The goal of this interventional phase III clinical trial is to evaluate objective intracranial response rate (iORR) after a treatment with total cranial radiation therapy plus concomitant transdermal nitroglycerin (NTG) addition or total cranial radiation therapy only in patients with stage IV non-small cell lung cancer with brain metastases and EGFR mutation. The main questions it aims to answer are:

Determine progression-free survival (PFS) to CNS and overall survival (OS). Evaluate and compare the quality of life (QoL) of patients during and after treatment.

Evaluate the cognitive function of patients before, during and after treatment. Evaluate treatment-associated toxicity to grade adverse treatment events Evaluation of HIF1α, VEGF and ROS1 in peripheral blood before and after nitroglycerin treatment.

All participants will have laboratory tests at the beginning and end of radiation therapy. Cranial MRI will be performed prior to treatment and 12 weeks after the end of treatment, then every 16 weeks until intracranial progression. Patients in the interventional group will be given 36 mg patches of transdermal nitroglycerin for 24 hours with a 12-hour rest interval during treatment with radiation therapy. The control group will only receive total cranial radiation therapy at the same doses and with the same schedule.

The prognosis of patients with central nervous system (CNS) metastases is poor. About 50% of patients with CPCNP and EGFR mutation have tumor activity in the central nervous system during the first 2 years of diagnosis.

Treatment with total cranial radiation therapy (CRT) has shown to have a benefit in local response and patient survival. However, resistance factors such as intratumoral hypoxia decrease the response by CRT.

Thus, the use of nitric oxide generators, such as nitroglycerin, has been shown to avoid radio resistance. A previous study conducted at our Institute showed that the addition of transdermal nitroglycerin (NTG) CRT increases intracranial response evaluated by objective radiological response in patients with NSCLC and the subgroup in which a greater benefit was seen was in patients with mutations in the EGFR gene.

In this study we propose that the addition of transdermal nitroglycerin to patients with brain metastases and mutations in the EGFR gene receiving CRT will have an increase in intracranial objective response.

Inclusion Criteria:

• Patients diagnosed with advanced non-small cell lung cancer (which includes de novo stage IIIB-IV, according to the 8th edition AJCC, or recurrent disease), documented by histology and/or cytology.
• Presence of brain metastases, candidates for treatment with holocranial radiation therapy.
• Documented EGFR sensitivity mutation.
• Disease measurable by criteria: The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM).
• 18 years and up.
• Functional status, by ECOG scale 0-2
• Life expectancy at least 12 weeks.
• Not receive vasodilator treatment as calcium channel blockers.
• Electrocardiogram
• Neutrophil count 1.5 x 103/mm3, platelet count >100 x (103/mm3).
• Serum bilirubin should be 1.5 of the upper normal limit (ULN, upper normal limit).
• AST and/or ALT 2 ULN (or 5 x ULN in patients with liver metastases).
• Serum creatinine 1.5 (ULN), or creatinine clearance 60ml/min.
• Ability to comply with study and follow-up procedures.
• Informed written (signed) consent to participate in the study.
• Have tumor tissue (paraffin blocks from diagnostic biopsy) obtained before systemic treatment

Exclusion Criteria:

• Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart failure, ischemic heart disease, liver, kidney disease).
• Patients with a history of allergy to glyceryl tinistate
• Any other malignant pathology within the previous 5 years (except for cervical carcinoma in situ or basal-cell skin cancer, treated appropriately).
• Pregnant and/or breastfeeding women.
• Meningeal carcinomatosis corroborated by cytopathological study.

Disposal Criteria:

• Failure to follow protocol rules.
• Loss of patient follow-up.
• Patients who express their desire not to continue the study.
• Patients with unacceptable toxicity