Towards better outcomes for epidermal growth factor receptor L858R+ lung cancer patients: mutant-selective allosteric inhibitors and the potential for double-drugging.

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a frequent cause of non-small cell lung cancer (NSCLC). Osimertinib, a third-generation tyrosine kinase inhibitor (TKI) that is selective for mutant EGFR, is standard of care for patients with the classical exon 19 deletion variants and the L858R point mutation. Although osimertinib and a recently developed therapy that combines TKI lazertinib with the antibody amivantamab improve outcomes for these patients, resistance limits the durability of response to these agents. Additionally, patients with the L858R mutation do not respond as well as those with exon 19 deletions, highlighting the need for more effective therapies for these patients and for those with brain metastases, a common complication of these cancers. In this review, we survey the development of next-generation EGFR inhibitors with a particular focus on allosteric inhibitors developed for L858R-mutant NSCLC. EAI-432 and other allosteric EGFR inhibitors can co-bind with osimertinib, offering the possibility of double-drugging the mutant receptor to achieve deeper and more durable responses for EGFR L858R+ patients. This article is part of the discussion meeting issue 'Epidermal growth factor receptor after 40 years'.