Non-small Cell Lung Cancer Stage IV Clinical Trial
Official title:
Prospective Observational Trial to Evaluate the Efficacy of the Combination of Osimertinib and Aspirin in Patients With Disease Progression to 3st Generation Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor(EGFR-TKI) Osimertinib
The third generation epidermal growth gactor receptor-tyrosine Kinase Inhibitor(EGFR-TKI) osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. Previous studies show that apoptosis escape can lead to EGFR-TKI resistance.Osimertinib resistant cells show abnormal activation of PI3K/AKT/BIM activation(PMID 28765329). The classical drug aspirin can effectively decrease AKT phosphorylation and activate of BIM(PMID 28881293).So Investigators speculate that aspirin may decrease the PI3K/AKT/BIM signaling pathways, then promote osimertinib resistant cells apoptosis. The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations.
Reversible small-molecule EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown
dramatic therapeutic efficacy in non-small cell lung cancer (NSCLC) patients with
EGFR-activating mutations, and have been recommended as the standard first-line therapy in
these patients. However, despite excellent initial clinical responses, nearly all patients
eventually develop drug resistance after a median period of about 10 months(PMID 26497205).
Osimertinib is a 3rd-generation EGFR-TKI used to treat NSCLC patients with resistance to 1st
generation EGFR-TKI due to T790M mutation. But Osimertinib also face the problem of acquired
drug-resistance(PMID 27959700). Thus, innovative treatment strategies are urgently needed to
overcome therapeutic resistance to Osimertinib to improve the survival of patients with
NSCLC.
Molecular mechanisms underlying acquired Osimertinib resistance are still not fully
understood. Previous study showed that one principal mechanism accounting for majority of
acquired resistance to Osimertinib in lung cancer is mediated by an exon 20 C797S mutation
etc(PMID 29596911). More molecular mechanisms are still to be found. Apoptosis is a process
of programmed cell death that occurs in multicellular organisms. Biochemical events lead to
characteristic cell changes (morphology) and death. These changes include blebbing, cell
shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and
global mRNA decay. Apoptosis has been found to be related to drug resistance to 1st
generation EGFR-TKI(PMID 29731879). The investigators previous found apoptosis is also
related to Osimertinib resistance(PMID 28765329). Therefore, promoting apoptosis may be an
effective way to improve the response to Osimertinib treatment.
Investigators' group has focused on lung cancer targeted therapy for several years.
Previously, investigators have reported that metformin in combination with 1st generation
EGFR-TKI could enhance the effect of TKI (PMID 24644001). Therefore, investigators further
asked whether the drug combination approach could overcome osimertinib resistance. Aspirin is
a widely used and well-tolerated drug for Kawasaki disease, pericarditis, and rheumatic and
has arisen keen interest as a potential anticancer agent ever since the report of the
clinical evidence that the cancer risk and mortality are reduced in Colon cancer. Aspirin
exerts remarkable antitumor properties in tumor cells and mouse models. It strongly inhibited
the growth of lung cancer cells, and its combination with TKI agents, including Sorafenib
(PMID: 28857200), significantly suppressed RAS-mutant cancers growth and prolonged remission
in a xenograft model. Interestingly, Aspirin exposure significantly promoted the apoptosis
suggesting that aspirin may overcome Osimertinib resistance by promoting the apoptosis.
Here, investigators'group observed that in clinic, several patients who took osimertinib and
aspirin together have shown excellent effect.Investigators therefore conduct this clinical
trial to observe whether the combination of Aspirin and Osimertinib could enhance efficacy of
Osimertinib in lung cancer patients resistant to 1st generation EGFR-TKI with T790M.
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