Fourth-generation epidermal growth factor receptor-tyrosine kinases inhibitors: hope and challenges

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are among the most common driver mutations, particularly in certain populations, such as Asian patients and non-smokers.Deletions in exon 19 and the L858R point mutation in exon 21 are the most frequent aberrations and collectively account for over 80% of all EGFR mutations (1).In the past two decades, the emergence of targeted therapy has profoundly changed the treatment strategy for patients with advanced driver gene-positive NSCLC.As an important therapeutic target for NSCLC, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have completely rewritten the diagnosis and treatment of patients with EGFR mutant NSCLC (2).First-generation (e.g., gefitinib and erlotinib) and second-generation (e.g., afatinib) EGFR-TKIs have demonstrated increased response rates and progressionfree survival (PFS) compared to traditional chemotherapy.Third-generation EGFR-TKIs such as osimertinib were developed primarily for overcoming acquired resistance to earlier generations of EGFR-TKIs due to T790M resistance mutation, a common mechanism of resistance to early generations of EGFR-TKIs (3).Osimertinib has also shown efficacy as a first-line treatment in EGFRmutated NSCLC patients, due to its ability to target both common activating EGFR mutations and the T790M resistance mutation.However, patients treated with these third-generation EGFR-TKIs still inevitably develop disease progression with complex mechanisms of acquired resistance, resulting in treatment failure.Emergence of acquired resistance to osimertinib has posed a significant challenge in the treatment of NSCLC.Several mechanisms of osimertinib resistance have been identified (4), among which, acquisition of the resistance mutation, C797S, which inhibits the binding of osimertinib to the EGFR protein, is a primary mechanism, particularly when osimertinib is used as a second-line treatment option.Hence, it sounds logical to develop next generation of high-affinity reversible EGFR-TKIs aiming for C797S mutation. Overview of fourth-generation EGFR inhibitorsBLU945 is a fourth-generation EGFR-TKI that specifically targets T790M/C797S co-mutations and other T790M resistance mutations secondary to osimertinib resistance.The SYMPHONY (NCT04862780) study is a phase I/ II study of patients with metastatic EGFR-mutated NSCLC who have previously received TKI treatment.It aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of BLU-945 alone and BLU-945 combined with osimertinib