Osimertinib

Osimertinib is a third generation, irreversible tyrosine kinase inhibitor (TKI) designed to inhibit EGFR-sensitizing and T790M resistance mutations. The drug is highly selective as it forms a covalent bond to the cysteine-797 residue in the ATP-binding site of the EGFR kinase domain. As a result, it inhibits the phosphorylation and activation of mutant EGFR and its downstream signaling pathways (pAKT, pERK) but not wild-type EGFR, and this selectivity results in less off-target toxicity.
The drug also has a wide therapeutic window and shows little activity against other kinases such as the insulin receptor, which limits off-target side effects like hyperglycemia. The metabolite, AZ7550, shows similar high potency and selectivity. Osimertinib was shown to cause durable tumor regression in mutant-positive models with no effects on normal tissue, and as a result, it is a very effective drug for the treatment of non-small cell lung cancer in patients who have developed resistance to first- and second-generation TKIs.

Fig. 1 EGFR pathway and mechanism of action of osimertinib. (Santarpia M, et al. 2017)

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide. EGFR-targeting tyrosine kinase inhibitors (TKIs) are widely used for treating NSCLC harboring sensitizing mutations, while developed TKIs, such as osimertinib, are faced with acquired resistance from triple mutation (e.g., T790M/C797S). A potential solution is that osimertinib liposomes (OB-LPs) were conjugated with cetuximab (CTX) to form immunoliposomes (CTX-OB-LPs) for pulmonary delivery of treatment to NSCLC. CTX-OB-LPs showed superior therapeutic effect and less systemic toxicity by combining the advantages of both liposomes and CTX. In detail, CTX-OB-LPs with desirable properties of 150 nm particle size, 87% antibody conjugation efficiency, sustained osimertinib release, and aerosol property (3 μm aerodynamic diameter and 88% fine particle fraction) were obtained. Moreover, CTX-OB-LPs displayed the most superior cytotoxicity to H1975 cells in vitro among different formulations with IC50 of free osimertinib and OB-LPs reduced by 1.7-fold and 1.2-fold, respectively. Meanwhile, CTX-OB-LPs could inhibit tumor cell migration and colonization. This research provides a promising and effective inhalable EGFR-targeted immunoliposome for further improvement of NSCLC therapy.

Fig. 2 Schematic diagram for liposomal formulation preparation. (Daram A, et al. 2024)