Firmonertinib Versus Platinum Based Chemotherapy as First-line Treatment for NSCLC With EGFR PACC or EGFR l861q Mutation

1. Voluntarily sign the informed consent form (ICF).
2. Age ≥18 years at the time of ICF signing.

3. At least one measurable lesion per RECIST v1.1, meeting the following:

   • No prior local therapy (e.g., radiotherapy)
   • Not used for biopsy during screening

4. Histologically/cytologically confirmed non-squamous NSCLC, classified as:

   • Locally advanced (Stage IIIB/IIIC, unsuitable for curative surgery and/or definitive chemoradiotherapy)
   • Metastatic (Stage IV) (Based on UICC/AJCC 8th edition TNM staging)

5. Agreement to provide:

   • Recent tumor tissue (from untreated lesions)
   • Blood samples
   • Central lab-confirmed EGFR PACC or L861Q mutation (If tumor tissue is unavailable due to inaccessible lesions, sponsor consultation is required.)

6. No prior systemic therapy for advanced/metastatic NSCLC.

   • Allowed if: Prior (neo)adjuvant/definitive chemoradiotherapy completed ≥12 months before recurrence/progression
7. ECOG performance status 0-1.
8. Life expectancy ≥12 weeks.
9. Adequate bone marrow/organ function within 14 days before treatment (no transfusion/G-CSF within 2 weeks prior).

10. Women of childbearing potential (WOCBP):

    • Abstinence or contraception use
    • No egg donation

11. Non-sterilized males:

    • Abstinence or contraception use
    • No sperm donation
12. CNS metastases allowed if protocol-specified criteria are met.

Exclusion Criteria:

1. Histologically/cytologically confirmed tumor with >10% neuroendocrine carcinoma, sarcomatoid carcinoma, or squamous cell components.
2. Known ALK-positive, ROS1-positive, RET fusion-positive, NTRK fusion-positive, BRAF V600E mutation, MET exon 14 skipping mutation, or other targetable alterations with approved therapies.

3. Prior treatments including:

   1. Systemic anti-tumor therapy for advanced/metastatic NSCLC (e.g., chemotherapy/targeted/immunotherapy). Neoadjuvant/adjuvant therapy exceptions per Inclusion Criterion #6.
   2. >30 Gy thoracic radiotherapy within 6 months or non-thoracic radiotherapy within 4 weeks prior to first dose (brain radiotherapy exceptions per Inclusion Criterion #12).
   3. Any prior EGFR-targeted therapy (including investigational EGFR-TKIs, mAbs, bispecific antibodies, etc.).
   4. Strong CYP3A4 inhibitors within 7 days or inducers within 21 days prior to first dose.
   5. Anticancer traditional Chinese medicines within 2 weeks prior to first dose.
   6. Non-specific immunomodulators (e.g., interferon, IL-2, thymosin) within 2 weeks prior to first dose.
   7. Major trauma/surgery within 4 weeks prior to treatment initiation.

4. Clinically significant gastrointestinal abnormalities, including:

   • Moderate/severe atrophic gastritis
   • GI obstruction/perforation
   • Chronic diarrhea/short bowel syndrome
   • Major upper GI surgery (e.g., gastrectomy)
   • Inflammatory bowel disease (Crohn's/ulcerative colitis) or active intestinal inflammation
   • Inability to swallow tablets
5. Uncontrolled systemic diseases.
6. Severe acute/chronic infections.

7. Interstitial lung disease (ILD)/non-infectious pneumonia:

   • History requiring clinical intervention
   • Current presence
   • Suspicious imaging findings unresolved at screening
8. Clinically significant cardiovascular dysfunction (active or history).
9. Tumor invasion of critical adjacent structures (heart/esophagus/SVC etc.) with high bleeding/fistula risk. Exceptions may be considered if investigator assesses minimal risk.

10. Pulmonary comorbidities causing severe impairment, including:

    1. Baseline lung diseases (e.g., pulmonary embolism [≤3 months], severe asthma/COPD/restrictive disease)
    2. Autoimmune/connective tissue disorders with pulmonary involvement (e.g., rheumatoid arthritis, sarcoidosis)
11. Residual toxicity >Grade 1 (per NCI CTCAE v5.0) from prior anticancer therapy (except alopecia/neuropathy).

12. Concurrent malignancies except:

    • Cured localized skin cancers (BCC/SCC), superficial bladder cancer, cervical/breast DCIS, or papillary thyroid cancer
    • Other malignancies cured by radical therapy ≥3 years prior
13. Pregnancy/lactation or planned pregnancy within 6 months post-treatment.
14. Inability to comply with study procedures/follow-up.
15. Known hypersensitivity to furmonertinib or excipients.
16. History of allergic reactions to pemetrexed/cisplatin/carboplatin.

17. Other exclusionary per investigator judgment, including:

    • Alcohol/drug abuse
    • Severe comorbidities (including psychiatric) requiring treatment
    • Critical laboratory abnormalities
    • Social/familial factors compromising safety/data collection