Hippocampus-protective radiotherapy combined with osimertinib for symptomatic brain metastases in EGFR-mutated lung cancer

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 trial tests whether hippocampal-sparing whole-brain radiotherapy with a higher-dose simultaneous boost to brain tumors plus daily osimertinib can better control symptomatic brain metastases in people with newly diagnosed EGFR-sensitive non-small cell lung cancer.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 74 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Tianjin Medical University Cancer Institute and Hospital (other)
• Drugs / interventions: osimertinib, radiation
• Locations: 1 site (Tianjin)
• Trial ID: NCT07505173 on ClinicalTrials.gov

What this trial studies

This is a single-arm, multicenter, open-label phase 2 trial enrolling 74 treatment-naive patients with EGFR-sensitive mutations (exon 19 deletion or exon 21 L858R) and symptomatic brain metastases. Participants receive hippocampal-sparing whole-brain radiotherapy (20 Gy in 10 fractions) with a simultaneous integrated boost to brain metastases (40 Gy in 10 fractions) alongside osimertinib 80 mg orally once daily. The primary endpoint is intracranial progression-free survival (iPFS), with secondary endpoints including overall PFS, intracranial and systemic objective response rate, disease control rate, overall survival, adverse events per NCI-CTCAE v5.0, and neurocognitive function measured by MMSE and HVLT-R. Eligible patients must be 18–75 years old, treatment-naive for NSCLC, have 1–10 brain lesions with at least one measurable intracranial lesion ≥10 mm, and an ECOG performance status of 0–2.

Who should consider this trial

Good fit: Adults aged 18–75 with newly diagnosed NSCLC harboring EGFR exon 19 deletion or exon 21 L858R mutations who are treatment-naive, have symptomatic brain metastases (1–10 lesions with at least one measurable lesion ≥10 mm), and ECOG 0–2 are ideal candidates.

Not a fit: Patients with prior anti-tumor therapy for NSCLC, non-EGFR-mutant tumors, extensive/unmeasurable brain disease, poor performance status, or disease not meeting radiotherapy safety distance requirements are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could prolong the time without brain progression while minimizing hippocampal radiation exposure to help preserve memory and other cognitive functions.

How similar studies have performed: Third-generation EGFR-TKIs like osimertinib have demonstrated strong intracranial activity and hippocampal-sparing WBRT is known to reduce radiation-related cognitive decline, but the specific combination of hippocampal-sparing WBRT with a simultaneous integrated boost plus osimertinib is novel and not yet well established.

Eligibility criteria

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.

Where this trial is running

Tianjin

• Tianjin Medical University Cancer Institute and Hospital — Tianjin, China (RECRUITING)

Study contacts

• Study coordinator: pang qingsong Chief Physician, PhD

Conditions: Naive Advanced Non-small Cell Lung Cancer With EGFR-sensitive Mutations and Symptomatic Brain Metastases, EGFR exon 21 L858R mutation, Non-small cell lung cancer, EGFR-sensitive mutation, EGFR exon 19 deletion, Symptomatic brain metastasis, Hippocampal-sparing whole-brain, radiotherapy