only screen your patients who have a family history, you are going to miss half of your mutation carriers and thereby lose the potential benefit of PARP inhibitors when they become available. And of course, you will lose the potential benefit of preventing ovarian cancer in their relatives because risk-reducing removal of the ovaries and fallopian tubes does benefit mutation carriers.

Bevacizumab: The Giant in the Room

Dr. Markman: Obviously, we will look for more data from other groups to see what they come up with, certainly in the United States as well. Now "the giant in the room" -- 2 very interesting and very important randomized controlled trials looking at 2 different uses of bevacizumab in ovarian cancer were presented at the meeting. The first, for which many people were waiting with great interest is the OCEANS[3] [Carboplatin and Gemcitabine Plus Bevacizumab in Patients With Ovary, Peritoneal, or Fallopian Tube Carcinoma] trial. Comments?

OCEANS trial.

Dr. Fleming: There certainly was great interest. I noticed that once again the room for gynecologic oncology was full to overflowing. There was no place to sit down and then after the presentation of the large trials, a number of people left. The OCEANS trial, which as you know, [randomly assigned] women with platinum-sensitive recurrent ovarian cancer to platinum gemcitabine with concomitant and indefinite bevacizumab, was clearly positive. I don't think there is any way around it. The hazard ratio for progression-free survival was under 0.5 and although overall survival was still immature, there certainly seemed to be a numerical strong advantage for overall survival in patients who got bevacizumab.

The question is, is this going to be good enough to get bevacizumab approved in ovarian cancer and is this the way we really ought to be using it -- that is, in second-line, concomitantly, and for indefinite maintenance?

Dr. Markman: That's a very important question and it certainly still begs the very important question of bevacizumab as a single agent, whether it's in maintenance or a single agent of second-line therapy. One of the comments that has been made by many is that although bevacizumab may be active in other tumors as a single agent, it is really impressively active in ovarian cancer for a variety of reasons that you can come up with in terms of the normal ovarian cells and the role of angiogenesis in the normal physiology. It makes some sense, but the question is, is there any reason to give it with chemotherapy? We don't have the answer to that, of course, but the data that we see just continue to raise those questions.

ICON7 trial. Turning to the second trial,[4] this was actually the second time this trial [was presented] but the first time at ASCO®. The ICON7 study, which like the Gynecological Oncology Group (GOG) trial presented last year, was a frontline study. These were also very provocative data. Any comments?

Dr. Fleming: The ICON7 trial differed from the GOG-218 Frontline trial in one important way. The dose of bevacizumab that they used was only half of the dose used in the GOG trial and in the OCEANS trial. Both of those trials used 15 mg/kg every 3 weeks and the ICON7 trial used only half that but showed similar results, that there was a very slight improvement in progression-free survival up front. They presented their interim overall survival results, which were still negative at this point. The intriguing part of this study was their subgroup analysis where they looked at the so-called "poor risk patients." The ICON7 trial allowed early stage (stage 1) to make up 10% of their population. They found a strong benefit for progression-free survival in this poor-risk subgroup, which is very intriguing. It was a pretty impressive benefit. The OCEANS trial and the GOG trial both used a maintenance [schedule] of 1 year of bevacizumab and did not continue it indefinitely. When you look at the curves, there has always been that feeling that it's going to have to be continued indefinitely, or that has been the suggestion, which is a bit unsettling for something used front line that doesn't yet show an overall survival benefit.

Dr. Markman: These are obviously questions that we may get some of the answers to in the future. There certainly is one striking difference between the ICON7 and the GOG trial. They had very similar outcomes, which were unquestionably positive for progression-free survival, but as you noted, the striking difference was basically that half the dose was used in the European study. There is no way that we can directly compare the trials. Do you have a personal opinion as to the dose that one might use on the basis of these data or are you waiting for more data?

Dr. Fleming: It is hard to have a strong personal opinion in the absence of data, and certainly you are aware that early studies in other tumor types did not necessarily show a benefit with the higher dose and the higher dose may not be necessary, but I don't really know the answer.

Bevacizumab: Active and Costly

Dr. Markman: Obviously, doctors and oncologists are going to have to make their own decisions. Of course, it will be interesting. These data will be presented to the US Food and Drug Administration (FDA). It is possible, as has happened in other situations, that the FDA may actually say you can use a range. They may indicate one dose or another. Who knows? Obviously, however, the important point that you made, and I certainly support, is that at this point the data are as clear as one can get that bevacizumab is an active and important drug in ovarian cancer, and hopefully the regulatory agencies we speak with in the United States and wherever it's available will agree that this is an important drug in ovarian cancer. How we optimally use it remains to be determined.

Dr. Fleming: The cost issues are major, but we cannot allow cost to influence whether we say something is active. All we can do is conduct the clinical trials to determine whether the drug is active and how active it is. Cost then has to be brought in on the back end of the discussion, but ovarian cancer doctors have known for a long time that it is an active drug when used in the second line and more active in ovarian cancer than in any of the other tumor types for which it is already approved. I hope it becomes available.

Screening for Ovarian Cancer

Dr. Markman: There is so much more that can be said about these drugs, but turning to another very interesting study that was presented actually before the formal gynecologic cancer abstract oral session, the results of the PLCO [Prostate, Lung, Colorectal and Ovarian] trial.[5] This is a very important study that had actually been talked about a little bit previously, but this was a definitive presentation on the outcome of screening for ovarian cancer. Comments on the study results?

Dr. Fleming: This trial was about as negative a screening study as negative screening studies can be. It's nice if you are going to get a negative answer to have it at least be definitive, and this was fairly definitive, at least for the use of simple CA 125 testing in transvaginal ultrasound. This was an incredibly large study with many thousands of women. Women were invited to either have no screening or to be screened with annual transvaginal ultrasounds for 4 years and CA 125 for 6 years (just annually), and not using any complicated algorithms for changes in CA 125. They found that not only were there no decreases, there was also no better rate of detection of ovarian cancer, there was no decrease in ovarian cancer deaths, and there were thousands of unnecessary operations performed. One of the problems was that with ovarian cancer screening, there is no definitive way, without operating, to decide whether the screening test is a false positive.

Also, significant numbers of patients were harmed from those operations, so it is pretty clear that at this point, screening with transvaginal ultrasound and CA 125 annually in an unselected population is not of benefit. At least it's comforting to be able to say that definitely, although disappointing because we would love to be able to catch ovarian cancer earlier and not have to be talking about incurable advanced-stage disease, which is the case for many of our patients.

Dr. Markman: I agree with you. It certainly doesn't mean that in the future we will not come up with some strategy that might work, but what we have today is the idea that a woman should go into her gynecologist and get a CA 125 and have a vaginal ultrasound ovarian cancer [will be detected] early, but there is just no evidence to support it.

Dr. Fleming: That is correct, and while we still routinely do this in women who are, for example, BRCA mutation carriers who have not yet had their ovaries removed, we don't have any evidence that it is of benefit. Hopefully, as you said, there are numerous large ongoing screening trials using somewhat more complicated CA 125 algorithms for which a bit more optimistic preliminary evidence was presented at last year's ASCO®, but we will have to await those results. It's certainly not ready for primetime.

Closing Remarks

Dr. Markman: I want to thank you, Gini, and thanks to our audience for joining us for this edition of Medscape Oncology Insights. This is Maurie Markman coming to you from ASCO® 2011.

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