Hippocampus-Protective Radiotherapy Combined With Osimertinib for Symptomatic Brain Metastases in EGFR-Mutated Lung Cancer

• Study Rationale Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, with the central nervous system being one of the most common metastatic sites. Among NSCLC patients, those with epidermal growth factor receptor (EGFR)-sensitive mutations (exon 19 deletion and exon 21 L858R mutation) face a significantly higher risk of brain metastasis, with a 3-year cumulative incidence ranging from 29.4% to 60.3%. With the widespread application of third-generation tyrosine kinase inhibitors (TKIs), the median progression-free survival (PFS) of advanced EGFR-mutated NSCLC patients has been extended to over 24 months, but brain metastasis has become the most prominent failure mode due to the limited blood-brain barrier penetration of conventional treatments.

Current radiotherapy strategies for brain metastasis have inherent limitations: stereotactic radiosurgery (SRS) for ≤4 lesions is associated with a >50% risk of distant intracranial recurrence and increased radiation necrosis when combined with TKIs, while conventional whole-brain radiotherapy (WBRT) for >4 lesions results in suboptimal local tumor control and irreversible neurocognitive impairment, primarily attributed to hippocampal damage. Osimertinib, a third-generation EGFR-TKI, exhibits superior cerebrospinal fluid penetration (2.5%-16%) compared to first and second-generation agents, demonstrating potent intracranial efficacy. Hippocampal-sparing whole-brain radiotherapy with simultaneous integrated boost (HS-WBRT+SIB) is a novel technique that restricts the hippocampal mean dose to ≤9Gy (maximum dose ≤16Gy) while delivering a boosted dose to metastatic lesions, which has been shown to reduce cognitive decline risk (hippocampal metastasis rate only 1.4%-4.5%) and improve local control.

Preclinical and clinical evidence indicates that radiotherapy can disrupt the blood-brain barrier to enhance intracranial drug concentration, while TKIs can sensitize tumors to radiation, forming a synergistic therapeutic effect. However, there remains an unmet clinical need for an optimized combined strategy for symptomatic brain metastases in treatment-naive EGFR-mutated NSCLC patients. This study aims to validate the efficacy and safety of HS-WBRT+SIB combined with osimertinib, addressing the limitations of current treatments and providing a more effective and tolerable therapeutic option.

• Study Design 2.1 Trial Type Prospective, single-arm, multicenter, open-label, phase Ⅱ exploratory clinical trial (Investigator-Initiated Trial, IIT; Non-IND).

2.2 Study Period Expected start date: October 2025 Expected end date: October 2027 Total duration: 2 years, including a 24-month survival follow-up period after treatment completion or progression.

2.3 Study Sites Tianjin Medical University Cancer Institute and Hospital (leading site), Tianjin Chest Hospital, and Tianjin Huanhu Hospital.

2.4 Study Population 2.4.1 Target Population Treatment-naive patients with EGFR-sensitive mutations (exon 19 deletion or exon 21 L858R mutation) and symptomatic brain metastases from NSCLC.

2.4.2 Sample Size A total of 74 patients are planned to be enrolled. The sample size is calculated based on the primary endpoint of intracranial progression-free survival (iPFS), with a historical control iPFS of 17 months (derived from the FLAURA2 study's cEFR cohort). Assuming a two-sided α of 0.1, power of 0.8, 24-month enrollment and follow-up periods, and a 10% dropout rate, the required sample size is 74 patients (66 evaluable cases plus 8 dropouts).

• Intervention Measures 3.1 Radiotherapy Regimen Technique: Hippocampal-sparing whole-brain radiotherapy with simultaneous integrated boost (HS-WBRT+SIB).

Dose: Planning Target Volume (PTV, whole brain): 20 Gy in 10 fractions; Planning Gross Target Volume (PGTV, brain metastases): 40 Gy in 10 fractions.

Fractionation: Once daily, 5 days per week, consecutive radiotherapy. Hippocampal Dose Constraints: Mean dose (Dmean) ≤9 Gy (acceptable ≤10 Gy); Maximum dose (Dmax) ≤16 Gy (acceptable ≤17 Gy).

3.2 Drug Regimen Study Drug: Osimertinib mesylate tablets (Tagrisso®). Dosage and Administration: 80 mg orally once daily, taken within 30 minutes after breakfast, 28 days as one cycle.

Timing of Radiotherapy: Initiated within 28 days after the first dose of osimertinib.

Duration: Continuous administration until disease progression, intolerable toxicity, withdrawal of informed consent, or investigator-determined termination.

Dose Adjustment: For grade ≥3 adverse events (AEs) per NCI-CTCAE v5.0, treatment may be interrupted or dose reduced to 40 mg/day. Missed doses are not made up; subsequent doses are administered as scheduled.

3.3 Concomitant Medications Avoid concurrent use of strong CYP3A4 inducers (e.g., rifampicin, phenytoin) and St. John's Wort. If unavoidable, osimertinib dose may be increased to 160 mg/day and restored to 80 mg/day 3 weeks after discontinuing the inducer.

Caution with P-gp/BCRP substrates (e.g., digoxin, dabigatran) and QT-prolonging drugs (e.g., fluoroquinolones, amiodarone); close monitoring is required.

Acid-suppressing agents may be used without dose adjustment.

• Outcome Measures 4.1 Primary Endpoint Intracranial Progression-Free Survival (iPFS): Time from treatment initiation to first documented intracranial disease progression, worsening of previously controlled intracranial hypertension, or death from any cause.

