The news yesterday from Amgen that panitumumab (Vectibix) failed in Head and Neck cancer got me thinking.  Why did it fail where cetuximab (Erbitux) succeeded? They're both monoclonal antibodies to EGFR, so that makes it rather interesting.

Many of you will remember that bevacizumab (Avastin) and Erbitux were both approved within a month of each other for colorectal cancer, both monoclonals, to VEGF and EGFR respectively.  That was after a long string of failures for anti-angiogenesis compounds.  Subsequently, vatalanib (PTK787), a small molecule tyrosine kinase inhibitor (TKI) of VEGF from Novartis failed in the same indication and did not achieve statistical significance in survival.

It gets even more interesting when you consider prostate cancer as another example:

  1. Abbott's atrasentan got villified at it's ODAC meeting and never received approval.  In a few months, however, we will hear what happens in the phase III trial for another endothelin-A inhibitor, zibotentan (AstraZeneca).  The phase II data showed a difference in OS, but not PFS, so who knows what will happen with the phase III study?
  2. Avastin also failed to achieve a survival advantage in prostate cancer, but does that mean that other VEGF inhibitors, such as sanofi-aventis/Regeneron's aflibercept (VEGF-Trap), will fall the same fate?  We don't know yet, but as far as I know, that one's still alive and kicking.

I find it fascinating trying to work out why some drugs work and some don't even in the same class in the same indication.  It could be all sorts of reasons:

  • Dosing
  • Scheduling
  • Patient population
  • Study design
  • Drug combinations
  • Compound structure
  • Availability of suitable biomarkers
  • Indications

Or one of many many other things or combination of reasons.

And there there is the related issue of 'pure' inhibitors (single target such as VEGF or BCR-ABL) versus multi-kinases or monoclonals (more than one target such as VEGF, EGFR, PDGF or FGFR, for example).  Does it make a difference in efficacy and tolerability, will they affect outcomes differently?

Hopefully, we can learn from the failures to date for the future, allowing us to design better drugs and trials that have a more positive impact on outcomes.

Curiousity is killing this cat… R&D is such a crapshoot sometimes.