To assess the efficacy and safety of Almonertinib versus platinum-based chemotherapy as first-line therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutation.

This is a randomized, open-lable, multicenter, phase III study to assess the efficacy and safety of Almonertinib versus platinum-based chemotherapy as first-line therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring at least one uncommon EGFR mutation, including L861Q, G719X or S768I. Patients who have not received any systemic treatment to receive Almonertinib or platinum-based chemotherapy in a 1:1 ratio, and treatment will be continued until disease progression, unacceptable toxicity or other discontinuation criteria are met. After progression, patients may receive Almonertinib for as long as their treating physician considers they are deriving clinical benefit.

Inclusion Criteria:

1. Subjects are willing to participate in this clinical study, understand the study procedures and are able to sign the informed consent in person.
2. Age at least 18 years.
3. Histologically or cytologically confirmed diagnosis of primary non-small lung cancer (NSCLC), histologically confirmed non-squamous pathology.
4. Locally advanced or metastatic NSCLC.
5. Patients must be treatment-naïve for locally advanced or metastatic NSCLC.
6. The tumor harbors uncommon EGFR mutations (one of the following EGFR mutation: L861Q, G719X or S768I), assessed by Xiamen AmoyDx EGFR (ADx-ARMS, Super-ARMS method) kit in central laboratory.
7. Measurable disease by RECIST 1.1.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. Female patients should be using adequate contraceptive measures and should not be breastfeeding during the study and six months after the last dosing of study. Male patients should be willing to use barrier contraception (condoms) during the study and six months after the last dosing of study.
10. A pregnancy test should be done before randomization unless having an evidence of non-child-bearing potential.

Exclusion Criteria:

1. Treatment with any of the following:

   1. Prior treatment with EGFR-TKI therapy.
   2. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks prior to randomization.
   3. The presence of pleural effusion/peritoneal effusion/pericardial effusion requiring clinical intervention.
   4. Major surgery within 4 weeks prior to randomization.
   5. Spinal cord compression or unstable brain metastasis; Meningeal or brainstem metastases.
   6. Patients had received medications or herbal supplements known to be strong inducers and inhibitors of cytochrome CYP3A4 within 7 days prior to randomization or required to continue these agents during the study period.
   7. Patients are receiving medications known to prolong QT interval or may cause tip torsion ventricular tachycardia, or are still in the washout period (relatively random phase), or need to be continued during the study period.
   8. Patients were subjects in another clinical trial within 4 weeks prior to randomization or patients were within 5 half-lives of any other investigational agent.

2. Any unresolved toxicity Common Terminology Criteria for Adverse Events (CTCAE) ≥ Grade 2 from the prior anticancer therapy.

3. Inadequate bone marrow reserve or organ function.

4. Any of the following cardiac criteria:

   1. Mean resting corrected QT interval (QTc) > 470 ms obtained from 3 electrocardiograms (ECGs), using the screening clinic's ECG machine and Fridericia's formula for QT interval correction (QTcF).
   2. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG (e.g., PR interval > 250 ms).
   3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure or any concomitant medication known to prolong the QT interval.
   4. Left ventricular ejection fraction (LVEF) <50%.

5. History of other malignancies, excluding fully treated non-melanoma skin cancer, Malignant freckled nevus, in-situ cancer, other solid tumors that hadn't been recurrent for > 5 years following the end of treatment, or local prostate cancer after radical resection.

6. Any evidence of severe or uncontrolled systemic diseases (including uncontrolled hypertension and active bleeding diatheses) or active infection (including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV), etc.).

7. Acquired or congenital immune deficiency diseases, or history of organ transplantation.

8. Serious gastrointestinal function abnormalities that may interfere with drug ingestion, transport, or absorption.

9. Any severe and uncontrolled ocular disease that may, in the ophthalmologist's opinion, present a specific risk to the patient's safety.

10. Pregnant or lactating, or intending to become pregnant during the study

11. 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.

12. Any disease or condition that, in the opinion of the investigator, would compromise the safety of the patient or interfere with study assessments.