How effective are EGFR inhibitors?
Our main finding was that the addition of EGFR MAb drugs to standard treatment in people whose tumours were KRAS wild type reduces the risk of disease progression by 30%. The risk of death is reduced by 12% (i.e. patients live longer overall), and the chance of tumour shrinkage is increased from 31% to 46%.
What are EGFR inhibitors?
A substance that blocks the activity of a protein called epidermal growth factor receptor (EGFR). EGFR is found on the surface of some normal cells and is involved in cell growth. It may also be found at high levels on some types of cancer cells, which causes these cells to grow and divide.
How long do EGFR inhibitors work?
EGFR inhibitors that target cells with the T790M mutation EGFR inhibitors can often shrink tumors for several months or more. But eventually these drugs stop working for most people, usually because the cancer cells develop another mutation in the EGFR gene. One such mutation is known as T790M.
How does T790M mutation result in resistance to first-generation EGFR inhibitors?
The T790M mutation structurally inhibits the binding of first-generation EGFR-TKIs to the ATP binding site. When the T790M mutation is added to the activation mutation of EGFR, the affinity of EGFR for ATP is increased, whereas the binding property of EGFR-TKIs is relatively decreased.
How is EGFR inhibited?
The two primary means of inhibiting the EGFR pathway are small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). EGFR TKIs (molecular weight 400–500 daltons) exert their effects intracellularly.
How do EGFR inhibitors work?
Epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER-1) inhibitors are medicines that bind to certain parts of the EGFR and slow down or stop cell growth. EGFR is a protein that is found on the surface of some cells that causes cells to divide when epidermal growth factor binds to it.
What do EGFR inhibitors do?
Why does Tagrisso stop working?
Recent clinical research has shown that some EGFR+ patients who develop Tagrisso resistance also may develop a new mutation in their tumor that may play a role in Tagrisso no longer working.
How long does Tagrisso extend life?
People taking TAGRISSO lived significantly longer than people taking erlotinib or gefitinib. The median overall survival was 38.6 months for TAGRISSO vs 31.8 months for erlotinib or gefitinib.
How does T790M resist?
The most common resistance mechanism results from the development of the so-called ‘gatekeeper’ T790M mutation in EGFR exon 20, which sterically hinders the binding of first- and second-generation TKIs to the ATP-binding site of EGFR.
How do you test for T790M mutation?
Testing for the presence of EGFR T790M as a mechanism of resistance can be performed on either ctdna from plasma or dna from tissue. A liquid biopsy analyzes small fragments of cell-free ctdna that is shed into the blood.
How does EGFR TKI work?
The working mechanism of first-generation EGFR-TKIs is to block the activation of downstream signaling induced by EGFR through binding to the ATP-binding sites.