4.2 Secondary Endpoints 4.2.1 Efficacy Indicators Overall Progression-Free Survival (PFS): Time from treatment initiation to first documented systemic disease progression or death from any cause.

Intracranial/Systemic Objective Response Rate (ORR): Proportion of patients achieving complete response (CR) or partial response (PR) per RECIST v1.1.

Intracranial/Systemic Duration of Response (DoR): Time from first confirmation of CR/PR to disease progression or death.

Intracranial/Systemic Disease Control Rate (DCR): Proportion of patients achieving CR, PR, or stable disease (SD) per RECIST v1.1.

Overall Survival (OS): Time from treatment initiation to death from any cause. 4.2.2 Safety Indicators Adverse Events (AEs)/Serious Adverse Events (SAEs): Assessed and graded per NCI-CTCAE v5.0, including onset time, severity, duration, management, and outcome.

Neurocognitive Function: Evaluated by Mini-Mental State Examination (MMSE) and Hopkins Verbal Learning Test-Revised (HVLT-R).

Performance Status: ECOG score assessed at each cycle. Quality of Life (QoL): Evaluated by EORTC QLQ-C30 questionnaire. Laboratory Tests: Routine blood, biochemistry, coagulation, and cardiac function (echocardiogram) at specified time points.

• Study Procedures 5.1 Screening Period (Day -14 to Day 1) Obtain informed consent, review medical history, and perform physical examination.

Conduct baseline assessments: ECOG score, MMSE, HVLT-R, EORTC QLQ-C30, vital signs, EGFR gene testing, contrast-enhanced brain CT/MRI, chest CT/PET-CT, abdominal/neck ultrasound, laboratory tests (hematology, biochemistry, coagulation), and echocardiogram.

5.2 Treatment Period (28-day cycles) Initiate osimertinib administration on Day 1; start radiotherapy within 28 days.

Cycle Assessments: Routine blood (weekly for the first 2 cycles, then per cycle), biochemistry (Cycle 1 Day 15 and end of each cycle), ECOG score, MMSE, HVLT-R, and AE monitoring at each visit.

Efficacy Evaluation: Contrast-enhanced brain CT/MRI and chest CT every 3 cycles (±7 days) per RECIST v1.1.

5.3 Follow-up Period Safety Follow-up: Continue monitoring AEs, laboratory tests, and QoL until 30 days after treatment discontinuation.

Survival Follow-up: Telephone follow-up every 3 months for 24 months to collect survival status and subsequent antitumor treatments.

• Statistical Analysis 6.1 Analysis Populations Full Analysis Set (FAS): All enrolled patients who received at least one dose of osimertinib.

Per-Protocol Set (PPS): Subset of FAS without major protocol violations. Safety Set (SS): All enrolled patients who received at least one dose of osimertinib and had at least one post-baseline safety assessment.

6.2 Statistical Methods Descriptive Statistics: Continuous data (e.g., age, laboratory values) summarized as mean, standard deviation, median, min/max; categorical data (e.g., AE incidence) as frequency and percentage.

Time-to-Event Analysis: iPFS, PFS, and OS estimated by Kaplan-Meier method with 95% confidence intervals (CIs).

Efficacy Indicators: ORR and DCR presented as point estimates with 95% CIs. Safety Analysis: AE incidence summarized by frequency and percentage; changes in laboratory parameters and neurocognitive scores described descriptively.

• Quality Assurance and Data Management Compliance with Good Clinical Practice (GCP), Declaration of Helsinki, and local regulations. Protocol revisions require ethical committee approval.

Regular monitoring by clinical research associates to ensure data accuracy, completeness, and protocol adherence.

Electronic Data Capture (EDC) system used for data collection; database locked after verification by investigators, data managers, and statisticians.

Study records (informed consent forms, CRFs, laboratory reports) retained per regulatory requirements.

• Study Termination and Withdrawal 8.1 Patient Withdrawal Voluntary withdrawal by the patient. Intolerable toxicity or adverse events. Disease progression (radiological or clinical). Pregnancy or loss to follow-up. Investigator-determined withdrawal (e.g., protocol violation, new comorbidities).

8.2 Study Termination Unacceptable or unexpected risks to patients. Major protocol design flaws identified during implementation. Lack of therapeutic efficacy deemed futile by the investigator. Early termination by the ethical committee or regulatory authorities.

Inclusion criteria

• 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.

Exclusion criteria

• Presence of uncontrollable third space effusion (e.g., pleural effusion, ascites) that cannot be managed with drainage or other interventions;
• Presence of multiple factors impairing oral drug administration and absorption (e.g., inability to swallow, post-gastrointestinal resection, chronic diarrhea, intestinal obstruction, etc.);
• Patients who are known to be pregnant, planning pregnancy, or women of childbearing potential who refuse to adopt effective contraceptive measures throughout the study period;
• Patients with severe concomitant diseases or those deemed ineligible for enrollment by the investigator;
• Patients with meningeal metastasis;
• Participation in other drug clinical trials within 4 weeks prior to enrollment;
• Concurrent receipt of other anti-tumor therapies;
• A known history of psychotropic drug abuse, alcoholism, or drug addiction in the subject;
• Underlying diseases that may interfere with study drugs (e.g., clinically significant electrocardiographic abnormalities, active interstitial lung disease);
• Any other conditions deemed by the investigator to potentially harm the subject or render them unable to meet or comply with the study requirements.