Osimertinib, sold under the brand name Tagrisso, is a specialized, targeted therapy for non-small cell lung cancer (NSCLC). It is designed to interfere with specific molecular drivers of cancer growth. Its development was driven by the need to overcome drug resistance in patients whose tumors initially responded to treatment. Understanding how this drug works requires examining the genetic changes in cancer cells it is designed to neutralize.
The Target: Understanding EGFR Mutations
Non-small cell lung cancer often depends on the activity of the Epidermal Growth Factor Receptor (EGFR) protein for its unchecked growth. EGFR is normally found on the cell surface, receiving signals that instruct the cell to grow and divide in a controlled manner. In certain NSCLC cases, the gene coding for this protein develops specific mutations.
These genetic alterations, most commonly deletions in Exon 19 or the L858R point mutation in Exon 21, fundamentally change the receptor’s structure. The mutated EGFR becomes constitutively “on,” signaling constantly for cell division and survival regardless of external growth factors. This uncontrolled signaling leads directly to tumor formation and spread.
The presence of these activating mutations makes the cancer susceptible to initial targeted therapies, known as first and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs). These earlier drugs interrupt the growth signal by blocking the active site of the mutated receptor.
Overcoming Resistance: The T790M Challenge
While first and second-generation EGFR TKIs are initially effective, most patients eventually relapse because the cancer develops acquired resistance. Tumor cells evolve a secondary mutation in the EGFR gene that shields the receptor from the drug’s effect, necessitating the creation of newer, more potent inhibitors.
The most frequent cause of this acquired resistance is a specific genetic change known as the T790M mutation, which is present in approximately 50 to 60% of cases that progress on initial TKI therapy. This mutation involves the substitution of the amino acid threonine (T) with methionine (M) at position 790 in Exon 20 of the EGFR gene. Position 790 is often referred to as the “gatekeeper” residue because of its strategic location within the enzyme’s ATP binding pocket.
The presence of the bulky methionine residue at this position causes two effects that undermine older drugs. It structurally alters the binding pocket, physically hindering first-generation TKIs from accessing their target site. More importantly, the T790M mutation increases the receptor’s affinity for adenosine triphosphate (ATP). Since older TKIs work by competing with ATP, restoring the receptor’s high ATP affinity effectively reduces the drug’s ability to block the signaling pathway.
Osimertinib’s Specific Mechanism of Action
Osimertinib was developed as a third-generation EGFR TKI to overcome the T790M resistance mechanism. Its mechanism of action is distinct from earlier drugs because it does not simply compete with ATP; instead, it forms a permanent, irreversible covalent bond with the target protein.
The drug targets the cysteine residue at position 797 (Cys797), located near the ATP binding pocket of the EGFR protein. By chemically reacting with and forming a covalent bond with the sulfur atom of this cysteine residue, Osimertinib permanently inactivates the receptor’s tyrosine kinase function. This strong, permanent attachment allows the drug to maintain its inhibitory effect even when the T790M mutation is present.
This unique binding property results in Osimertinib having high selectivity for the mutated forms of the EGFR protein. The drug is highly potent against the initial sensitizing mutations (Exon 19 deletions and L858R) as well as the double mutant containing the T790M resistance mutation. Osimertinib demonstrates significantly lower activity against wild-type EGFR, often showing nearly 200-fold selectivity for the mutant forms.
This selectivity minimizes the inhibition of normal EGFR function in healthy tissues, reducing side effects associated with earlier, less selective TKIs. By irreversibly shutting down the hyperactive tyrosine kinase domain, Osimertinib effectively blocks the downstream signaling pathways responsible for cell growth and survival. This results in the complete inhibition of cancer cell proliferation and the induction of programmed cell death (apoptosis) in the tumor cells.
Clinical Role and Administration
Osimertinib is widely used as a first-line therapy for metastatic NSCLC in patients whose tumors harbor common activating EGFR mutations, such as Exon 19 deletions or the L858R mutation. It is also utilized as a second-line treatment for patients whose cancer has progressed following initial treatment with a first or second-generation TKI, provided the tumor has acquired the T790M resistance mutation.
Before treatment begins, a validated diagnostic test is required to confirm the presence of the specific EGFR mutations. Osimertinib is administered as an 80 mg oral tablet, typically taken once daily. The medication can be taken with or without food, and the tablet can be dispersed in a small amount of water for patients who have difficulty swallowing.