Cranial Radiotherapy Plus Chemoimmunotherapy in Untreated Driver-mutation Negative NSCLC With Stable Brain Metastasis

Official title

Cranial Radiotherapy Plus PD-1/PD-L1 Inhibitors and Chemotherapy in Patients With Driver-mutation Negative Non-small Cell Lung Cancer With Stable Brain Metastasis (BRILLIANT)

Overview

Non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer, has a significant risk of brain metastasis (BM). Historically, the median overall survival for advanced NSCLC patients with BM was under six months with traditional chemotherapy. However, recent advancements with immune checkpoint inhibitors (ICIs) have shown promise, with some studies reporting improved intracranial objective response rates, progression-free survival, and overall survival when combined with chemotherapy. Despite these improvements, challenges remain, such as treatment resistance, recurrence, and the need for better therapeutic strategies. Local interventions like stereotactic radiotherapy (SRT) and whole brain radiation therapy (WBRT) have been crucial for treating BM, with SRT being particularly effective. The combination of immunotherapy and radiotherapy is emerging as a synergistic approach, with studies suggesting it may enhance local control and survival rates while maintaining safety. Guidelines recommend SRT for patients with limited BMs, and clinical data support the safety and efficacy of combining brain radiotherapy with immunotherapy. A meta-analysis and other studies have shown promising results with this combination, including local control rates and overall survival benefits, with manageable toxicities. However, there is still a need for more prospective clinical trials to verify the safety and efficacy of combining cranial radiotherapy with immunotherapy in NSCLC patients with BM, especially those without driver gene mutations. Therefore, we plan to conduct a phase 2 prospective study, focusing on combining brain radiotherapy with PD-1/PD-L1 inhibitors. We will stratify eligible patients based on the status of BMs (active BM vs stable BM) .

Interventions

• Drug PD-L1/PD-1 inhibitor and chemotherapy
  Stable brain metastases patients in this arm will receive PD-L1/PD-1 inhibitors and chemotherapy.
• Radiation SRT or WBRT
  Stable brain metastases (BM) patients in this arm will receive stereotactic radiotherapy (SRT) and whole brain radiation therapy (WBRT) according to their BM condition.

Primary outcome measures

• Objective Response Rate (ORR) [Time frame: 2 years]

Secondary outcome measures (5)

• Intracranial Progression-Free Survival (iPFS) [Time frame: 2 years]
• Intracranial Objective Response Rate (iORR) [Time frame: 2 years]
• Progression-Free Survival (PFS) [Time frame: 2 years]
• Overall Survival (OS) [Time frame: 2 years]
• Treatment-Related Adverse Event (TRAE) [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years;
• KPS score ≥ 70;
• Negative genetic testing for common driver genes including EGFR, ALK, ROS-1;
• Pathologically confirmed non-small cell lung cancer;
• Clinical stage IV (AJCC, 8th edition, 2017);
• Diagnosed with brain metastasis at the time of diagnosis, with at least one lesion in the brain with a diameter greater than 5mm on thin-section brain MRI;
• Complete baseline assessment of systemic lesions before treatment, including enhanced brain MRI;
• Informed consent from the patient.

Exclusion criteria

• Multiple primary or metastatic tumors (except early skin cancer, cervical carcinoma in situ that has been treated radically, with no recurrence or progression for more than 5 years);
• Severe autoimmune diseases: active inflammatory bowel disease (including Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (such as Wegener's granulomatosis), etc.;
• Patients judged by the researcher as unsuitable for brain MRI or stereotactic brain radiotherapy;
• EGFR, ALK, or ROS1 gene mutations;
• Active BMs that could not be controlled by symptomatic treatment, such as mannitol and dexamethasone
• Uncontrolled epilepsy, central nervous system disease, or history of mental disorders, judged by the researcher to potentially interfere with the signing of the informed consent form or affect patient compliance;
• Symptomatic interstitial lung disease or active infection/non-infectious pneumonia;
• Patients with risk factors for intestinal perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal cancer, or other known risk factors for intestinal perforation;
• Patients with active infection, heart failure, myocardial infarction within 6 months, unstable angina, or unstable arrhythmia;
• Other uncontrollable diseases or findings from physical examination or clinical experiments judged by the researcher to potentially interfere with the results or increase the risk of treatment complications for the patient;
• Mixed with small cell lung cancer components;
• Pregnant or lactating women;
• Congenital or acquired immunodeficiency diseases including HIV, or history of organ transplantation, allogeneic stem cell transplantation;
• Known HBV, HCV, active pulmonary tuberculosis infection;
• Patients who have received tumor vaccines, or have been vaccinated with other vaccines within 4 weeks before starting treatment (Note: Seasonal influenza vaccines are usually inactivated vaccines and are allowed, while nasal preparations are usually attenuated live vaccines and are not allowed);
• Concurrent use of other immunomodulators, chemotherapy drugs, drugs in other clinical studies, and long-term use of corticosteroid treatment are not eligible for inclusion;
• Patients allergic or contraindicated to PD-1/PD-L1 inhibitors or chemotherapy drugs.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Fudan University Shanghai Cancer Center — Shanghai

Identifiers

NCT: NCT06501391 · 2024Lung-PD1-stable BM

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