A Study to Evaluate GFH375 Versus Docetaxel in Participants With Non-Small Cell Lung Cancer With KRAS G12D Mutation

A Phase III, Randomized, Open-Label, Multicenter Study to Evaluate GFH375 Versus Docetaxel in Participants With Locally Advanced and Unresectable or Metastatic Non-Small Cell Lung Cancer With KRAS G12D Mutation Failed Prior Standard Therapy

The purpose of this study is to compare the effectiveness, safety and tolerability of GFH375 versus docetaxel in participants with KRAS G12D-mutant non-small cell lung cancer (NSCLC).

GFH375 is an oral, highly selective, non-covalent small-molecule inhibitor targeting the KRAS G12D mutation. Preclinical studies showed GFH375 strongly blocks KRAS-driven signaling and cancer cell growth, and demonstrated anti-tumor activity in NSCLC animal models. Docetaxel is a chemotherapy drug for locally advanced or metastatic NSCLC.

This is an open-label, randomized controlled trial. Both participant and study doctor will know which study medication each participant receives.

After enrollment, participant will be randomly assigned to either the GFH375 group or docetaxel group by chance. Neither participant nor study doctor can pick your treatment group. You have a two-thirds chance to receive GFH375 and a one-third chance to receive docetaxel.

• GFH375 group: Take GFH375 tablets by mouth once daily as scheduled; each treatment cycle lasts 21 days.
• Docetaxel group: Receive docetaxel via intravenous infusion at 75 mg/m² once every 3 weeks.

Study treatment will continue until cancer gets worse, participant can't tolerate the study treatment, or other conditions make participant unable to keep receiving study treatment.

Some participants on docetaxel may be able to switch to GFH375 during the study if their cancer becomes worse. There will be safety checks at each visit, and the doctors will continue to check for medical problems and participant 's wellbeing throughout the study. Participants will continue to have scans of their tumor every 6 weeks for the first year, then every 9 weeks until their cancer becomes worse. After participant's cancer becomes worse, clinic staff will telephone participant every 3 mouths to check on their cancer.

Inclusion Criteria:

• 1. Voluntary participation in the study and signed informed consent form (ICF).
• 2. Age ≥ 18 years at the time of signing the ICF; male or female.
• 3. Histologically or cytologically confirmed locally advanced unresectable or metastatic non small cell lung cancer (NSCLC).
• 4. Participants must provide adequate and qualified tumor tissue slides samples or agree to undergo tumor biopsy to obtain tissue samples for central laboratory confirmation of KRAS G12D mutation.
• 5. Disease progression or intolerance to toxicity after at least one prior line of platinum based chemotherapy and anti PD 1/PD L1 antibody therapy.
• 6. At least one measurable target lesion according to RECIST version 1.1.
• 7. Investigator assessed life expectancy ≥ 12 weeks.
• 8. Adequate organ function.
• 9. Ability to communicate well, comply with scheduled follow up visits, and adhere to protocol requirements.

Exclusion Criteria:

• 1. Presence of other driver gene mutations in NSCLC, or concurrent other KRAS or RAS mutations.
• 2. Other malignancy that has progressed or required treatment within 3 years prior to randomization.
• 3. Leptomeningeal metastasis, or symptomatic or progressive central nervous system (CNS) metastasis.
• 4. Existing or potential severe bone injury due to bone metastasis, or uncontrolled pain related to bone metastasis.
• 5. Prior treatment with KRAS G12D targeted therapy or pan RAS/KRAS targeted therapy.
• 6. Prior treatment with docetaxel as part of systemic therapy.
• 7. Radiotherapy within 4 weeks prior to randomization, or other local anti tumor therapy within 4 weeks prior to randomization.
• 8. Other anti tumor therapy within 28 days or 5 half lives prior to randomization, or cell therapy within 3 months prior to randomization.
• 9. Clinically significant severe cardiovascular disease.
• 10. Stroke or other severe cerebrovascular disease within 6 months prior to randomization.
• 11. Major acute or chronic infectious disease.
• 12. Other poorly controlled systemic diseases.
• 13. Severe psychiatric or psychological disorder, or history of drug abuse, or severe alcohol abuse.
• 14. Pregnancy or breastfeeding.
• 15. Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.