Hippocampus-protective Synchronous Progressive Whole Brain Radiotherapy Combined With Osimertinib for Symptomatic Brain Metastases in Advanced EGFR-Mutated Non-Small Cell Lung Cancer: A Prospective Phase II Multicenter Single-Arm Clinical Study
This is a single-arm, multicenter, open-label, phase Ⅱ exploratory clinical study, which plans to enroll 74 treatment-naive patients with EGFR-sensitive mutations (exon 19 deletion, exon 21 L858R mutation) and symptomatic brain metastases from non-small cell lung cancer (NSCLC). The primary objective is to evaluate the intracranial progression-free survival (iPFS) of hippocampal-sparing whole-brain radiotherapy (PTV: 20Gy/10 fractions) combined with simultaneous integrated boost to brain metastases (PGTV: 40Gy/10 fractions) plus osimertinib (80mg orally once daily). The secondary objectives are to assess efficacy indicators including overall progression-free survival (PFS), intracranial/systemic objective response rate (ORR), as well as safety. The primary endpoint is iPFS, supplemented by secondary endpoints such as PFS, ORR, disease control rate (DCR), overall survival (OS), adverse events (AE) evaluated per NCI-CTCAE v5.0 criteria, and neurocognitive function scores (MMSE/HVLT-R). By optimizing the combined mode of radiotherapy and targeted therapy, this study aims to provide a safer and more effective treatment option for such patients, balancing tumor control and quality of life protection.
• Signed a written informed consent form prior to enrollment;
• Aged 18-75 years;
• Histopathologically confirmed non-small cell lung adenocarcinoma (NSCLC); EGFR gene test confirmed EGFR sensitive mutations, including exon 19 deletion (19del) and exon 21 L858R mutation (verified and confirmed by investigators at the respective study centers);
• Brain metastasis confirmed by contrast-enhanced cranial CT/MRI; the number of brain metastatic lesions requiring local dose escalation is 1-10, with at least one measurable intracranial lesion having a diameter ≥10 mm; the distance between metastatic lesions and important cerebral functional areas meets radiotherapy-related requirements; at least one measurable lesion (per RECIST v1.1 criteria) confirmed by contrast-enhanced extracranial CT/PET-CT;
• Symptomatic brain metastasis;
• ECOG performance status score: 0-2;
• Expected survival time of no less than 12 weeks;
• No prior anti-tumor treatment received for NSCLC;
• Normal function of vital organs, meeting the following requirements (no blood components or cell growth factors administered within 14 days):
⁃ A) Routine blood test criteria: Hb ≥100 g/L; ANC ≥1.5×10⁹/L; PLT ≥75×10⁹/L; B) Biochemical test criteria: TBIL ≤1.5×ULN (upper limit of normal); ALT and AST ≤2.5×ULN (for patients with liver metastasis, ALT and AST ≤5×ULN); serum creatinine ≤1.5×ULN, creatinine clearance rate ≥50 ml/min (calculated based on the Cockroft-Gault formula); C) Coagulation function criteria: INR ≤1.5×ULN and APTT ≤1.5×ULN; D) Cardiac color Doppler ultrasound: left ventricular ejection fraction (LVEF) ≥50%;
⁃ \- For non-surgically sterilized patients or women of childbearing potential: a medically approved contraceptive method (e.g., intrauterine device, oral contraceptives, or condoms) must be used during the study treatment period and for 3 months after the end of study treatment; non-surgically sterilized women of childbearing potential must have a negative serum or urine HCG test within 7 days prior to study enrollment, and must not be breastfeeding.
⁃ All subjects voluntarily participate in the study, with good compliance and willingness to cooperate with safety and overall survival follow-up.