Maurie Markman, MD; Gini F. Fleming, MD


June 18, 2012

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Maurie Markman, MD: Hello. I am Maurie Markman, Senior Vice President for Clinical Affairs and National Director for Medical Oncology at Cancer Treatment Centers of America, based in Philadelphia, Pennsylvania. Welcome to this edition of Medscape Oncology Insights on gynecologic cancer, coming to you from the 2012 American Society of Clinical Oncology (ASCO®) annual meeting.

Joining me today is Dr. Gini Fleming, Professor of Medicine and Director of Medical Gynecologic Oncology, University of Chicago, Chicago, Illinois. Welcome, Gini. It's delightful for me to have the opportunity to discuss with you a very interesting gynecologic cancer session at ASCO®. First, what do you think is the major highlight of the meeting in the gynecologic cancer area?

AURELIA: Golden Results

Gini F. Fleming, MD: We have been waiting for the outcome of AURELIA,[1] the trial testing bevacizumab in the setting of platinum-resistant disease. The outcomes were very satisfactory.

Dr. Markman: I agree. What makes it so different? I was surprised, even shocked, to see a positive trial in this setting. What do you take from it and what should we do with the information?

Dr. Fleming: A positive trial in patients with platinum-resistant disease, something that doubles your response rate and progression-free survival, which is short, with absolutely minimal toxicity, is wonderful news. The trial design was very nice. They allowed physicians to use the most common regimens for that setting. They were allowed to use topotecan either weekly or in a daily-times-5 regimen. They could use weekly paclitaxel or a liposomal doxorubicin. Patients were randomly assigned to bevacizumab or no bevacizumab. Of interest, the study was designed to allow patients to cross over, which may of course make overall survival difficult to interpret.

The toxicities were incredibly manageable. In the platinum-resistant setting we always had concerns that there would be more bowel perforations, because in general there is a larger bulk of disease in this setting. There were only 2 bowel perforations in the whole group. Overall, the drug was well tolerated and we are all hoping that this is going to lead to US Food and Drug Administration approval for the drug.

Dr. Markman: I agree completely. The presenter very appropriately acknowledged the risk for perforation and pointed out as an eligibility criterion that they excluded patients thought to have a high risk for perforation, such as any evidence of previous bowel involvement and CT scan evidence of potential concerns.

Dr. Fleming: They didn't exclude patients simply with large, bulky, intra-abdominal disease. Patients had to have evidence on scan of invasion in the bowel. A large percentage of patients, nonetheless, is going to be able to receive the drug in this setting safely.

Dr. Markman: No one knows exactly how this will be examined by the regulatory agencies, but hopefully very positively, because there hasn't ever been a positive trial of anything close to this magnitude in ovarian cancer. One of the most interesting aspects of this study was the objective response rate. One can always challenge a study by asking, what does a response mean? In the setting of platinum-resistant ovarian cancer, patients whose cancers have grown despite treatment with platinum, it is highly likely that there are cancer-related symptoms. This isn't just a patient who recurs, with a rising CA-125 18 months later. This is a patient whose tumor has progressed through platinum. A tripling of the response rate (which it was close to) is likely to have a clinical impact in and of itself, in addition to the fact that it was twice as long before the patients progressed. Do you have any comments about that?

Dr. Fleming: I agree entirely. It's completely different from the setting of minimal disease, in which you are treating someone who is asymptomatic. Many patients are symptomatic or become symptomatic very soon in this setting. As you mentioned, the quality-of-life data were not presented, but they did collect them. I would be very optimistic that quality-of-life data will reflect an improvement with the decline in tumor burden and a delay in time until tumor recurrence. It was a very welcome, positive outcome.

Dr. Markman: I agree. Obviously, as we always say at ASCO® presentations, it is an abstract. It is a presentation. We wait for the peer-reviewed paper, but on the basis of what we heard, it was very impressive. From the patient's perspective it will be an important outcome. That was one highlight.

PARP Inhibitors: Not There Yet

Dr. Fleming: The next highlight wasn't quite so "high," perhaps. We have all been interested in PARP inhibitors for years now, and everybody continues to refer patients and call and ask, "Why don't we have any PARP inhibitors approved yet?" There was another randomized phase 2 trial, but it was another reasonably sized trial of PARP inhibitors with perhaps not quite such an exciting outcome.

