Although some small sample studies have reported the possible resistance mechanisms of Osimertinib in the first-line treatment, it is still an urgent need to explore the whole gene profile in EGFRm advanced NSCLC patients post Osimertinib 1L treatment by paired tissue and plasma to guide subsequent treatment strategy. Thus, the gene profile post Osimertinib 1L treatment in tissue and plasma may help to guide the following treatment.

Participants will be required to provide paired tissue and whole blood after disease progression following 1L Osimertinib. 200 tissue samples and 200 whole blood samples will be used to detect gene alteration by NGS, respectively. 200 tissue samples will be used to detect pathological transformation by IHC. Approximately 80-100 tissue samples will be used to test MET overexpression by MET IHC and MET amplification by FISH respectively. Approximately 80-100 whole blood samples will be used to test MET amplification by ddPCR.

"Tumor tissue samples will be obtained by biopsy."

Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

Informed Consent

1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

2. Provision of signed and dated, written informed consent form prior to any mandatory study-specific procedures, sampling, and analyses.

   The ICF process is described in Appendix A3., Sex and Age

3. Male or female, age at least 18 years. Type of Participant and Disease Characteristics

4. Pathologically confirmed non-small cell lung cancer (NSCLC) with documented EGFR sensitive mutation (EGFR 19del and L858R) positive before Osimertinib 1L.

5. Locally advanced (clinical stage IIIB, IIIC) or metastatic NSCLC(clinical stage IVA or IVB) or recurrent NSCLC (per Version 8 of the International Association for the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology), not amenable to curative or radiotherapy (e.g., this may occur as systemic recurrence after prior surgery for early stage disease or patients may be newly diagnosed with stage IIIB/IV disease, which is at the start of Osimertinib therapy).

6. Patients must have been treated with Osimertinib as first line therapy until disease progression. Evidence of disease progression following 1L Osimertinib can be confirmed by investigators with criteria in Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1.

7. Agree to provide adequate tissue and whole blood for testing after disease progression following 1L Osimertinib.

   Reproduction

8. Female participants who are not abstinent (in line with the preferred and usual lifestyle choice of the participant) and intend to be sexually active with a male partner must be using highly effective contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to the enrolment or must have evidence of non-child-bearing potential by fulfilling 1 of the following criteria at screening:

   • Post-menopausal, defined as more than 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
   • Women under 50 years old would be considered as postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution
   • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

   Further information is available in Appendix E (Definition of Women of Childbearing Potential and Acceptable Contraceptive Methods).

9. Male participants must be willing to use barrier contraception. Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

1. Any concurrent and/or other active malignancy that may affect tissue or whole blood testing results.

2. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, which in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol,. Screening for chronic conditions is not required.

   Prior/Concomitant Therapy

3. Any concurrent anticancer treatment except local radiotherapy and radiotherapy for CNS metastasis. Concurrent use of hormonal therapy for non cancer related conditions (eg, hormone replacement therapy) is allowed.

Prior/Concurrent Clinical Study Experience 5 Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

Other Exclusions 6 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

7 In addition, the following are considered criteria for exclusion from the exploratory genetic research:

• Prior allogeneic bone marrow transplant
• Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.