Tagrisso

Tagrisso
IUPAC name	N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
Tradename	Tagrisso
Drugs.com	Monograph
MedlinePlus	a616005
Licence US	Tagrisso
Routes of administration	Oral
CAS number	1421373-65-0
PubChem	71496458
DrugBank	DB09330
ChemSpiderID	34991516
UNII	3C06JJ0Z2O
KEGG	D10575
ChEMBL	CHEMBL3301587
Chemical formula	C28H33N7O2
Molecular weight	499.618 g·mol−1

Tagrisso. It is a third-generation, irreversible tyrosine kinase inhibitor specifically designed to target epidermal growth factor receptor mutations, most notably the T790M mutation which confers resistance to earlier therapies. Developed by the multinational pharmaceutical company AstraZeneca, it is a cornerstone treatment for certain forms of non-small cell lung cancer. Its approval by regulatory bodies like the U.S. Food and Drug Administration and the European Medicines Agency marked a significant advancement in precision medicine for oncology.

Medical uses

Tagrisso is indicated for the first-line treatment of metastatic non-small cell lung cancer in patients whose tumors have specific EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. It is also approved for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after prior tyrosine kinase inhibitor therapy. Treatment decisions are guided by companion diagnostics that identify these genetic alterations, aligning with practices at major cancer centers like the Memorial Sloan Kettering Cancer Center. Its use is supported by comprehensive guidelines from organizations such as the National Comprehensive Cancer Network.

Mechanism of action

Tagrisso functions as an irreversible inhibitor that covalently binds to certain mutant forms of the epidermal growth factor receptor. It selectively targets both the activating EGFR mutations (like exon 19 deletions and L858R) and the resistance-conferring T790M mutation, while sparing wild-type EGFR. This selectivity is achieved through its specific interaction with a cysteine residue (C797) in the adenosine triphosphate-binding pocket of the mutant receptor. By inhibiting EGFR-mediated signaling, it blocks critical downstream pathways such as MAPK/ERK pathway and PI3K/AKT/mTOR pathway, leading to reduced tumor cell proliferation and survival.

Adverse effects

Common adverse effects include diarrhea, rash, dry skin, paronychia, and decreased appetite. More serious but less frequent adverse reactions can involve interstitial lung disease, QTc interval prolongation, cardiomyopathy (including heart failure), and keratitis. Patients are monitored for signs of pneumonitis and undergo regular assessments of left ventricular ejection fraction via echocardiogram or MUGA scan. Management often involves dose interruptions or reductions, as outlined in the prescribing information from the FDA.

Clinical trials

The pivotal AURA3 trial demonstrated Tagrisso's superiority over platinum-based chemotherapy in patients with T790M-positive advanced NSCLC who had progressed on prior EGFR-tyrosine kinase inhibitor therapy. The landmark FLAURA trial established its efficacy as a first-line treatment, showing superior progression-free and overall survival compared to earlier EGFR inhibitors like gefitinib and erlotinib. These international studies, often presented at conferences like the American Society of Clinical Oncology annual meeting, led to its global regulatory approvals. Subsequent trials, such as ADAURA, investigated its use in the adjuvant therapy setting following tumor resection.

History and society

Tagrisso (osimertinib) was discovered by scientists at AstraZeneca in collaboration with researchers from institutions like The University of Texas MD Anderson Cancer Center. It received its first accelerated approval from the U.S. Food and Drug Administration in 2015 for the T790M mutation-positive indication, followed by full approval and expanded first-line indications. Its development and rapid approval pathways were highlighted by the FDA's Oncology Center of Excellence. The drug's high cost has been a subject of discussion within healthcare systems, including the National Health Service in the United Kingdom and various insurers in the United States.

Chemistry

Tagrisso is chemically described as N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide. It is presented as the mesylate salt (osimertinib mesylate), a yellow solid that is slightly soluble in water. The compound is a quinazoline derivative and contains a Michael acceptor moiety (an acrylamide group) that is critical for its irreversible binding mechanism to the target cysteine residue. Its synthesis and structure-activity relationship studies were pivotal in optimizing selectivity against the T790M mutation while minimizing activity against wild-type EGFR.

Category:Drugs