Firmonertinib Plus Chemotherapy for Unresectable EGFR PACC-Mutant Stage III Lung Cancer: A Phase II Study

Prior treatment

• Prior systemic anti-tumor therapy for NSCLC, including investigational drug therapy.
• Other malignancies other than non-small cell lung cancer within 5 years prior to the first dose. Malignancies with negligible risk of metastasis or death (e.g., expected disease-free survival \> 5 years) and expected to achieve curative outcomes after treatment (e.g., adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, radically resected ductal carcinoma in situ) may be exempted.

Other illness

• Pathological type of squamous cell carcinoma or small cell lung cancer.
• Known history of severe hypersensitivity reactions to the active or inactive excipients of Firmonertinib, or to drugs with a similar structure or class to Firmonertinib.
• History of (non-infectious) pneumonitis/interstitial lung disease requiring steroids, or current pneumonitis/interstitial lung disease requiring steroid therapy.
• Known active autoimmune disease requiring systemic therapy.
• Known human immunodeficiency virus (HIV) infection (known positive HIV antibody).
• Known severe or uncontrolled underlying diseases, including but not limited to hemodynamically unstable cardiovascular events, symptomatic cerebrovascular events, or cirrhosis of Child-Pugh Grade A or higher within 6 months.

Lab values

• Any subject with known or suspected autoimmune disease or immunodeficiency, EXCEPT: Subjects with hypothyroidism who do not require hormone therapy or are receiving stable dose hormone replacement therapy; subjects with Type 1 diabetes mellitus whose blood glucose is stably controlled.
• Uncontrolled active hepatitis B (defined as positive HBsAg at screening AND HBV-DNA level above the upper limit of normal of the testing laboratory at the study center. Exception: Subjects with HBV-DNA \< 500 IU/mL within 28 days prior to enrollment, who have received at least 14 days of local standard antiviral therapy, and are willing to continue antiviral therapy during the study may be enrolled); Active hepatitis C (defined as positive hepatitis C virus surface antibody \[HCsAb\] at screening, with positive HCV-RNA).
• Any history or current evidence of diseases, treatments, or laboratory abnormalities that, in the investigator's judgment, may confound the trial results, interfere with the subject's participation in the full trial, or are not in the best interest of the subject.

Other

• Subjects meeting any of the following exclusion criteria cannot be enrolled in this study:
• Pregnancy or lactation.

• Histologically confirmed locally advanced (Stage IIIA-IIIC according to the AJCC 9th edition) lung adenocarcinoma that is assessed by the investigator as unresectable or unsuitable for surgical resection.
• Confirmed presence of EGFR PACC mutations by genetic testing at a tertiary Grade A hospital.
• No prior local or systemic anti-tumor therapy for Stage III non-small cell lung cancer, including standard chemotherapy, biological therapy, targeted therapy, immunotherapy, or investigational therapy.
• According to RECIST 1.1 criteria, at least one measurable lesion that has not been previously irradiated and has not undergone tissue biopsy during the screening period.
• Fully understands the study and voluntarily signs the Informed Consent Form (ICF).
• Age ≥ 18 years, both genders.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1, with no deterioration within 2 weeks prior to enrollment.
• Life expectancy ≥ 12 weeks.
• Adequate organ function:
  • Hematology: Absolute neutrophil count (ANC) ≥ 1500/µL; Platelet count ≥ 100×10\^9/L; Hemoglobin ≥ 9.0 g/dL.
  • Renal: Serum creatinine ≤ 1.5 × ULN, or calculated creatinine clearance (CrCl) ≥ 60 mL/min (using the Cockcroft-Gault formula).
  • Hepatic: Total bilirubin ≤ 1.5 × ULN, or direct bilirubin within normal limits for subjects with total bilirubin \> 1.5 × ULN; AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN.
  • Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN. Exception: Subjects receiving anticoagulation therapy must have PT or APTT within the intended therapeutic range of the anticoagulant.
• Women of childbearing potential must have a negative serum pregnancy test within 3 days prior to the first dose. Women of childbearing potential and male subjects with partners of childbearing potential must agree to use highly effective contraception during the study and for 180 days after the last dose of study treatment.