To explore the efficacy and safety of first-line EGFR-TKI combined with Trastuzumab Rezetecan in advanced NSCLC patients harboring EGFR mutations with concomitant HER2 genomic alterations or HER2 protein expression (1+/2+/3+)

Inclusion Criteria:

1. Aged 18-75 years, male or female without restriction;
2. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1; Estimated survival time ≥ 3 months;
3. Histologically or cytologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC);
4. At least one measurable lesion per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1);
5. No prior systemic anti-tumor therapy before enrollment (oral EGFR-TKI administered within 2 weeks prior to screening is permitted);
6. Confirmed EGFR mutations via genetic testing, including Exon 19 deletion or L858R point mutation;
7. Presence of HER2 alterations, any of the following subtypes is acceptable: confirmed HER2 mutations or amplification by genetic testing; HER2 low expression or overexpression by immunohistochemistry (IHC 1+/2+/3+);
8. Adequate laboratory parameters. No blood product transfusion or hematopoietic growth factor support administered within 14 days prior to the first study drug dose to correct lab abnormalities.
9. Female subjects of childbearing potential must have a negative serum pregnancy test within 3 days before the initial study drug administration. 10. They must agree to use a medically approved highly effective contraceptive method (e.g., intrauterine device, oral contraceptives, condoms) throughout the study and for 180 days after the last dose of study drug. Male subjects with female partners of childbearing potential must be surgically sterilized or agree to effective contraception during the study and for 180 days after the last study drug administration.

11. Voluntarily participate in this trial, sign written informed consent, demonstrate good treatment compliance, and agree to complete all scheduled visits and study-related procedures.

12. Estimated survival time ≥ 3 months.

Exclusion Criteria:

1. Histologically confirmed tumor containing small cell lung cancer components.

2. Medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid intervention, or any clinical evidence of active ILD.

3. Symptomatic or actively progressive central nervous system (CNS) metastases or leptomeningeal metastases confirmed by CT/MRI during screening and prior to radiological assessment.

   Asymptomatic patients with stable CNS lesions who have received local therapy may be enrolled only if all of the following criteria are simultaneously met:

   Fewer than 5 brain metastatic lesions; At least one measurable lesion per RECIST v1.1 exists outside the CNS; No history of intracranial or spinal hemorrhage; No neurosurgical resection within 28 days prior to the first study treatment dose, no whole-brain radiotherapy within 14 days, and no stereotactic radiotherapy within 7 days; Imaging confirms lesion stability for at least 4 weeks before enrollment, and systemic steroid therapy has been discontinued for more than 2 weeks (equivalent to ≤10 mg prednisone per day or equivalent steroids); Metastases do not involve the midbrain, pons, medulla oblongata, or spinal cord.

4. Subjects requiring systemic corticosteroids or other immunosuppressive agents within 14 days before the first study drug administration. 5. Nasal/inhaled corticosteroids or physiological doses of systemic steroids (i.e., ≤10 mg prednisolone per day or equivalent physiological doses of other corticosteroids) are excluded from this restriction.

6. Received systemic anti-tumor vaccines, anti-tumor traditional Chinese herbal medicines, or immunomodulatory drugs (including thymopeptides, interferons, interleukins, excluding local administration for pleural effusion control) within 4 weeks prior to the first dose.

7. Prior anti-HER2 therapy or anticipated need for any other anti-tumor treatment during the study.

8. History of other malignant tumors within 5 years before enrollment, except for in situ carcinomas that have achieved complete remission after treatment and require no additional therapy during the trial.

9. Received live attenuated vaccines within 4 weeks before the first dose or planned to receive such vaccines during the study.

10. Currently receiving treatment in another interventional clinical trial, or administered any other investigational product/device within 4 weeks before the first study dose.

11. Complicated with severe infection, localized infection within 4 weeks prior to the first dose (including but not limited to infectious complications requiring hospitalization or ≥2 weeks of intravenous antibiotics, bacteremia, severe pneumonia, etc.), or any active infectious disease.

12. History of active tuberculosis infection within 1 year before the first dose.

Diagnosis of any active, known or suspected autoimmune disease, or past medical history of autoimmune disease. Subjects with stable disease not requiring systemic immunosuppressants are eligible for enrollment.

HBsAg positive with HBV DNA above the upper limit of normal (1000 copies/mL or 500 IU/mL); HCV positivity indicating acute or chronic HCV infection via HCV RNA or HCV antibody testing; active hepatitis B or C; known HIV positivity or AIDS diagnosis.

13. Received major surgery within 4 weeks before the first dose; invasive minor procedures (catheter placement, biopsy, bronchoscopy) within 7 days before the first dose; non-thoracic radiotherapy >30 Gy within 4 weeks before the first dose; thoracic radiotherapy >30 Gy within 24 weeks before the first dose; or palliative radiotherapy <30 Gy within 2 weeks before the first dose.

14. Have not fully recovered from toxicities and/or complications induced by any prior interventions before the first dose (i.e., residual toxicity > Grade 1 or not returned to baseline; fatigue and alopecia are exempted).

15. Grade ≥2 myocardial ischemia or myocardial infarction; uncontrolled arrhythmia (QTc interval ≥450 ms for males, ≥470 ms for females); New York Heart Association (NYHA) Class III-IV cardiac insufficiency; or left ventricular ejection fraction (LVEF) <50% on echocardiography.

16. History of severe bleeding events, arterial/venous thrombosis, or pulmonary embolism.

17. Patients at risk of gastrointestinal perforation. 18. History of allogeneic solid organ transplantation or allogeneic hematopoietic stem cell transplantation.

19. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage.

20. Known allergy, hypersensitivity or intolerance to the study drug or its excipients.

21. Diagnosed with psychiatric disorders or substance abuse; female patients who are pregnant, breastfeeding, or planning pregnancy during the trial.

22. Any medical condition that, in the Investigator's judgment, may harm the subject or prevent the subject from complying with study requirements and procedures.