This study is a multicenter, open-label, randomized clinical trial aimed at exploring the efficacy and safety of three treatment regimens for treatment-naive advanced NSCLC patients with KRAS G12D mutation: GFH375 monotherapy (Cohort 1), GFH375 combined with cetuximab (Cohort 2), and GFH375 combined with pemetrexed (Cohort 3).Every cohort will recruit 30 participants.

This study is a multicenter, open-label, randomized clinical trial designed to evaluate the efficacy and safety of three treatment regimens in patients with previously untreated advanced NSCLC harboring KRAS G12D mutations: GFH375 monotherapy (Cohort 1), GFH375 combined with cetuximab (Cohort 2), and GFH375 combined with pemetrexed (Cohort 3).

The study population consists of participants with advanced, previously untreated NSCLC carrying KRAS G12D mutations. Participants must not have received any prior systemic anti-tumor therapy. After enrollment, participants will be randomized to one of the following cohorts:

Cohort 1: GFH375 monotherapy (600 mg, QD, oral), approximately 30 participants. Cohort 2: GFH375 (600 mg, QD, oral) combined with cetuximab (500 mg/m², Q2W, intravenous), approximately 30 participants.

Cohort 3: GFH375 (600 mg, QD, oral) combined with pemetrexed (500 mg/m², Q3W, intravenous), approximately 30 participants.

A total of approximately 90 participants will be enrolled in this study, and each participant will be randomized to only one cohort.

Inclusion Criteria:

1. Voluntarily agree to participate in this study and sign the written informed consent form.
2. Male or female, aged 18 to 75 years at the time of signing the informed consent form.
3. Pathologically (histologically or cytologically) confirmed advanced (Stage IV) or locally advanced non-squamous non-small cell lung cancer that is not amenable to radical surgery or radiotherapy.
4. Have a written report confirming KRAS G12D mutation positive.
5. Able to provide an archival tumor tissue sample [formalin-fixed, paraffin-embedded (FFPE) block or unstained FFPE tumor sections] or to undergo a tumor biopsy prior to treatment.
6. No prior systemic anti-tumor therapy for advanced disease; or not eligible for standard of care therapy; or in the investigator's judgment, may benefit more from GFH375 monotherapy or combination therapy than from available standard therapy.
7. Have at least one measurable lesion outside the central nervous system (CNS) per RECIST v1.1. Lesions that have received prior local radiotherapy can be considered measurable only if they have demonstrated clear progression after radiotherapy; otherwise, they are not considered measurable.
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

9.Life expectancy of at least 3 months as assessed by the investigator. 10.Adequate organ function.

Exclusion Criteria:

1. Has had another invasive malignancy that progressed or required treatment within 3 years prior to randomization, except adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, squamous cell carcinoma in situ, superficial bladder cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, or papillary thyroid carcinoma.
2. Pathologically (histologically or cytologically) confirmed squamous cell lung cancer, adenosquamous carcinoma, neuroendocrine carcinoma (including small cell lung cancer and large cell neuroendocrine carcinoma), or mixed small cell lung cancer.
3. Known to harbor other targetable driver gene alterations.
4. Has active or symptomatic brain metastases, leptomeningeal metastases, or spinal cord compression.
5. Has clinically significant severe cardiovascular disease.
6. Has had a stroke or other serious cerebrovascular event within 6 months prior to randomization.
7. Has a history of deep vein thrombosis or other severe thromboembolism within 3 months prior to randomization.
8. Has pleural effusion, ascites, or pericardial effusion requiring frequent drainage (≥2 times per month) or associated with moderate to severe symptoms.
9. Has clinically significant interstitial lung disease, radiation pneumonitis, or immune-related pneumonitis requiring treatment.
10. At high risk of gastrointestinal bleeding or perforation.
11. Has pyloric obstruction, persistent or recurrent vomiting (≥3 episodes within 24 hours); is unable or unwilling to swallow tablets; or has other impaired gastrointestinal function or gastrointestinal disease that may significantly affect the absorption of GFH375.
12. History of chronic diarrhea.
13. Has a major acute or chronic infectious disease.
14. Has other uncontrolled systemic medical conditions.
15. Planned major surgery as determined by the investigator.
16. History of organ transplantation or preparing to undergo organ transplantation (except corneal transplantation).
17. Known allergy to the investigational drug or its components.
18. Received or planned to receive a live attenuated vaccine within 28 days prior to randomization or during the administration of the investigational drug.
19. Having severe mental or psychological disorders, a history of substance abuse, or a history of severe alcoholism.
20. Pregnant or breastfeeding women.
21. Other conditions deemed by the investigator to be inappropriate for participation in the study.