A Phase Ib/II, Multi-Center, Open-Label Study to Evaluate the Safety/Tolerability, Pharmacokinetics, and Efficacy of GFH925 in Combination with Cetuximab in Previously Untreated Advanced NSCLC Harboring KRAS G12C Mutation

Prior treatment

• Patients with any other malignancies that have progressed or have required active treatment within the last 3 years prior to be enrolled, except for carcinoma in situ or basal or squamous cell skin cancer that has undergone potentially curation therapy.
• Therapeutic or palliative radiation therapy within 2 weeks prior to first study treatment. Except for bone metastasis which is not the target lesion within 2 weeks prior to initiation of study treatment.
• Major surgery within 4 weeks prior to initiation of study treatment.
• Use of proton pump inhibitors or H2 antagonists within 7 days prior to the initiation of the study treatment.
• Use of strong inhibitors or strong inducers of CYP3A4 or P-gp within 14 days or 5 half-lives (whichever is longer); or herbal medicine/or grapefruit juice or grapefruit containing products within 7 days prior to initiation of study treatment (refer to protocol Table 9).
• Use of sensitive substrates of CYP3A4 or CYP2D6 (with a narrow therapeutic window), within 14 days or 5 half-lives (whichever is longer) prior to initiation of study treatment that was not reviewed and approved by the principal investigator and sponsor (refer to protocol Table 10).
• Active central nervous system (CNS) metastases and/or carcinomatous meningitis that require therapeutic intervention or are causing clinical symptoms. Patients with previously treated brain metastases may participate provided the participants are stable at least 7 days prior to the initiation of the study treatment.
• With conjunctivitis and keratitis within 4 weeks prior to initiation of study treatment.
• Prior treatment with an inhibitor specific to KRAS G12C.

Other illness

• With known allergies to the study drugs or components.
• With history of interstitial lung diseases or pulmonary fibrosis.
• Other conditions judged by the investigator as inappropriate to participate in the study.
• With clinically significant gastrointestinal diseases, such as intractable hiccup, ≥ grade 2 nausea, ≥ grade 2 vomiting, severe peptic ulcer and liver cirrhosis, active gastrointestinal bleeding, or other conditions that interfere swallowing the tablets or significantly alter the absorption; patients with liver metastases who have severe portal hypertension due to Budd-Chiari syndrome or portal vein thrombosis.
• With active infections, including: 1) Positive human immunodeficiency virus antibody (HIV-Ab). 2) Active hepatitis B virus infection (positive HBsAg with positive HBV-DNA). 3) Active hepatitis C virus infection (positive HCV-Ab with positive HCV-RNA). 4) Active infections requiring systemic treatment.
• With uncontrolled systemic diseases, such as hypertension or diabetes.

Lab values

• With clinically significant cardiovascular diseases: - Clinically significant cardiovascular events within 6 months before the first study treatment, such as myocardial infarction, severe/unstable angina, heart failure (New York Heart Association class III or IV), arrhythmia requiring medication, angioplasty, stent implantation, and coronary artery bypass grafting. - QT/QTcF prolongation (QTcF > 470 ms for females or QTcF > 450 ms for males.

Other

• Pregnant or lactating females, or female patients intend to become pregnant during participation.
• With uncontrollable or symptomatic pleural effusion, ascites, or pericardial effusion.

• Patient has provided informed consent form (ICF) prior to initiation of any study specific activities/procedures. For patients who are incapable of giving consent, they also be allowed if they have legal representative to consent on their behalf.
• Women of childbearing potential (WOCBP) and male patients with WOCBP partners must agree to use effective contraception method during the study period and within 30 days after the last dose of GFH925 or within 2 months after the last dose of Cetuximab, whichever is longer. WOCBP must have negative pregnancy test results within 1 week (inclusive) prior to initiation of study treatment.
• Males or females aged ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0~1.
• Life expectancy > 3 months judged by the investigator
• Willing to provide archival or new tumor tissue and plasma for the analysis of biomarkers.
• Have histologically or cytologically confirmed advanced NSCLC with no prior systemic antitumor therapy given as primary therapy for advanced or metastatic disease; and meet all the following requirements: 1) Unwilling to receive immunochemotherapy, or with a potential to benefit from treatment with the combination of GFH925 and cetuximab as compared to available standard treatment (i.e. immunochemotherapy) as judged by investigator. 2) Have documented KRAS G12C mutation 3) Without other targetable oncogenic driver mutation or alteration, i.e., EGFR active mutation, ALK/ROS1 rearrangements, RET rearrangements. 4) Have received prior neo-adjuvant, adjuvant chemotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months prior to initiation of study treatment since the last chemotherapy or completion of chemoradiotherapy.
• Have at least one measurable lesion except for patients only have CNS metastases per RECIST 1.1.
• Have sufficient organ functions, including: 1) Adequate hematopoietic functions: absolute neutrophil count (ANC) ≥ 1.5 × 109 /L, platelet count ≥ 75 × 109 /L, hemoglobin ≥ 9 g/dL, without blood transfusion or treatment with hematopoietic stimulating factors within 14 days prior to screening. 2) Adequate liver functions: i. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 2.5 ×upper limit of normal (ULN) (if liver metastases are present, < 5 × ULN). ii. Total bilirubin (TBIL) < 1.5 × ULN (< 2 × ULN for patients with documented Gilbert's syndrome or < 3 × ULN for extrahepatic obstruction). 3) Adequate renal functions: serum creatinine (SCr) ≤ 1.5 × ULN, or creatinine clearance (CrCl) ≥ 60 mL/min (calculated by Cockcroft-Gault formula) if SCr > 1.5 × ULN. 4) Prothrombin time (PT) or activated partial thromboplastin time (APTT) < 1.5 ×ULN, along with international normalized ratio (INR) < 1.5 or within target range if on prophylactic anticoagulation therapy. 5) Level of Magnesium is within normal limits
• With toxicities left from prior anti-tumor therapy resolved to baseline or CTCAE Grade 1 (neurotoxicity or alopecia ≤ Grade 2).