Sotorasib: the fifth fragment-derived drug approved

Today the US FDA approved sotorasib (AMG 510) for a subset of patients with non-small cell lung cancer. This is the fifth fragment-derived drug approved.

 

Last year Practical Fragments outlined the discovery of sotorasib, tracing its origins to two independent fragment-based efforts. (Disclosure: I was part of this work at my previous company, Carmot Therapeutics.) Today's approval illustrates another aspect of the story: the speed with which the program progressed. From the Nature publication demonstrating that KRAS^G12C is ligandable it took just five years to deliver sotorasib to the clinic, and less than three to demonstrate sufficient safety and efficacy to win approval.

 

This is fast for any drug, and all the more so for a target previously deemed undruggable.

 

In addition to commending the scientists and clinicians, credit is also due to Amgen, which cleared all bureaucratic hurdles to push this program forward. Every company with even a passing interest in cancer saw the 2013 Nature paper, but many were put off by the covalent nature of the molecule. It took organizational vision - in addition to great science - to succeed.

 

It is also worth noting that of the five fragment-derived drugs now approved, two are for difficult targets; venetoclax blocks a protein-protein interaction.

 

Of course, the raison d'être for all these efforts is to help patients, and the emerging clinical data for sotorasib clearly demonstrate this. Of 126 patients with advanced, previously treated non-small cell lung cancer, 43 had partial responses, and 3 had complete responses. For those not familiar with cancer research this may not sound impressive, but these are patients with no other options. And this is just the beginning for sotorasib, the first drug to work via this long-sought mechanism. Combination therapies are already actively being pursued, and these often show dramatic improvements as physicians figure out how best to use new drugs.

 

Congratulations - and thanks - to everyone involved in bringing this new gift to humanity.