As you know, Dr. Amit Oza[2] presented the results of a randomized trial of women with platinum-sensitive disease. The women could have had numerous previous platinum regimens, but platinum-sensitive, unknown BRCA mutation status for the vast majority, and they were randomly assigned to receive olaparib (which, at this point, is still the best-tested PARP inhibitor) in combination with carboplatin/paclitaxel, and continued as maintenance therapy afterwards vs carboplatin/paclitaxel alone.

The response rate was not changed at all by the addition of olaparib to chemotherapy. This could be attributed to the fact that they had to reduce the carboplatin dose to combine it with olaparib. As Dr. Oza pointed out, the area under the curve for carboplatin was 4 in the combination arm vs 6 in the single-agent arm. It could just be that olaparib doesn't add anything to response rate patients who are already receiving platinum. There was a progression-free survival benefit, but it was small: less than 3 months. This was in the platinum-sensitive setting, albeit with multiple previous therapies, so it was smaller than we achieved with bevacizumab alone in the platinum-resistant setting. Overall, it was somewhat disappointing. Clearly, these are active drugs, but we don't yet know how best to use them and in whom they are active. Dr. Oza stated that although development of the drug will continue, trials currently are more or less halted while the drug is being reformulated. They are trying to identify who will benefit from this drug and how it should be used.

Dr. Markman: Do you have an opinion about whether this is a drug that should ever be used? Obviously this is asking you to go pretty far out on a limb, but it is certainly on people's minds. This goes back to the very interesting studyof maintenance therapy with olaparib that looked at the "BRCAness profile" presented last year[3] and then published in the New England Journal of Medicine.[4] As you might theorize, the drug is best used in women with BRCA1 and BRCA2 mutations. Do you see a role for olaparib that goes beyond that, do you just think the jury is still out, or don't you know?

Is BRCAness Real?

Dr. Fleming: The documentation that there are responses to olaparib as a single agent in women who do not have a germline BRCA mutation is pretty clear. That being said, I would not assume that "BRCAness" is real yet. There was a small poster at this meeting looking at methylation of BRCA in women with ovarian cancer.[5] Methylation has been hypothesized as one mechanism of "BRCAness" because methylating the gene may prevent it from being expressed, so it would be similar to a deleterious mutation.

In this particular poster, patients whose tumors had a methylated BRCA gene did not have different platinum response or survival than patients whose tumors did not have a methylated BRCA gene. These are non-mutation carriers. The jury is definitely out on this. I don't know how it's going to end up. However, doing trials and reporting them without the mutation status is wrong. We should know this and be able to look at the data.

Dr. Markman: The concern is that we are dealing with a subset of a small population. Fortunately, ovarian cancer isn't terribly common, which is good. We are talking about a subset of women (if we are talking about BRCA1 and BRCA2) -- it affects 5%-15% of the total population of women with ovarian cancer. How do we develop any drug in this space? A lot of the focus has been on trying to expand that patient population to get the drug approved. This, of course, has a lot to do with the discussion of whether this company or any other company will move forward with this drug.

It's a difficult issue, and I don't know if you have any thoughts on how one might try to approach it. In other words, should we basically try to look at randomized trials or should we just look at the activity of the drug in and of itself? Should we say that this is clear activity in, for example, women with BRCA1 and BRCA2, as a single agent, with enough patients, and hope we can convince the regulatory agencies to approve it on that basis? It's a very complicated issue in an uncommon tumor.

Olaparib Useful, but Gone?

Dr. Fleming: It is a complicated and money-related issue. I am not sure that I have the right opinion as to the regulatory path. Industry seems to have voted with its feet that developing it only for BRCA mutation carriers is not necessarily the right approach, and I'm not going to gainsay them. However, to me it seems that you have a drug that is clearly active in the randomized trial vs liposomal doxorubicin in women who are mutation carriers. The outcomes were the same. Were they considered disappointing because they weren't superior? Nonetheless, this is a pill that patients took every day with minimal toxicity. They didn't have to come in and get intravenous therapy.

Dr. Markman: I agree.

Dr. Fleming: As a potential BRCA carrier mutation, from the patient point of view, the drug seems like a very good thing. I see no reason why you wouldn't want it approved in that setting, even if it isn't going to improve overall survival in combination with the carboplatin/paclitaxel therapy. It will be very disappointing if the drug can't get approved when we know that it has the activity that it does.

