One of the biggest challenges with Vascular Endothelial Growth Factor (VEGF) therapy to date has been the singular lack of either predictive or prognostic biomarkers.
This means that we have no idea which patients are most likely to respond to therapy (ie predictive) when selecting either a monoclonal antibody (eg bevacizumab) or a small molecule tyrosine kinase (eg sorafenib, sunitinib or pazopanib), nor do we will know what their likely prognostic outcome might be in terms of survival.
In an ideal world, we would be able to predetermine and monitor therapy for specific subtypes, thereby avoiding exposing thousands of patients to the systemic effects (and costs) of a drug that may not work for them.
Of course, we all know that developing biomarkers is:
- not easy
- could be rather expensive
I was therefore greatly cheered while at the AACR meeting Denver on Molecular Diagnostics and Cancer Therapeutics last week to come across a little gem of a poster from the scientists at AVEO Pharmaceuticals.
AVEO ($AVEO), a biotech based in Boston, are developing an oral VEGF inhibitor called tivozanib, currently in phase III for renal cell cancer, and appear to have developed a method to predict which patients are more likely to respond to the compound. Whoa!
I've been watching this company for a couple of years now and have been impressed with what I see so far. Two years ago I met their CMO Bill Slichenmyer over lunch at the AACR meeting in Denver when he was at Merrimack Pharma and kept track of what was happening at AVEO when he moved there. Both companies have interesting technology platforms and smart scientists.
Aside from the poster, AVEO's head of translational medicine, Murray Robinson, also presented the data during an oral session. What was particularly interesting was that the findings were not what one might expect – at all. They wondered if the potential biomarker they identified in animal studies might be reproduced in humans.
AVEO found their biomarker by inserting specific oncogenes and other engineered genes altered in numerous cancer types into the tissue of animals then studying the variety of tumours that were produced. One example of this approach was to genetically alter the HER2 gene, resulting in tumours that naturally expressed different pathways for growth.
They then looked at 600 tumour samples in clinical trials across eight different tumour types and realised that essentially the same biomarker identified in their breast tumour model was indeed associated with clinical activity in a set of kidney tumour patients from a previous Phase II kidney cancer trial. This biomarker was associated with white blood immune cells that are recruited into the tumour to produce angiogenic growth factors and leads to intrinsic resistance to tivozanib.
I confess to being kind of awed by this sort of research.
For some time, clinicians have been grumbling about not having a biomarker for Avastin, Sutent or Nexavar to better help choose which patients would be most likely to respond, thereby avoiding the need to treat everyone to gain a benefit in a few. Here we have three big pharma companies and no biomarker. A little biotech comes along with some smart ideas, a rational approach to the problem and some creative thinking to developing a biomarker for their compound, which is not yet on the market.
Of course, this biomarker is specific to AVEO's tivozanib, as no work has been completed to show that the myeloid component they identified is relevant in the others.
The good thing is that it's now the first biomarker associated with a VEGF therapy.
The bad news is that we will have to wait a little longer to see if the results of the phase III trials in kidney cancer are good enough for approval, but hopefully that won't be too long now.
Imagine one step further.
Currently, the FDA is reviewing Roche's Avastin in breast cancer and deciding whether or not to withdraw the application given the marginal data currently available from trials such as AVADO. Suppose Roche/Genentech had a biomarker that was relative to Avastin and could be helpful for either prognostic or better still, predictive purposes? Then you could actually make better use of the drug based on a biomarker.
Before anyone in big pharma jumps up and down and starts moaning about the cost and the difficulty, take a look at AVEO's logical, sensible technical approach to the problem. You realise that what we really need is more imagination and creativity in R&D and less objections to progress.
Now suppose the biomarker AVEO identified in their breast cancer models turns out to be useful in breast cancer for women on their compound? If you can clearly show an association between different subsets, who is likely to develop resistance and who is more likely to respond, plus better outcomes, what's not to like? The overall response rates will be higher in some subsets and lower in others, rather than a crapshoot of "well, it helps some women" or how about the vague "many women clearly benefitted". Great, but which ones and why?
In my opinion, AVEO have done a great job identifying a relevant biomarker for their compound which may actually increase rather than lessen the chances of successful approval down the road.
May the force be with them!