Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: rationale, evidence and place in therapy

Abstract

The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit. Unfortunately, virtually all patients who initially respond to treatment develop acquired resistance to EGFR-TKIs within 9–14 months. The EGFR T790M secondary mutation has emerged as a cause of treatment failure in approximately 60% of resistant cases. To date, several compounds designed with the aim to overcome T790M-mediated resistance are under clinical investigation. The aim of this review is to discuss emerging data regarding the third-generation EGFR-TKI, osimertinib, for the treatment of EGFR T790M mutant advanced NSCLC.

Real‐world outcomes of NSCLC patients receiving tissue or circulating tumor DNA‐guided osimertinib treatment

“…The response rates to first‐generation EGFR tyrosine kinase inhibitors (TKIs) range between 56% and 74%, and the median progression‐free survival (PFS) durations range from 9 to 13 months . However, most patients experience disease progression, and about 50%‐70% of them develop newly acquired resistance EGFR p.Thr790Met (T790M) point mutations . These acquired mutations enhance the binding affinity of adenosine triphosphate on the EGFR kinase domain and, in turn, decrease the efficacy of first‐ and second‐generation EGFR‐TKIs.…”

Neuropsychiatric Immune-related Adverse Events Induced by Pembrolizumab in a Patient with Lung Adenocarcinoma and Systemic Lupus Erythematosus

“…Despite their benefits, reports of immune-related adverse events (irAEs) in association with ICB therapy are accumulating (1,2,7). Although a multi-institutional retrospective analysis suggested that ICIs could be safely administered to patients with NSCLC and a history of autoimmune disease (AID) (8,9), their safety and efficacy in patients with NSCLC and systemic lupus erythematosus (SLE) have not been extensively studied.…”

Afatinib in the first-line treatment of patients with non-small cell lung cancer: clinical evidence and experience

“… 16 More recently, third-generation EGFR TKIs which are EGFR -mutant selective and wildtype (WT)-sparing inhibitors have been developed to selectively target T790M-resistant secondary mutations. Osimertinib is a third-generation EGFR TKI that binds covalently to EGFR isoforms (del19, L858R and double mutants containing T790M mutation) via a cysteine residue at codon 797 (C797) with minimal activity against WT EGFR 17 and is the third-generation EGFR TKI with the most advanced clinical development. Currently osimertinib is recommended worldwide for T790M-mutant patients who progress on or following first-generation EGFR TKIs based on data from the pivotal phase I/II AURA, phase II AURA 2 and from the confirmatory phase III AURA 3 trial which definitely confirmed its superiority over chemotherapy in T790M-positive patients who progress on or following gefitinib or erlotinib in terms of PFS [10.1 versus 4.4 months, hazard ratio (HR): 0.30; 95% confidence interval (CI), 0.23 to 0.41; p < 0.001) and ORR (71% versus 31%, p < 0.001].…”