FHND9041 Versus Afatinib for Non-small Cell Lung Cancer

The goal of this clinical trial is to evaluate the effectiveness and safety of FHND9041 compared to afatinib as first-line treatments for epidermal growth factor receptor mutation-positive (EGFRm+) locally advanced or metastatic non-small cell lung cancer (NSCLC). The main questions it aims to answer are:

* Does FHND9041 improve progression-free survival (PFS) compared to afatinib?
* Are there differences in safety profiles between FHND9041 and afatinib?

Researchers will compare FHND9041 (80 mg, orally, once daily) with afatinib (40 mg, orally, once daily) in a randomized, open-label, parallel-controlled, multicenter Phase III trial.

Participants who meet the inclusion criteria, including having EGFR mutations (L858R and/or Exon 19 deletion) and no prior treatment, will be randomly assigned in a 1:1 ratio to either the FHND9041 group or the afatinib group. Treatment will continue until disease progression, intolerable drug-related toxicity, or other pre-specified treatment discontinuation criteria are met.

Study Procedures:

Participants will:

* Be screened for eligibility and randomly assigned to one of two groups.
* Receive study drugs per their assigned group.
* Undergo regular tumor assessments by Response Evaluation Criteria in Solid Tumors, version 1.1( RECIST 1.1) every six weeks during the first 18 cycles, then every nine weeks until disease progression. For intracranial efficacy, Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM ) criteria will be applied.
* Participate in pharmacokinetic studies (FHND9041 group only) with blood samples collected pre-dose at specified cycles and on the day of discontinuation.

After disease progression, participants will be followed for survival every three months.


Eligibility Criteria:
Inclusion Criteria:

* Participants aged ≥ 18 years, with no gender restrictions.
* Histologically or cytologically confirmed diagnosis of locally advanced or metastatic non-small cell lung cancer (NSCLC), including patients with recurrent disease following prior surgical treatment or newly diagnosed Stage IIIb, IIIc, or IV NSCLC (staging based on the 8th edition of the AJCC guidelines).
* No prior systemic anti-tumor therapy (e.g., standard chemotherapy, targeted therapy, biological therapy, or immunotherapy). Patients who have received adjuvant or neoadjuvant therapy (chemotherapy, radiotherapy, or other treatments) are eligible if disease progression occurred at least 6 months after completing the prior treatment.
* Presence of a confirmed EGFR-positive gene mutation sensitive to EGFR-TKI treatment, including exon 19 deletion or L858R mutation.
* At least one measurable tumor lesion at baseline that meets the following criteria:

No prior radiotherapy or biopsy during the screening period (if the subject has only one measurable lesion, fine-needle aspiration cytology to confirm genetic status is permitted; however, baseline imaging must be performed at least 7 days after the biopsy).

Lesion can be accurately measured with a longest diameter ≥ 10 mm (or a short axis ≥ 15 mm for lymph nodes).

Lesion can be assessed using CT or MRI, with the same imaging modality used consistently for subsequent evaluations.

* An Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
* A life expectancy of ≥ 3 months.
* Female participants of childbearing potential must have a negative serum pregnancy test prior to enrollment. Male and female participants with reproductive potential must agree to maintain abstinence or use effective contraception during the study and for at least 3 months following the last dose of the investigational drug.
* Participants must demonstrate the ability to understand the study objectives and procedures, comply with protocol requirements, cooperate with study-related visits, and provide written informed consent, indicating their voluntary participation.

Exclusion Criteria:

● Pre-treatment History: Major Surgery: Subjects who have undergone major surgery within 28 days before the first dose of the study drug. For the purposes of this study, major surgery refers to level 3 and level 4 surgeries as defined in the "Administrative Measures for the Clinical Application of Medical Technology" (implemented on May 1, 2009).

Radiotherapy: Subjects who have received local radiotherapy or palliative radiotherapy for bone metastasis within 14 days prior to the first dose of the study drug.

CYP3A4 Interactions: Subjects who have received a strong CYP3A4 inhibitor or a strong inducer within 7 days before the first dose, or who need to continue using these drugs during the study period.

