One of the recurring themes across multiple tumor types is the fact that cancer is smart and develops resistance to new drugs.
A visual metaphor used for this is traffic in mid-town Manhattan – if you block a cross-street, the traffic will stop for a while then slowly pick-up again as they find alternative routes.
Cancers not only adapt by finding alternative routes known as escape mechanisms, but they can mutate in the process into forms of cancer that no longer respond to existing treatment.
We have seen this in CML and NSCLC with the development of acquired resistance to treatment through T315I and T790M mutations, respectively.
In melanoma we’ve seen dramatic responses with BRAF inhibitors in patients with BRAFV600E- mutant melanoma, only for most patients to relapse due to acquired resistance and clonal evolution. New treatments may need to consider not only different targets, but also sequencing, logical combinations and intermittent dosing strategies as described in the latest post on Pharma Strategy Blog on RAF resistance in metastatic melanoma.
In prostate cancer we see cross-resistance between enzalutamide and abiraterone, with the result that each drug is less effective when it follows the other.
You can’t assume that even though a drug has a different mechanism of action it will work: you have to look at the treatment landscape and how sequencing and resistance mechanisms may impact effectiveness. A key question is how durable is the response to a new drug?
At ASCO 2013, Dr Charles Sawyers, in his Science of Oncology Award lecture noted that drug resistance is universal and that we need to define mechanisms of resistance.
Key to overcoming resistance are drug combinations – can we get to combination therapy faster is one of the key questions he raised, given that pharma often prefer single agent trials to make registration easier, especially if they only have one side of the coin in their pipeline.
Combinations are the future, not only in oncology, but also immunotherapy. In her recent ASCO GI 2014 keynote lecture, Elizabeth Jaffee described the scientific rational for the combination of immune checkpoint inhibitors with vaccines.
Large pharmaceutical companies that have a pipeline of drugs that can be combined have a huge potential competitive advantage compared to small biotechnology companies.
Science is driving combination therapies to overcome resistance and increase effectiveness. That is the future oncology landscape that anyone bringing new products to market needs to be aware of.