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.
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.
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.
Parallel
GFH375
DrugGFH375 administered orally at the protocol-specified dose once daily. Each treatment cycle is 21 days.
Docetaxel
DrugReceive docetaxel via intravenous infusion at 75 mg/m² once every 3 weeks.
Objective Response Rate(ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. as assessed by blinded independent central review (BICR)
ORR is the proportion of participants whose best response is either complete response (CR) or partial response (PR) per RECIST v1.1 assessed by BICR.
Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. as assessed by blinded independent central review (BICR)
PFS is defined as the time from the date of randomization until the date of documented radiographic disease progression per RECIST v1.1, as assessed by BICR or until death due to any cause, whichever comes first.
Overall Survival (OS)
OS is defined as the time from the date of randomization until the date of death from any cause.
Objective Response Rate (ORR) per RECIST v1.1, as assessed by the investigator
ORR is defined as the proportion of participants whose best overall response (BOR) is rated as confirmed complete response (CR) or confirmed partial response (PR) per RECIST v1.1. as assessed by the investigator.
PFS per RECIST v1.1. as assessed by the investigator
PFS is defined as the time from the date of randomization until the date of documented radiographic disease progression per RECIST v1.1 as assessed by the investigator or until death due to any cause, whichever comes first.
DCR per RECIST v 1.1 as assessed by the investigator and the BICR
DCR is defined as the proportion of participants whose best overall response is rated as CR, confirmed PR or SD per RECIST v1.1 as assessed by the investigator and the BICR.
DoR per RECIST v 1.1 as assessed by the investigator and the BICR
DOR is defined as the time from the date of first documented response (CR or PR subsequently confirmed) to the date of first documented PD per RECIST v1.1 as assessed by the investigator and the BICR or death due to any cause, whichever occurs first.
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