Chinese Herbal Medicines: Subjects who have received Chinese herbal medicines or proprietary Chinese medicine preparations for anti-tumor indications within 7 days prior to the first dose, or who need to continue using these during the study period.

QT Prolongation Medications: Subjects who are receiving drug treatments known to prolong the QTc interval or potentially cause torsades de pointes, and who need to continue using these medications during the study period.

* Unhealed Toxicity: Subjects who have unresolved toxic reactions of grade ≥ 2 (according to NCI-CTCAE 5.0 standards) related to previous treatments, except for hair loss and grade 2 neuropathy caused by platinum-based drugs.
* Spinal Cord Compression/Brain Metastases:

Subjects with spinal cord compression or brain metastases, except those who are asymptomatic, stable, and have not required steroid treatment for at least 4 weeks prior to the start of the study.

Subjects with brain metastases who have received local radiotherapy must show stable symptoms for at least 28 days following completion of the radiotherapy.

* Uncontrolled Systemic Diseases: Subjects with severe or uncontrolled systemic diseases (e.g., hypertension not controlled by medication, active bleeding disorders) that, in the investigator's opinion, may interfere with the participant's ability to comply with the study protocol.
* Active Infections:

Subjects with active infections that require medical treatment, including HBV (HBsAg positive, HBV-DNA \> 1000 cps/ml or 200 IU/ml, and AST or ALT \> 2.0 ULN), HCV (HCV antibody positive and HCV-RNA ≥ 1000 IU/mL), HIV, syphilis, or other serious infections.

● Gastrointestinal Dysfunction: Subjects with clinically significant gastrointestinal issues that may affect the intake, transport, or absorption of the study drug. This includes inability to take oral medication, uncontrolled nausea or vomiting, history of extensive gastrointestinal resection, unresolved recurrent diarrhea, or gastrointestinal diseases such as Crohn's disease or ulcerative colitis requiring long-term use of proton pump inhibitors (PPI).

● Cardiac Exclusion Criteria: QTc Prolongation: Subjects with an average QT interval (QTcF) corrected by Fridericia's formula greater than: 450 ms for males; 470 ms for femaleS; ECG Abnormalities: Subjects with clinically significant arrhythmias, heart block, or other abnormalities in resting ECG, such as complete left bundle branch block, third-degree heart block, second-degree type II block, PR interval \> 250 ms, or recent myocardial infarction within 6 months; Risk Factors for QTc Prolongation: Subjects with factors increasing the risk of QTc prolongation or arrhythmia, such as heart failure, moderate or severe hypokalemia, congenital long QT syndrome, family history of sudden cardiac death under 40 years of age, or concurrent use of drugs that may prolong the QT interval; Left Ventricular Ejection Fraction (LVEF) ≤ 50%.

* Interstitial Lung Disease (ILD): History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid treatment, or clinically active ILD.
* Bone Marrow or Organ Dysfunction:Subjects who do not meet the laboratory standards for organ function, including but not limited to: Neutrophil count \< 1.5 x 10\^9/L; Platelet count \< 90 x 10\^9/L; Hemoglobin \< 90 g/L;ALT or AST \> 2.5 times the upper limit of normal (ULN), or \> 5 times ULN in cases of liver metastasis ;Serum total bilirubin \> 1.5 times ULN (or \> 3 times ULN if the subject has Gilbert syndrome or liver metastasis); Creatinine \> 1.5 times ULN, with a creatinine clearance rate \< 50 mL/min (confirmed by Cockcroft-Gault formula, if creatinine is \> 1.5 times ULN).
* Allergic Reactions: Subjects with a known history of allergy or hypersensitivity to the active ingredients or excipients of the study drug, or to drugs with similar chemical structures to the investigational drug.
* Lactating Women: Lactating women are excluded from participation.
* Other Malignant Tumors: Subjects with a history of other malignant tumors, except for those with clinically cured cervical carcinoma in situ, basal cell carcinoma, squamous cell skin cancer, or papillary thyroid carcinoma within the past 5 years.
* Serious Eye Diseases: Subjects with any serious or uncontrolled eye disease that may increase the safety risk of the investigational drug, as determined by the investigator.