COMMENTARY

BEV: New Standard in Resistant Ovarian Cancer?

Stanley B. Kaye, MD

Disclosures

October 12, 2012

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Introduction

Hello. My name is Stan Kaye. I am Professor of Medical Oncology and Head of the Drug Development Unit at the Institute of Cancer Research at the Marsden Hospital at Sutton in the United Kingdom. Welcome to this edition of Medscape Oncology Insights on Ovarian Cancer. I am going to talk about some of the studies in ovarian cancer presented at the 2012 annual meeting of the European Society for Medical Oncology (ESMO) taking place here in Vienna, Austria.

I want to cover 3 broad areas: first, where we are now with antiangiogenics -- this is an important growth area in ovarian cancer. I will say a little bit about one particular new novel target in ovarian cancer and also about one novel cytotoxic, lurbinectedin.

Where Are We With Bevacizumab?

Let me start with antiangiogenics and raise the question of where we are with bevacizumab. We now know from randomized trials in first-line, recurrent disease and in platinum-resistant disease that the drug is clearly going to make an impact in this disease. We had updates today on studies that we have heard about before. We heard from the team on the AURELIA study[1] (the platinum-resistant study) that in fact the addition of bevacizumab to chemotherapy for platinum-resistant disease clearly is making an impact. We heard today for the first time the individual data for the chemotherapy given for resistant ovarian cancer when bevacizumab was added. The response rates significantly increased with the addition of bevacizumab. Indeed, in patients on weekly paclitaxel, which is an important treatment for advanced ovarian cancer in the recurrent setting, the response rate went from 28% without bevacizumab to more than 50% with bevacizumab.

For the other drugs that were used in this study -- pegylated liposomal doxorubicin and topotecan -- the response to topotecan alone was almost nil. But when bevacizumab was added, the response increased to more than 20%. Indeed, one begins to wonder whether there is any point in giving chemotherapy in this context. We are seeing the substantial effect of bevacizumab, and we can conclude that in the future weekly paclitaxel with bevacizumab for platinum-resistant ovarian cancer is going to be a standard that will be hard to beat.

In the other bevacizumab study, the OCEANS study[2] in platinum-sensitive relapse, bevacizumab was added to gemcitabine and carboplatin for the treatment of platinum-sensitive relapsed ovarian cancer. We knew that there was a clear benefit in terms of progression-free survival. We heard today a further update on overall survival in that study. We had suspected that in fact there would not be an overall survival benefit, and that was confirmed. There is a substantial progression-free survival benefit but not an overall survival benefit.

The question is whether one should interpret that as being a negative finding. In my mind, and in the minds of many others, we should not interpret it that way. It tells us that in a situation where there is crossover to bevacizumab at relapse, it will clearly affect overall survival. Almost twice the number of patients who had not received bevacizumab as part of the randomized initial comparison went on to receive the drug at crossover. We knew that those patients would have a clear impact on the overall survival analysis. This is an important positive trial. The toxicity data were confirmed as demonstrating acceptability. By a happy coincidence, we heard last week that the European authorities have granted regulatory approval for the use of bevacizumab in the context of platinum-sensitive relapsed disease, not just for first-line treatment. So we now have 2 out of the 3 indications approved by European authorities -- first-line and second-line. Following the AURELIA data, we have high hopes that next year we will see approval in the resistant setting.

Brivanib: An Answer to Bevacizumab Resistance

However, that is not the end of the story. Patients eventually will become resistant to this drug, and we have to think ahead. How can we use other agents for the treatment of ovarian cancer to target angiogenesis? I presented a study[3] with a drug called brivanib, which is a vascular endothelial growth factor (VEGF)-targeted small molecule. It is an oral tyrosine kinase inhibitor that inhibits VEGF and fibroblast growth factor (FGF).

When patients become resistant to bevacizumab, what are the pathways that contribute to that? One of these pathways is FGF. So the question is: In patients who have had bevacizumab, will a drug such as brivanib have an effect? The study that I presented was a randomized discontinuation study, a subgroup of a much larger study with the drug. But it did contain more than 100 patients with ovarian cancer, 23 of whom had taken bevacizumab. The study was positive. The randomized discontinuation design looks at whether patients who have developed stable disease have a better progression-free survival when assigned to continue brivanib or to move to placebo. The findings for that were positive, with an almost doubling of progression-free survival. In addition, we saw that more than 20% of the patients who had previously taken bevacizumab responded to brivanib. We are beginning to see at least one clue as to how we might deal with what is going to be a significant problem -- the development of resistance to VEGF therapy. Brivanib has proven to be just one of several agents that can be used under those circumstances.

