It is not easy to follow an evolving story of EGFR mutations in NSCLC and other cancers. Most common are mutations called the exon 19 deletions and exon 21 L858R mutation. Other mutations including exon 20 insertion mutations are less common. To treat patients with most common mutations, two drugs, Iressa and Tarceva were developed. BTW, David Epstein and Elizabeth Buck, were involved in the development of Tarceva. They know this field. Patients treated with Iressa or Tarceva sooner or later progress. One of the reasons for disease progression is the emergence of an additional mutation, called a resistant mutation, T790M. Tarceva or Iressa are ineffective against T790M. AstraZeneca found the way to overcome this resistance by inventing Osimertinib (Tagrisso). It turned out to be such a great drug that oncologists started using it as a first line treatment instead of chemotherapy, Iressa or Tarceva. Osimertinib is less toxic and more effective. And as David Epstein mentioned, patients treated with Osimertinib never develop T790M mutation. However, after some years on Osimertinib, patients become resistant to this drug as well. Why? Because new mutations emerge. Some of them are in EGFR again, some are in other proteins. Most common mutation in EGFR causing resistance to Osmertinib, is C797S. In addition, several less common Osimertinib resistance mutations were identified. To make EGFR mutation landscape more complicated, these Osimertinib resistance mutations can co-exist with other so-called intrinsic mutations. Now, how BDTX-1535 can help? It can block activation of EGFR caused by Osimertinib-resistant mutations and EGFR intrinsic mutations. Possibly it doesn’t work so good against T780M, but after Osimertinib you don’t have it. In GBM, EGFR mutations are different and one of the reasons why Osimertinib doesn’t work in GBM could be low brain penetrance.
