Patients suffering from advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations have emerged as groundbreaking treatment for with osimertinib, a potent EGFR TKI (TKI).The management of these patients is posed with a major challenge by the development of resistance to osimertinib.

This article delves into the most common resistance mode to osimertinib and explores the fundamental mechanisms, diagnostic methods, treatment plans, and current research endeavors for overcoming this resistance.The most common resistance mechanism to osimertinib is characterized by the development of the T790M mutation in the EGFR catalytic domain, known as EGFR T790M Mutation.

MET amplification, which involves the amplification of the MET proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-proto-oncogene and leads to increased MET signaling pathway pathway, is another common resistance mechanism to osimertinib.Other less frequent resistance mechanisms, including additional mutations in the EGFR catalytic domain, alterations in the PI3K/AKT/mTOR signaling pathway, and increased drug efflux by P-gp (P-gp), are also present.

Next-Generation Sequencing, which is the gold standard, is used for detecting Epidermal Growth Factor Receptor mutations and T790M resistance mutations.Circulating Tumor DNA (Circulating Tumor DNA) analysis is a minimally invasive method capable of identifying resistance mutations in NSCLC patients.tissue biopsy remains an essential diagnostic procedure for determining resistance mechanisms in NSCLC patients.

In cases of T790M mutation, second-generation tyrosine kinase inhibitors, such as erlotinib, afatinib, or lorlatinib, can be considered.immunotherapy drugs, such as checkpoint inhibitors, have shown encouraging results among patients with osimertinib resistance.combined therapies, including the combination of osimertinib with immunotherapy or targeted therapies, are being investigated as potential strategies to surmount resistance and improve patient outcomes.

The development of new tyrosine kinase inhibitors, which can overcome T790M mutation and additional resistance mechanisms, is actively being worked on by investigators.Research efforts are focused on developing targeted therapies that can block MET signaling and surmount resistance, given the role of MET amplification in osimertinib resistance.

Combination of strategies in personalized medicine, including genetic profiling and circulating tumor DNA analysis, is crucial for identifying tailored treatment regimens for patients with osimertinib resistance.The management of non-small cell lung cancer patients with epidermal growth factor receptor gene mutations remains a significant challenge due to osimertinib resistance.

Comprehension of the most frequent resistance phenomena, employing innovative diagnostic modalities, and introducing focused therapeutic options is essential for conquering drug resistance and improving patient results.continuous scholarly endeavors are focused on developing novel therapies and individualized therapeutic strategies to resolve complexities of osimertinib resistance and to provide successful therapeutic alternatives for patients.