Adjuvant Befotertinib in Stage IB-IIIB Non-small Cell Lung Cancer With Positive EGFR Sensitive Mutations

A Multicenter, Randomized, Controlled, Double Blind, Double Simulated, Phase III Clinical Study of Befotertinib vs Icotinib for Postoperative Adjuvant Treatment of IB-IIIB (T3N2M0) Stage Non Small Cell Lung Cancer With Positive EGFR Sensitive Mutations

This multicenter, randomized, controlled, double-blind, double-simulated, Phase III study is designed to evaluate the efficacy and safety of Befotertinib compared with Icotinib as adjuvant treatment in EGFR-sensitive mutation-positive stage IB-IIIB (T3N2M0) non-small cell lung cancer after surgical resection.

Inclusion Criteria:

1. Willingness to sign informed consent prior to any study specific procedures, and ability to with scheduled visits, treatment plans, laboratory tests, and other study procedures.
2. Male or female, aged at least 18 years.
3. Histologically confirmed primary NSCLC, and mainly non-squamous cell carcinoma (including mixed type carcinoma mainly composed of adenocarcinoma components).
4. Absence of brain metastasis.
5. Complete resection of histologically confirmed Stage IB, II, IIIA or IIIB(T3N2M0) according to the TNM staging system for lung cancer (AJCC/UICC 8th edition), with negative margins.
6. Confirmation by the central laboratory that the tumor harbors one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R).
7. Patients who fully recover from surgery during randomization (any surgery must achieve complete postoperative wound healing) and should receive adjuvant treatment within 4-10 weeks after surgery.
8. ECOG-PS score of 0 or 1 and did not deteriorate 2 weeks before the first administration of the investigational drug, with a minimum expected survival greater than 12 weeks.
9. Female subjects with fertility need to have a negative serum pregnancy test during screening.
10. Female subjects who have possibility of becoming pregnant, as well as male subjects whose partners are women of childbearing age, must use a highly effective contraceptive method (such as oral contraceptives, intrauterine devices, abstinence or barrier contraception combined with spermicides) throughout the study and continue to use contraception for 3 months after the end of treatment.

Exclusion Criteria:

1. There are unresectable or metastatic diseases, pathological reports showing positive surgical margins under the microscope or extranodal invasion, or lesions left after surgery, or suspicious lesions determined by imaging after surgery. Subjects receiving only wedge resection.

2. Upper lung groove cancer.

3. Patient with complete resection of the right lung with NSCLC.

4. Malignancies other than NSCLC within 5 years prior to first dosage, except for malignant tumors that can be cured after treatment (including but not limited to fully treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell skin cancer, or breast ductal carcinoma in situ treated with radical surgery).

5. Received systematic anti-tumor therapy, including chemotherapy, radiotherapy or targeted therapy (including but not limited to monoclonal antibodies, small molecule tyrosine kinase inhibitors), immunotherapy, investigational therapy, etc., before being enrolled in this study.

6. Within 3 weeks prior to the first administration of the investigational drug, the patient underwent major surgery (including primary tumor surgery, craniotomy, thoracotomy, or laparotomy, excluding vascular pathway establishment procedures).

7. Within 14 days prior to first dose of the investigational drug, Traditional Chinese medicine with anti-tumor indications have been received.

8. After the start of the study, any form of systemic or local anti-tumor treatment (including maintenance therapy with another drug, radiotherapy, and/or surgical resection) is still required.

9. Clinically significant cardiovascular diseases, including:

   1. QTcF interval >450 ms (men) or >470 ms (women), symptomatic bradycardia (<45 beats /min), or other significant ECG abnormalities as determined by the investigator (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec).
   2. Echocardiography showed LVEF <50%.
   3. Hypertension was clinically uncontrollable (e.g., blood pressure >160/100 mmHg; Except that isolated elevated readings that were determined by the investigators to be clinically insignificant or controllable hypertension.)

   Within 6 months before the first medication, there were the following situations:

   1. Congestive heart failure (New York Heart Association rating III or IV).
   2. Arrhythmias or conduction abnormalities that require medication treatment. Note: Patients with drug-controlled atrial fibrillation/flutter, as well as those with pacemaker- controlled arrhythmia, can be selected.
   3. Severe/unstable angina, coronary artery/peripheral bypass grafting, or myocardial infarction (Note: Severe angina is classified as Grade III or IV by the Canadian Society of Cardiology).
   4. Cerebrovascular accidents or transient ischemic attacks, transient myocardial ischemia.

10. Previous history of concomitant interstitial lung disease (ILD), drug-induced ILD, radiation pneumonia requiring hormone therapy, or clinical evidence of concomitant active interstitial lung disease.

11. Patients who have a history of thrombosis or are currently present with thrombosis or have a potential risk of thrombosis assessed by the investigator.

12. Any clinical evidence of a serious active infection, or any serious concomitant disease that may affect the subject's acceptance of investigational drugs, such as active bleeding predisposition, active hepatitis B, hepatitis C, or tuberculosis, syphilis, or HIV antibody positive.

13. There are serious gastrointestinal functional abnormalities in clinical practice that may affect drug intake, transportation, or absorption, such as inability to take medication orally, uncontrollable nausea or vomiting, history of extensive gastrointestinal resection, untreated recurrent diarrhea, atrophic gastritis, untreated stomach diseases requiring long-term use of proton pump inhibitors, gastrointestinal obstruction, active diverticulitis, Crohn's disease, ulcerative colitis, etc.

14. Abnormal laboratory parameters.

15. Known hypersensitivity to the befotertinib, icotinib or their inactive excipients.

16. Within one week before the first administration of the investigational drug, it is currently in use or needs to be combined with CYP3A strong inhibitors or inducers during the study period.

17. Patients who are still using warfarin within 7 days prior to initial dosing (low molecular weight heparin sodium is allowed).

18. Participating in clinical research and receiving treatment with the study drug or research device, or participating in clinical research and receiving treatment with the study drug or research device within 4 weeks before the first administration, or planning to participate in any other clinical trial during this study period.

19. Inoculate with a live vaccine within 180 days before the first medication.

20. Researchers believe that it may affect protocol compliance or affect the signing of informed consent forms by participants (such as a history of mental illness or drug abuse, alcoholism or other addiction), or any other clinically significant disease or condition that is not suitable for participation in this clinical trial (such as laboratory abnormal results, clinically active diverticulitis, abdominal abscess).