Almonertinib Plus Chemotherapy as First-line Treatment in Patients With EGFR Concomitant Non-EGFR Driver Gene Mutant, Locally Advanced or Metastatic NSCLC

Treatment with any of the following:

1. Prior treatment with systemic anti-cancer therapy for locally advancer or metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug.

2. Prior treatment with an EGFR TKI.

3. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug.

4. Radiotherapy with a limited field of radiation for palliation within 4 week of the first dose of study drug, with the exception of patients receiving radiation to \> 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.

5. Medications that are predominantly CYP3A4 strong inhibitors or inducers or sensitive substrates of CYP3A4 with a narrow therapeutic range within 7 days of the first dose of study drug.

Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of study drug.

Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment, with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.

Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 2 weeks prior to start of study treatment.

Patients who received yellow-fever vaccine or other attenuated live vaccine during pemetrexed treatment.

Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension or active bleeding diatheses, which, in the Investigator's opinion, makes it undesirable for the patient to participate in the trial OR which would jeopardize compliance with the protocol such as active infection. Screening for chronic conditions is not required.

Refractory nausea, vomiting, or chronic gastrointestinal diseases, inability to swallow the study drug, or previous significant bowel resection that would preclude adequate absorption of Almonertinib.

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., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval \> 250 ms).

3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.

4. Left ventricular ejection fraction (LVEF) ≤ 40%.

Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis that required steroid treatment, or any evidence of clinically active interstitial lung disease.

Inadequate bone marrow reserve or organ function, as demonstrated by any of the following laboratory values:

1. Absolute neutrophil count (ANC) \<1.5×109 / L

2. Platelet count \<100×109 / L

3. Hemoglobin \<90 g/L（\<9 g/dL）

4. Alanine aminotransferase \> 2.5 × upper limit of normal (ULN) if no demonstrable liver metastases or \> 5 × ULN in the presence of liver metastases.

5. Aspartate aminotransferase (AST) \> 2.5 × ULN if no demonstrable liver metastases or \> 5 × ULN in the presence of liver metastases.

6. Total bilirubin (TBL) \> 1.5 × ULN if no liver metastases or \> 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases.

7. Creatinine \> 1.5 × ULN concurrent with creatinine clearance \< 50 mL/min (measured or calculated by the Cockcroft-Gault equation); confirmation of creatinine clearance is only required when creatinine is \> 1.5 × ULN.

Women who are breastfeeding or have a positive urine or serum pregnancy test at the Screening Visit.

History of hypersensitivity to any active or inactive ingredient of Almonertinib, or to drugs with a similar chemical structure or class to Almonertinib.

Patients who are allergic to pemetrexed or any other component of the preparation, carboplatin or other platinum containing compounds.

Patients with contraindications of pemetrexed and carboplatin.

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

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.

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

What this study is about