Dr. Markman: One of the other questions that came up was the issue of continued activity of chemotherapy after treatment with a drug such as olaparib. Do you want to comment on that?

Dr. Fleming: There is always concern when, as you know, the previous trial showed a fairly meaningful improvement in progression-free survival with maintenance olaparib but did not show any difference in overall survival. This has been shown in numerous trials with bevacizumab and other drugs. It's a little bit hard to make sense out of this. Why should there be such a big delay in progression and no change in overall survival? Unless either toxicity is killing more people -- which doesn't seem to be the case here; not a chance -- or in some way it is making them more resistant to therapies afterwards. The concern in that situation always is, are people going to be more resistant to subsequent therapies?

There was an abstract in which patients who had progressed on olaparib were given subsequent chemotherapy and there was a reassuring overall response rate of approximately 38%.[6] Clearly, people are not entirely chemotherapy-resistant when they progress on olaparib. Whether there might be any difference in chemotherapy sensitivity couldn't be answered by this study, but it was somewhat reassuring.

Genetic Picture Unclear

Dr. Markman: Agreed -- a very important observation. Finally, the unfortunate "giant in the room": the work looking at genetic profiling of ovarian tumors demonstrating the unbelievable heterogeneity and difficulty finding a particular signature. It is something we have seen most prominently in lung cancer, and in other tumors as well, but are unable to see in ovarian cancer. Do you have any comments? How do we deal with that as a community of investigators?

Dr. Fleming: On the glass-half-full side, although the vast majority of ovarian cancer deaths are high-grade serous tumors, and there is a huge amount of heterogeneity with the only common mutations being the p53 abnormalities, we nonetheless understand a lot better that there are rarer subtypes of ovarian cancer -- clear-cell, low-grade serous tumors, endometrioid tumors, and mucinous tumors -- that are biologically completely different.

We are beginning to understand that there are "druggable mutations" in some subsets of these, and we're beginning to develop separate trials for them. There was an encouraging abstract on a possible way forward for clear-cell carcinomas,[7] which is one of our more resistant tumors. There were a number of interesting abstracts just highlighting the different mutations found in these other subsets. That's the glass-half-full side. When we understand this heterogeneity, we will be able to approach things differently.

As you mention, a high-grade serous carcinoma, which accounts for the vast majority of ovarian cancer deaths, has been discouraging in terms of being able to find a so-called "druggable mutation." Dr. Michael Seiden, who discussed several of the abstracts at the oral session, had a very discouraging point of view that because we don't have these mutations, and because none of the interventions or the drugs that we have tried so far have really decreased the number of patients who eventually recur with ovarian cancer, that we ought not to conduct any more clinical trials right now. We should just sit back, do deep sequencing on a very large number of ovarian cancers, and hope that we find something better.

This is a bit of a discouraging point of view. I am not saying that we shouldn't do deep sequencing on 10,000 cases of ovarian cancer, but I do think that we have made small gains. Incremental gains are still worth having, and I don't feel quite so discouraged as he does about the situation.

Dr. Markman: Obviously, it just makes us have to do a lot more thinking on how to move forward. Going back to our discussion about the "BRCAness profile," which I agree we have to work on, it may be that systems are relevant, more than just a particular abnormality. In the lung cancer area they have identified a particular mutation which allows you to get to a druggable target. We may be able to find that in ovarian cancer and other tumor types, but rather than a particular mutation, we may be able to identify various systems. That is hopeful.

Dr. Fleming: It is hopeful, although very complicated. As you know, at the Clinical Science Symposium, they had a discussion of using known mutations in the PI3 kinase AKT pathway to try to look for a positive benefit, whether it be response or prolonged progression-free survival with rapalogs or a careful look for PI3 kinase mutations for P10 immunohistochemistry for stathmin, the new kid on the block. It's an immunohistochemical marker for overall activation of the PI3 kinase AKT pathway. None of these were able to predict benefit, and yet we know that there is a subset of patients who have responses and dramatically prolonged progression-free survival with rapalogs in endometrial cancer.

I agree that that's the direction we possibly need to go in, and I don't think we're quite there yet.


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