Stanley B. Kaye, MD


October 07, 2011

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New Treatments for Ovarian Cancer

Hello. My name is Stan Kaye. I am Head of the Drug Development Unit at the Institute of Cancer Research at the Royal Marsden Hospital in Sutton, United Kingdom. Welcome to Medscape Oncology Insights on Gynecologic Cancer. Today I would like to discuss some of the data on developments in ovarian cancer treatment presented at the 2011 European Multidisciplinary Cancer Congress taking place in sunny Stockholm, Sweden. I will put this in the context of some of the presentations that I have made on this topic.

Targeted treatments in ovarian cancer are already making a difference. I want to discuss 4 or 5 areas in which new treatments are already in the clinic and looking very promising.

Bevacizumab: New Data, Emerging Uses

Let me start off with the vascular endothelial growth factor (VEGF) receptor, which is a key target in ovarian cancer, and because it underpins the biology of the disease, is a rich source of agents. Bevacizumab is the key agent in the disease, and what we have been hearing at this meeting and what we have heard in presentations over the past year are the results of the randomized, first- and second-line trials that have led us to believe that the drug is going to play a role in ovarian cancer.

In the US GOG 218 study[1] and the UK European GOG 217 study,[2] we saw a progression-free survival benefit for the use of bevacizumab in combination with chemotherapy and continued for 12 or 15 months afterward. At the American Society of Clinical Oncology® (ASCO®) this year we saw the overall survival data for ICON7[3] showing a benefit in the subgroup of suboptimal patients. At the meeting today,[4] we saw the first data on quality of life, which confirmed that there was no significant clinical detriment to the use of bevacizumab either in combination with chemotherapy or given afterward, although there was a small mathematical difference that was not clinically significant. It is good news that bevacizumab does not carry any significant toxicity or problem with patient acceptability.

One of the things that has also been happening in the past year or so is that in first-line chemotherapy of ovarian cancer, we have had exciting data from Japan. The Japanese study published in TheLancet[5] showed that weekly paclitaxel might be a better way of giving the drug than giving it twice weekly with the usual 3 weeks of carboplatin. The question that is already being addressed is whether bevacizumab can be added to that novel therapy (3-weekly carboplatin, weekly paclitaxel) safely?

We heard the results of the feasibility study called OCTAVIA,[6] which confirmed that this was a safe combination, and what we will know in the next year or two with new randomized studies is whether that might be a better way forward for the standard of care (adding bevacizumab to a novel combination rather than the conventional 3-weekly paclitaxel/carboplatin). So, that was good news.

The other presentation that we had at the meeting was from Carol Aghajanian on the second-line study called OCEANS.[7] This was presented at the ASCO® meeting, so we knew that bevacizumab added to gemcitabine and carboplatin for platinum-sensitive relapsed ovarian cancer, given until progression rather than to a defined stopping point, clearly was beneficial, with a hazard ratio of 0.35 on the improvements in progression-free survival.

Now we have a dilemma. In second-line platinum-sensitive relapsed disease, there is also a benefit from bevacizumab. One of the issues is going to be how to put all of this together. At today's meeting, from the OCEANS data, we saw that this benefit actually seemed to be slightly better in the 6-12 months' platinum-sensitive group (the so-called "partially platinum-sensitive," group), which was interesting, and implies that patients with a slightly worse outlook might benefit even more from the addition of bevacizumab. The hazard ratio was 0.35 compared with 0.62 in the more than 24 months' interval.

We are beginning to get a sense that perhaps patients with a less favorable outlook in first- and second-line treatment have the most to gain from bevacizumab. In first-line treatment, it could be the patients with the worse prognosis, as demonstrated by the ICON-7 overall survival data, and in second-line treatment, perhaps it's the partially sensitive, 6-12 months' patients who have the most to gain. This could begin to make sense. We will have to grapple, in the next year, with how to use bevacizumab in ovarian cancer: how to put together the first- and second-line indications. One way forward might be to say that patients with suboptimal disease might benefit at the beginning. In others, it might be better to save it until second-line treatment. There is a lot of interest around VEGF receptor therapy. Bevacizumab is clearly out there. Over the next year or two, we are going to hear more about the tyrosine-kinase inhibitors that are in clinical trials.

Choices for Platinum-Sensitive Relapsed Disease

The next thing that I want to talk about -- for which no new data were presented at this meeting -- is homologous recombination (HR) deficiency and the use of PARP [poly (ADP-ribose) polymerase] inhibitors because it is something on which we have worked and about which we have seen a lot of data over the last few months. At this year's ASCO® meeting, we saw for the first time clear evidence that patients who have platinum-sensitive relapsed ovarian cancer -- not exclusively patients with the BRCA-associated cancer for which PARP inhibition has already been shown that to have real potential, but a much larger group of women who have BRCA-negative or BRCA-unknown disease -- benefit from the PARP inhibitor olaparib, as shown in a randomized maintenance trial.[8] The issue is now we are beginning to have choices, that is, a maintenance treatment in first-line and potentially a second-line treatment.