Another Way to Head Off Bevacizumab Resistance

Another way of looking at the problem of resistance to VEGF therapy is to think about other pathways in angiogenesis. One of these involves angiopoietin access. Angiopoietin-1 and -2 are secreted by tumor cells and endothelial cells. They inhibit another set of receptors called the Tie-1 (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) and Tie-2 receptors. The agent that could work here is a drug called AMG 386, which is a very interesting peptibody. Essentially, it is an agent that blocks the angiopoietin interaction with Tie-2. It is now known that that the agent will block angiogenesis in a way that complements the VEGF inhibitors such as bevacizumab. So, this drug is already being considered for ovarian cancer.

At the meeting today we heard the results of a feasibility study[4] in which AMG 386 was combined with chemotherapy, paclitaxel/carboplatin, for the first-line treatment of ovarian cancer. For the first time, this study used a dose of 15 mg/kg, higher than doses that had been used before in an earlier study with the weekly paclitaxel, so the question answered by the study was whether it was feasible to do this. It was very feasible, and it seems to be a very acceptable treatment. This drug is given intravenously once weekly, with a maintenance that continues for up to 18 months.

AMG 386 doesn't have some of the drawbacks of bevacizumab. Although bevacizumab is a very important agent, it has drawbacks. It can cause hypertension, bowel perforations, proteinuria, and occasionally thrombotic events. None of these appear to be the case with AMG 386. There is a different toxicity, a curious peripheral edema, which we need to better understand. But on the face of it, AMG 386 is a very well-tolerated agent. We are going to need to look with interest at the results of a new, large, randomized, first-line trial (TRINOVA-1), which will look at AMG 386 in combination with chemotherapy for the first-line treatment of advanced ovarian cancer, and we'll have to compare those data with the earlier data with bevacizumab. So, a lot is happening with angiogenesis.

MM-121: New Agent in Relapsed Disease

I would like to tell you about another novel agent for ovarian cancer. It's a new target in the ErbB family. Epidermal growth factor is an important target in many cancers, including human epidermal growth factor receptor 2 (HER-2) in breast cancer. These have not made much of an impact in ovarian cancer, but there are other members of the ErbB family, including ErbB-3, a target that is commonly present in ovarian cancer. More than half of all cases have increased expression with amplification. It provides a rather interesting target because of an autocrine growth loop. Ovarian cancer cells secrete a compound molecule called "neuregulin," which actually binds to this target and turns on pathways that lead to increased growth and drug resistance. So, it is an important pathway to try to block. MM-121 is an antibody that very selectively blocks HER-3 and dimerizes with HER-2 to turn on a pathway that essentially leads to increased growth and drug resistance. It is a target that makes sense in ovarian cancer, and we heard today about its use combined with weekly paclitaxel. That is sensible because weekly paclitaxel is a very good treatment for relapsed ovarian cancer, but we need to get better at reversing resistance to it.

One of the mechanisms for resistance actually involves a pathway downstream of HER-3 -- the MAP kinase (AKT) pathway. If we can block that, we might be able to enhance the activity of weekly paclitaxel. Today we saw that it is very feasible to do that. We saw the results of the feasibility study[5] showing that MM-121 (which is an intravenous antibody given as a loading dose and then weekly) adds very little toxicity to weekly paclitaxel. It is probably not any different. We saw that the efficacy is promising, but this was not a randomized trial; it was a fairly small feasibility study that led to a randomized study, which has already half completed recruitment. So next year we will see the results of the first randomized trial of weekly paclitaxel with MM-121, the first anti-HER-3 targeted agent in ovarian cancer.

From the Sea Depths a New Cytotoxic

The last thing is a new cytotoxic agent. People sometimes say that there is no point in developing new cytotoxics; we have done all that. However, one cytotoxic that is already approved for ovarian cancer is called trabectedin. It comes from a marine compound. A company called PharmaMar (Zeltia Group, Madrid, Spain) has a hypothesis that at the bottom of the sea there are novel agents that we just need to identify and isolate, and the hypothesis is partly right. The problem with trabectedin (the drug was approved) is that it turned out to be a little disappointing. We thought that it would be active in platinum-resistant ovarian cancer, and it isn't.

Another compound with subtle but important changes in the structure, called "lurbinectedin," is a sort of successor to trabectedin. Today we heard that lurbinectedin is active in the group of patients with platinum-resistant disease that eluded us with trabectedin.[6] That has confirmed some laboratory data. There are still side effects, however. It is myelosuppressive, and there is a degree of vomiting, so there is quite a lot still to do. But it is a potential way forward. It may be a drug that could be used in combination with others. We have just heard for the first time that the drug is active, and it is going into a randomized trial. So there is scope for more novel cytotoxics, potentially even in combination with some of the targeted agents.

Closing Remarks

To summarize, I'm an optimistic medical oncologist, and this continues to be an important time for the therapy of ovarian cancer. I have said nothing about poly (ADP-ribose) polymerase (PARP) inhibitors because we didn’t hear about those at this meeting, but I am sure we will at the next one. So thank you very much for joining me today for Medscape Oncology Insights. This is Stan Kaye signing off from ESMO 2012.

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