The last 18 months have seen a lot of failed cancer studies in phase III development after early promising phase II results, teaching us that sometimes rushing full steam ahead without fully understanding the issues is not always the smartest strategy.

168715438_9c4af6f9f7_mLet's start with Pfizer's figitumumab, an IGF-1R antibody, which we have previously discussed in non-small cell lung cancer (NSCLC) (here and here). There was one phase II trial at MD Anderson that led to what many of us thought was a rather cavalier, aggressive and hasty phase III program, without really seeking to understand the underlying biology behind the pathway first. Interestingly, other competitors have taken a much slower and more methodical approach to thinking through the various issues and may well come out ahead as a result.  

Given the front-line trial produced a negative response, I think many of us were expecting the 2nd line study to eventually go the same way.  The endocrine and biochemical interactions happening around IGF-1R will need more careful reflection before the concept has a real chance of working.  There are various things happening around cross-talk between receptors, interaction with the insulin receptor and AKT may well turn out to have an important role to play.  All in all, manipulating the biochemistry of the pathways needs a little more sophistication than a mere sledgehammer to crush a grape approach.

Pfizer also announced that two phase III trials with sunitinib (Sutent) also failed to meet their primary endpoint.  Sutent is approved for the treatment of renal cell cancer and gastrointestinal stromal tumours (GIST) and as an oral VEGF/KIT inhibitor that was originally developed by Sugen before it was snapped up by Pharmacia, I think it has done pretty well.  It is unrealistic to expect every drug to work in every indication and there may be differences between how monoclonal antibodies such as bevacizumab (Avastin) work compared to small molecules such as Sutent and Bayer's sorafenib (Nexavar).

Like Pfizer, Bayer recently announced promising phase II results in breast cancer.  Given that Pfizer previously announced last year that a Sutent trial in breast cancer was negative (see previous post), I wasn't expecting the two current trials to be positive.  Had they done so, it would have been akin to a miracle.

Roche's Avastin has had a string of good results and also a few setbacks.  The original program focused on breast cancer rather than colorectal cancer before the trial was negative.  To give Genentech credit though, they went back to the drawing board to figure out what worked and where the issues were before eventually having another success in breast cancer much later.  This is probably what Pfizer need to do now too, scientific and clinical reflection is sometimes a necessary part of the pain on the journey. 

Avastin has been now approved in colorectal, lung, breast, renal and brain cancers, so a setback in prostate cancer, as Genentech announced this morning, is probably not going to matter too much.  This is unfortunate because there really aren't that many options for advanced stage patients who have become hormone resistant.  All is not completely lost for men with prostate cancer though, as sanofi-aventis (a client) have reported that their next generation taxane, cabazitaxel, increased survival in this population, so hopefully we will see more of the data at this year's ASCO meeting in June.

One thought we should perhaps reflect on.  'Oncogenic addition' is a phrase bandied around quite a bit these days, and for sure, some approaches have been very successful.  We need to remember though, that targeting kinases and enzymes is only going to work if the enzyme is actually critical to the survival of the tumour, which will rarely happen in isolation.  The way forward is most likely going to need a more sophisticated approach that combines multiple inhibitors in a logical fashion.  To achieve that approach though, will require more iterative phase II trials to really determine exactly what is going on.  

Pfizer and Roche/Genentech both have smart scientists and clinicians in their organisations, so my feeling is that they will go back to the drawing board and evaluate these trials and the data very carefully.  You can't have a home run every time, but you can sometimes figure out ways to see if an agent can be made to work by tweaking things.  Often, we're limited by our knowledge of the biology and sometimes negative trials can actually help us understand things better.

Photo Credit: Stuck in Customs