Two forms of therapy have had positive randomized trials: the VEGF receptor inhibitor bevacizumab and the PARP inhibitor olaparib. We are going to have to work out how to put these together: perhaps in combination; perhaps in sequence; perhaps trying to select who should have one drug and who should have the other. This is going to be a really important area for clinical trials. It is good news for those of you treating ovarian cancer because when women ask, "Is there a treatment that will reduce the chance of relapse or delay my recurrence?" in the next year or two, there will be options out there. We are also going to need to look in detail at the PARP inhibitors to find the best way of combining them with chemotherapy as well as giving them as maintenance therapy.

PI3 Kinase Inhibitors: More Options

The third area -- and there were presentations on this topic at the meeting in Stockholm -- is more speculative, and that is the PI3 kinase AKT pathway. It's a really important pathway in cancer therapy, mutations of which are quite common in various cancers. The notion is that this pathway is important to the extent to which cancers will respond to chemotherapy, particularly the agents in ovarian cancer such as paclitaxel and carboplatin. What we need to understand is how best to incorporate these drugs into the treatments of this disease.

The paradigm for novel targeted treatments is patient selection. Can we identify patients who will benefit most from these selective inhibitors? The problem in ovarian cancer is that PI3 AKT mutations are actually quite rare -- less than 10% -- but increased activity of the pathway is quite common either through amplifications of PI3 itself or AKT. Therefore, there is scope for using inhibitors of this pathway, but we need to understand how best to develop them.

At the meeting today we saw a presentation from the group in London[9] that looked at one of the earlier PI3 kinase inhibitors from GlaxoSmithKline in a carefully controlled phase 1 trial, showing that to really understand whether the drug has hit the target, careful phase 1 trials need repeat biopsies. It's not trivial. Patients would be required to have a biopsy before treatment and at careful time points afterward to demonstrate -- and they did demonstrate -- that there was target inhibition in the tumor. Immunohistochemical and other assays demonstrated that indeed the pathway was inhibited. PET scans -- an important way of getting a metabolic readout that you can visualize -- also showed that the pathway was being inhibited. That was important. Now, what does that mean? It means that the drug is getting to the right place, but does it have an effect?

Of note, on its own the drug was active in 2 or 3 patients. It was a small study, but there were 3 responses, one of which was a patient with clear cell ovarian cancer, and clear cell ovarian cancer is one of the most difficult to treat once it has metastasized. Patients with clear cell ovarian cancer who responded had mutations of the PI3 AKT pathway. In fact, it is known that of the various ovarian cancers, clear cell is one that has a higher frequency of the mutation.

We are beginning to see examples of what we really want to achieve in ovarian cancer, and that is dissecting out from this label of ovarian cancer the distinct treatments for the distinct subtypes. Clear cell is a good example. We also had a presentation showing that mec amplifications could be relevant in clear cell, and that's another clue to new treatments. The PI3 kinase AKT pathway is certainly one of them. That is an area that we want to pursue.

Practice-Changing Agents, Future Targets

Finally, I would like to mention briefly the folate receptor, which is expressed in high levels in serous ovarian cancer and in others. Although it was not presented at the meeting, there are now several ways to target -- using antibodies and novel agents -- the folate receptor, which is highly expressed in ovarian cancer. We need to understand how best to combine novel agents such as the agent from Endocyte (EC145) that targets the folate receptor with chemotherapy.

A lot of you will be involved in treating the disease, and over the next year or two, as bevacizumab becomes approved (and has actually been approval already in Europe for first-line therapy), clinical practice will change. Next PARP inhibitors will begin to play a role.

It will behoove us as clinicians managing this disease, when we see a patient with ovarian cancer, to ask what is the type of ovarian cancer. Which of these therapies makes the most sense? For the VEGF receptor, or for bevacizumab, that's a challenge, and understanding who is going to benefit most from that at the molecular level is going to be difficult. From the clinical level, my sense is that it might be the patients who have the most to gain at the beginning, depending on the extent of previous surgery and response to treatment, and that's something with which we are all familiar. I hope that this information has been helpful.

Thank you very much for joining us for this edition of Medscape Oncology Insights. This is Stan Kaye signing off from the 2011 Multidisciplinary ECCO/ESMO Congress in Stockholm.


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