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Osimertinib and Aspirin starting at a dose of 80 mg and 100mg once a day, orally with meals. Aspirin treatment will be initiated one week before beginning TKI therapy, if possible, but TKI therapy will not be delayed for Aspirin loading. Drug: Osimertinib and Aspirin will be administered once every day. If subject has complete response, partial response, stable disease, or unacceptable toxicity.

Osimertinib starting at a dose of 80 mg once a day, orally with meals. Drug: Osimertinib will be administered once every day. If subject has complete response, partial response, stable disease, or unacceptable toxicity.

Aspirin, also known as acetylsalicylic acid (ASA), is a very safe medication used to treat pain, fever, or inflammation.

Aspirin 100mg

Osimertinib, also known as azd9291, is a 3rd-generation EGFR-TKI used to treat NSCLC patients with resistance to 1st generation EGFR-TKI due to T790M mutation. It has been approved in clinical applications by the FDA in 2015.

Osimertinib 80 MG

yong he, doctor

The third generation epidermal growth factor 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 with EGFR mutation.

Combination of Osimertinib and Aspirin to Treat EGFR Mutation NSCLC Patients

Prospective Observational Trial to Evaluate the Efficacy of the Combination of Osimertinib and Aspirin in Patients With Epidermal Growth Factor Receptor(EGFR)-Mutation

To evaluate the response to therapy and progression-free survival rate of the combination of Osimertinib and Aspirin in advanced lung cancer patients who has EGFR-mutation.

To evaluate the overall survival of the combination of Osimertinib and Aspirin in advanced lung cancer patients who has EGFR-mutation.

To evaluate the response to therapy and Objective Response Rate of the combination of Osimertinib and Aspirin in patients who has EGFR-mutation.

To evaluate the response to therapy and Time to progression of the combination of Osimertinib and Aspirin in patients who has EGFR-mutation.

Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Department of Respiratory Disease, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

SBRT with photon and dose is 40Gy/5F after three months after Osimertinib treatment

Received SBRT after three months of Osimertinib treatment

SBRT+Osimertinib

Li Zhang, MD,PhD

Ping Peng, PhD

This is a Prospective, Multicenter, Randomized Controlled study to evaluate Stereotactic Body Radiation Therapy (SBRT) as a potential treatment for stage IV non-small cell lung cancer (NSCLC) that has a mutated epidermal growth factor receptor (EGFR) and has been receiving treatment with Osimertinib

SBRT Combined With Osimertinib Compared With Osimertinib for Stage IV NSCLC

Effect of SBRT Combined With Osimertinib Compared With Osimertinib Alone for Stage IV Non-small Cell Lung Cancer

the time from the beginning of Osimertinib treatment to disease progression or death

the time from the beginning of Osimertinib treatment to death

Hubei Cancer Hospital

Li Zhang

Professor

Osimertinib is administered according to clinical practice at the recommended dose of 80 mg, orally, once a day.

This study (FLOWER) will investigate effectiveness, safety, progression patterns and clinical management of untreated advanced NSCLC patients receiving fist-line osimertinib in the real-world.

FLOWER is a real-world, prospective, observational study enrolling patients with histological and/or cytological diagnosis of EGFR-mutant aNSCLC, receiving first-line treatment with the third-generation EGFR-TKI, osimertinib. All the patients received osimertinib at the recommended dose of 80 mg, orally, once a day. Dosing interruptions or reductions required, based on individual tolerability, were managed according to clinical practice in compliance with label indications.

The FLOWER study aims at evaluating effectiveness, safety, progression pattern and clinical management of untreated EGFR-mutant aNSCLC patients in the real-world.

First Line Osimertinib in the Real World: an Inter-regional Prospective Study

First Line Osimertinib in the Real World: an Inter-regional Prospective Study: FLOWER

To describe the diagnostic-therapeutic pathway of patients included in the study

To evaluate the effectiveness of osimertinib in the real-world

to evaluate safety of patients treated with osimertinib in the real-world

To evaluate the pattern of progression to first-line osimertinib in the real-world

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination of Osimertinib and Aspirin to Treat EGFR Mutation NSCLC Patients	NCT04184921	Lung Cancer Non...	Aspirin 100mg Osimertinib 80 ...	18 Years - 80 Years	Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
SBRT Combined With Osimertinib Compared With Osimertinib for Stage IV NSCLC	NCT05583409	Stage IV Non-sm...	SBRT+Osimertini... Osimertinib 80 ...	18 Years - 75 Years	Tongji Hospital
First Line Osimertinib in the Real World: an Inter-regional Prospective Study	NCT04965701	EGF-R Positive ...	Osimertinib 80 ...	18 Years -	Istituto Oncologico Veneto IRCCS

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