What is the difference between Osimertinib and first, second and third generation targeted drugs?

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) targeted drug. It is mainly used to treat non-small cell lung cancer (NSCLC) with EGFR gene mutations. Compared with the first and second generation EGFR targeted drugs, osimertinib is significantly different in structural design and mechanism of action. The first-generation drugs, such as gefitinib and erlotinib, are reversible EGFR tyrosine kinase inhibitors. They mainly target common sensitive mutation sites, but have limited effect on drug-resistant mutations such as T790M. Second-generation drugs such as afatinib are irreversible inhibitors that target multiple HER family members, but have relatively large side effects.

As a third-generation targeted drug, the biggest advantage of osimertinib is that it has a strong inhibitory effect on EGFR T790M resistance mutations. This mutation is a major cause of treatment failure with first- and second-generation drugs. Osimertinib can overcome T790M-mediated drug resistance by irreversibly binding to EGFR mutants and improve the efficacy and survival rate in the later stages of treatment. In addition, osimertinib has weaker inhibition of wild-type EGFR, reducing damage to normal cells, resulting in better tolerability and lower risk of side effects.

In clinical application, osimertinib is not only suitable for patients with T790M mutations after treatment with first- or second-generation EGFR inhibitors, but is also approved as a first-line treatment for patients with EGFR mutation-positive NSCLC patients. Studies have shown that the first-line use of osimertinib can significantly prolong progression-free survival (PFS) and overall survival (OS), and can effectively control brain metastases and improve patients' quality of life. In contrast, early first- and second-generation drugs were weak in brain penetration and had limited therapeutic effects.

Overall, osimertinib has made up for the shortcomings of the first two generations of drugs by targeting drug resistance mutations and optimizing safety design, and has become an important treatment option for EGFR mutated non-small cell lung cancer. As research continues to deepen, osimertinib is increasingly used in clinical practice, bringing patients better treatment prospects and hope for survival.

Reference materials:https://go.drugbank.com/drugs/DB09330