Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer

Abstract

Non-small-cell lung cancer (NSCLC) represents the most common type of lung cancer. The majority of patients with lung cancer characterized by activating mutations in the epidermal growth factor receptor (EGFR), benefit from therapies entailing tyrosine kinase inhibitors (TKIs). In this regard, osimertinib, a third-generation EGFR TKI, has greatly improved the outcome for patients with EGFR-mutated lung cancer. The AURA and FLAURA trials displayed the superiority of the third-generation TKI in both first- and second-line settings, making it the drug of choice for treating patients with EGFR-mutated lung cancer. Unfortunately, the onset of resistance is almost inevitable. On-target mechanisms of resistance include new mutations (e.g., C797S) in the kinase domain of EGFR, while among the off-target mechanisms, amplification of MET or HER2, mutations in downstream signaling molecules, oncogenic fusions, and phenotypic changes (e.g., EMT) have been described. This review focuses on the strategies that are currently being investigated, in preclinical and clinical settings, to overcome resistance to osimertinib, including the use of fourth-generation TKIs, PROTACs, bispecific antibodies, and ADCs, as monotherapy and as part of combination therapies.

Keywords: EGFR; NSCLC; bispecific antibodies; combination therapy; drug resistance; osimertinib.

Figure 1

Mechanisms of resistance to osimertinib in NSCLC. The cartoon illustrates the common mechanisms of resistance in patients treated with osimertinib, both in first- and second-line therapy. Resistance mechanisms can be subdivided into two categories: “on-target”, referring to alteration in EGFR, and “off-target”, involving alternative signaling pathways [77,78,79,80,81]. Mut, mutation; amp, amplification; upreg, upregulation; overex, overexpression; act, activation; del, deletion; gain, gain of copy number; EMT, epithelial-to-mesenchymal transition; SCLC, small-cell lung cancer; NEC, neuroendocrine carcinoma; SCC, squamous cell carcinoma.