Observation or Upfront Cranial RT in Oncogene Mutated NSCLC With Asymptomatic BM: A Phase III RCT

Study Overview
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Brief Summary
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Tyrosine Kinase Inhibitors (TKIs) especially higher generation TKI have higher CNS penetration rates and have shown favorable response rates in brain metastases. Brain radiotherapy/surgery is the standard treatment in brain metastases especially symptomatic metastases, however, the role of local treatment especially in driver mutation-positive non-small cell lung cancer with asymptomatic brain metastases is being questioned given their potential side effects. No randomized trial has shown the superiority of early vs delayed cranial RT in asymptomatic BM of driver mutated NSCLC.

Official Title
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Observation or Upfront Cranial RT in Oncogene Driver Mutated NSCLC With Asymptomatic Brain Metastases: A Phase III Randomized Controlled Trial

Conditions
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Asymptomatic Brain Metastases, Driver Mutation Positive Non-small Cell Lung Cancer

Intervention / Treatment
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* Radiation: Stereotactic radiosurgery/whole brain radiotherapy
* Drug: Tyrosine kinase inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Patients with ECOG performance status of 0-2 Patients with pathologically proven diagnosis of NSCLC Patients with positive oncogene mutation status (EGFR/ALK) Patients with radiologically confirmed parenchymal brain metastases Patients with asymptomatic Synchronous or Metachronous brain metastases Patients willing for written informed consent and must be willing to comply with the specified follow-up schedule Exclusion Criteria: Patients with CSF dissemination only without any parenchymal brain metastases Patients with brain metastases in the brain stem Patients with prior history of radiation therapy to the brain Patient not suitable for TKI therapy as per the medical oncologist Pregnant or lactating females

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Upfront Cranial Radiotherapy<br>Stereotactic radiosurgery or Whole brain radiotherapy upfront in asymptomatic brain metastases | Radiation: Stereotactic radiosurgery/whole brain radiotherapy<br>* SRS/ WBRT for asymptomatic brain metastases depending on the number of brain metastases<br>Drug: Tyrosine kinase inhibitor<br>* TKI<br>|
| Experimental: Observation (Delayed Cranial Radiotherapy)<br>Observation (Delayed Cranial radiotherapy) of Asymptomatic brain metastases | Drug: Tyrosine kinase inhibitor<br>* TKI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial progression free survival at 24 months | Intracranial progression free survival will be defined as the time from the date of randomization until the date of intracranial progression is documented. Death without intracranial progression will be considered as a competing event. Intracranial response will be graded as per the Response Assessment in Neuro-Oncology (RANO) guidelines for brain metastases | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival will be defined as the time from randomization until the date of death from any cause in the presence or absence of recurrence. | Upto 5-year | 
| Progression free survival | Progression free survival will be defined from the date of randomization to the date of progression or the date of death whichever is earlier. | upto 2 year | 
| Neurocognition toxicity | Neuro-cognition assessment will be done using HVLT-R (Total Recall) at baseline and at 3, 6 and 12 months for assessable patients | Upto 12 months | 
| Toxicity using CTC v5.1 | Toxicity assessment will be defined as per the common terminology criteria version 5.0 at baseline and at subsequent follow up till 2 years | Upto 2 years | 
| Local Control |  | Upto 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asymptomatic brain metastases, EGFR mutation, Whole brain radiotherapy, Stereotactic radiosurgery, ALK rearrangement