Osimertinib Plus Chemotherapy vs Osimertinib in EGFRm NSCLC With Persistence Week-3 ctDNA EGFRm After 1L Osimertinib

Inclusion Criteria:

* Provision and signed of informed consent prior to any study specific procedures;
* Male or female, aged at least 18 years;
* Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1;
* Newly diagnosed, and histologically documented metastatic non-squamous NSCLC with sensitizing EGFR mutations positive, and classified as stage IV or recurrent NSCLC which are not amenable to curative surgery or radiotherapy;
* Life expectancy of at least 3 months at recruitment;
* Only the patients receiving osimertinib as 1L treatment and meeting the following criteria will be considered:

A. Prior to 1L osimertinib:

1. History of EGFRm (exon 19 deletion or exon 21 L858R) in the plasma ctDNA by the local testing methods.
2. No previous systemic treatment. Adjuvant therapies, or definitive radiation/chemoradiation are permitted as long as treatment was completed at least 6 months prior to receiving 1L treatment.
3. Patients with asymptomatic and stable CNS metastases for at least 2 weeks will be allowed, including leptomeningeal metastases.

B. Prior to randomization: Patients after 3 weeks of 1L osimertinib treatment who have persistence ctDNA EGFRm by SuperARMS at 3 weeks will be considered to be enrolled. They will need to further meet the criteria below before randomization:

1. Patients without disease progression by RECIST 1.1 evaluation;
2. At least 1 measurable extracranial lesion according to RECIST 1.1 .
3. Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential.
4. Male subjects should be willing to agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm.

Exclusion Criteria:

* Involvement in the planning and/or conduct of the study;
* History of hypersensitivity to active or inactive excipients of Osimertinib and/or Pemetrexed and/or Carboplatin or drugs with a similar chemical structure or class to Osimertinib and/or Pemetrexed and/or Carboplatin;
* For patients, inability to collect plasma samples at baseline and disease progression;
* QT prolongation or any clinically important abnormalities in rhythm;
* Any evidence of severe or uncontrolled systemic diseases;
* Currently receiving medications or herbal supplements known to be strong inducers of CYP3A4;
* Any unresolved toxicities from prior therapy greater than CTCAE 5.0 grade 1 at the time of starting study treatment.
* Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
* Inadequate bone marrow reserve or organ function;
* Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
* 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.
* Contraindication for osimertinib, pemetrexed and carboplatin according to China approved label.
* Women who are pregnant or breast-feeding.