EGFRm+ non-small cell lung cancer – new treatments in development

For patients with activating mutations to the EGFR receptor kinase, small molecule specific inhibitors Iressa (gefintinib) or Tarceva (erlotinib) are administered as front-line treatments.  But, non-small cell lung cancers develop resistance after about one year of treatment via a single recurrent missense mutation (T790M) to the tyrosine kinase.  This is similar to resistance observed in patients with CML (Chronic Myeloid Leukemia) following treatment Gleevec (imatinib), which is mediated by a mutation to the Bcr-Abl transgene.

The EGFR is a critically important transmembrane receptor that triggers the ras signaling cascades, including MEK and Akt/PKB, which results in proliferation, and blocking of differentiation and apoptosis – see diagram from NEJM.  Development of drugs to overcome the T970M mutation is very important.

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Two such drugs are CO1686 (Clovis Oncology) and AZD9291 (AstraZeneca), which are designed to irreversibly block both the tyrosine kinase receptors of the activated EGFR mutation, and the T970M mutation – EGFRm+/T970M cancers.  So, these could then be used in lieu of gefitinib or erlotinib.  The chemical structures of all 4 compounds are shown, below:

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Chemical-Structures-of-third-generation-irreversible-EFGR-tyrosine-kinase-inhibitors_AZD9291_CO-1686-第三代不可逆表皮生长因子受体酪氨酸激酶抑制剂的化学结构

In recent data reported at ASCO, CO1686 showed a 58% response rate in patients with the T970M mutation, however, 22% developed hyperglycemia requiring insulin treatment.  AZD9291 showed a 50% response rate in Phase 1 studies.  It will be interesting to see whether undesirable side effects also develop with AZD9291 given their different chemical structures.

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