CFS 2011, Chemotherapy Foundation Symposium, 8-12 November, New York, USA

Active angiogenesis drugs in development

Professor Bradley Monk – University of California Irvine, USA


Bevacizumab, if you haven’t already heard, was the first active targeted agent in epithelial ovarian cancer, in fact, to this date, we don’t have any improved agents, although in Europe bevacizumab will be approved very, very soon, the launch date is in 2012. It’s important that we understand that bevacizumab is not the only anti-antiogenesis drug and I was asked to talk about others. Particularly I discussed VEGF trap, this is an FC fusion molecule, so another ligand binding molecule that binds and inactivates VEGF. Then I talked about other anti-angiogenesis strategies that target other pathways, specifically I spoke about AMG 386. AMG 386 is another, a third, ligand binding strategy, they use what’s called a peptibody to bind and inactivate angiopoietin 1 and 2. So bevacizumab, VEGF trap bind VEGF, AMG 386 binds the tie-1 and tie-2 ligand, angiopoietin 1 and 2. This anti-angiopoietin 1 and 2 molecule is very active, at least in a randomised phase II, and is in phase III studies. So we have multiple anti-angiogenesis molecules in phase III studies, the most experienced, of course, is bevacizumab and that will get approved very soon in the EU, but other strategies – VEGF trap and AMG 386.

Are there any new targets?

One of the other interesting new targets in ovarian cancer is the folate receptor. If it hasn’t dawned on you, the folate receptor is selectively over-expressed on ovarian cancer cells and that allows us to target specifically ovarian cancer cells where this folate receptor is. There are two strategies: one is to have an antibody called farletuzumab, which can bind that folate receptor on the ovarian cancer cell and stimulate an immune response. And that has been shown in phase II studies to be active and is now in a phase III study in recurrent ovarian cancer.

The second folate strategy is to take the folate vitamin and to attach to it a chemotherapy drug. So then when the folate vitamin binds to the folate receptor on the ovarian cancer cell, it brings the chemotherapy next to the cancer. That chemotherapy then selectively kills the cancer and that strategy is a molecule called EC 145 and, again, in a randomised phase II trial it’s been shown to enhance the activity of liposomal doxorubicin. So now there’s a phase III trial of this vitamin-chemotherapy conjugate with liposomal doxorubicin in resistant ovarian cancer.

Then, finally, I think we’ve all heard about PARP inhibitors. PARP inhibitors are molecules that target cells that are deficient in DNA repair and by making them even more deficient, by inhibiting PARP, which is another DNA repair mechanism, the cells become so unstable that they die. So there are a number of PARP inhibitors in development, these are also an active class of molecules, something that we’re very, very excited about as now a third concept. So anti-angiogenesis and anti-vascular drugs, second, folate and then third PARP inhibitors. And I guess the fourth category is cytotoxics, we can’t give up on cytotoxics.

Ovarian cancer, if it hasn’t dawned on you, is not like lung cancer where there is a specific mutation that caused it; ovarian cancer has so many mutations that really occurred because of this genetic instability that I talked about with PARP inhibitors. So because they’re so genetically unstable they’re susceptible to standard cytotoxic drugs and the two newest ones are trebectedin, trebectedin has been studied in combination with liposomal doxorubicin, we’re trying to hone in on exactly who the best population is and those are patients who probably recur between 6-12 months after front line therapy, that study is called the INNOVATION trial and is open.

And then the other cytotoxic is NKTR102, what this is is that this is the old drug, if you will, irinotecan, that is fused or pegylated, if you will. By pegylating the chemotherapy, just like pegylating a growth factor or interferon, pegylated irinotecan can selectively, because it’s a big molecule, extravasate in the tumour. So it circulates in the body until it gets next to a tumour where the blood vessels are leaky, gets into the tumour then the hydrolysis cleaves off the pegylation and then the cytotoxic irinotecan selectively kills the cancer. Very exciting, recently been shown to be active and also is in further study. We can’t give up on the cytotoxics and because, really, the cytotoxics are so active that is why we don’t have a targeted agent approved yet but bevacizumab is coming.

Is this the first time chemotherapy has been combined with a vitamin?

It is the first time that a vitamin chemotherapy conjugate has been combined with a chemotherapy. What we’re trying to do is, the trick in oncology is to selectively target the cancer and we can do that in ways like pegylation, we can do that if there’s a receptor on the cancer, like a folate, bind it with an antibody or combine it with something that binds that receptor, or we can target the microenvironment because the tumour microenvironment, angiogenesis, is very different than the host where angiogenesis is not nearly as important.