Almonertinib Vs. Erlotinib/Chemotherapy for Neo-adjuVant Treatment of Stage IIIA-N2 EGFR-mutated NSCLC

Almonertinib Vs. Erlotinib/Chemotherapy for Neo-adjuVant Treatment of Stage IIIA-N2 EGFR-mutated NSCLC: a Multicenter, Open-label, Phase II Randomized Controlled Trial

This is a multicenter, randomized, controlled, phase II study assessing the efficacy and safety of Almonertinib compared Erlotinib or platinum doublet chemotherapy (carboplatin or cisplatin + pemetrexed) as neoadjuvant therapy to EGFRm+ IIIA-N2 NSCLC patients.

Inclusion Criteria:

1. Male or female, age at least 18 years, no more than 75 years.

2. Previously untreated, histologically documented NSCLC with completely or potentially resectable IIIA-N2 nonsquamous NSCLC(according to Version 8 of AJCC staging). N2 is defined as as radiologically and pathologically confirmed, nonbulky metastases to single-station mediastinal lymph nodes (lymph nodes < 2 cm in short axis) that are expected to be completely resectable.

3. Tumor tissue samples or blood samples are confirmed as EGFR sensitive mutations by central laboratory tests (including Ex19del or L858R, both alone or with other EGFR mutations). If the tumor tissue is accessible, the tumor tissue is recommended to be submitted for examination. If tumor tissue is not accessible or patient cannot undergo tissue biopsy, blood sample is also allowed.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.

5. At least 1 lesion that has not previously been irradiated, that has not been chosen for biopsy during the study screening period, and that can be accurately measured at Baseline as >= 10 mm in the longest diameter (except lymph nodes, which must have short axis >= 15mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), whichever is suitable for accurately repeated measurements. If only one measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not been previously irradiated and baseline tumour assessment scans are done at least 14days afar the screening biopsy is performed.

6. Women of childbearing potential must use a contraception method during the study treatment and for at least 3 months after the treatment is completed; must have a negative pregnancy test prior to starting treatment or proved no risk of pregancy by meeting one of the following criteria:

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

7. Male patients should be willing to use barrier contraception (i.e., condoms) during the study treatment and for at least 3 months after the treatment is completed.

8. Signed and dated informed consent form.

Exclusion Criteria:

1. Treatment with any of the following:

   1. Prior surgical resection of lung cancer.
   2. Prior treatment with any EGFR TKI.
   3. Prior treatment with any chemotherapy for NSCLC
   4. Prior treatment with any radiotherapy for NSCLC
   5. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug.
   6. 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.

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

3. 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.

4. Patients with malignant pleural effusion. [only exception: pleural effusion on CT scan (not visible on CXR) or considered too small and pericardial effusion]

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

6. 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.

7. 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.

8. 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%.

9. 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.

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

    1. Absolute neutrophil count (ANC) < 1.5 x 10^9 / L;
    2. Platelet count <100 x 10^9 / L;
    3. Hemoglobin < 90 g/L (<9 g/dL);
    4. Alanine aminotransferase > 2.5 x upper limit of normal (ULN).
    5. Aspartate aminotransferase (AST) > 2.5 x ULN.
    6. Total bilirubin (TBL) > 1.5 x ULN or > 3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia).
    7. Creatinine > 1.5 x 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 x ULN.

11. Women at breastfeeding or have a negative serum or urine pregnancy test in the 3 days prior to the start of the treatment..

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

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

14. With lactose in the tablets, patients with rare genetic disease like galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use use erlotinib.

15. Patients who are allergic to pemetrexed or any other component of the preparation, carboplatin or cisplatin.

16. Patients with contraindications of pemetrexed and carboplatin or cisplatin.

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

18. 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.

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