Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor

Abstract

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis

“…Recent breakthrough in the TKIs therapy occurs with the development of mutant selective pyrimidine-based thirdgeneration TKIs, typical drugs like AZD9291, WZ4002 and CO-1686, which could irreversibly block T790M mutant EGFR, sparing the wild type (WT) receptor (29). It demonstrated that the ORR of AZD9291 in patients with EGFR T790M positive tumors was 56%, which was higher than that of 12% in terms of afatinib in our meta-analysis outcome.…”

Targeting cancer with kinase inhibitors

“…There are a number of advantages to this approach, including (a) improvements in tolerability and therapeutic index, as well as enabling (b) the development of drug combination regimens, (c) validation of new targets and molecular dependencies of tumors, and (d) assessment of mechanisms of action. For instance, next-generation EGFR inhibitors that selectively target the inhibitor-sensitizing and resistance (T790M) mutations exhibit a dramatically improved safety profile (with reduced rash and diarrhea) by sparing wild-type EGFR activity in normal cells (110). In addition, concomitant inhibition of structurally related kinases using less-selective inhibitors, such as sunitinib or dasatinib, can have opposing and confounding effects in modulating the immune system (111), which could limit antitumor efficacy and complicate the interpretation of molecular mechanisms.…”

Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

“…Consequently, almost all of the reported, irreversible EGFR inhibitors displayed equal potencies against T790M mutant and wild-type enzyme, highlighting the current challenge in the search for EGFR T790M mutant-selective inhibitors [10,11]. WZ4002 (3) [12], rociletinib (4) [13], and osimertinib (5) [14,15] are typical EGFR T790M inhibitors and a phase trial has revealed capability in gefitinib-resistant NSCLC patients who suffer from EGFR mutations (Figure 1). Unfortunately, only osimertinib possesses exceptional biological properties, and has thus been approved in 2015 for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC [16].…”