Study to Evaluate SBRT for EGFR Mutant NSCLC Patients Receiving Osimertinib (CULTRO)

Inclusion Criteria:

* Be older than 18 years of age.
* Be capable of giving informed consent to participate in the study.
* Have histological confirmation compatible with EGFR mutant non-small cell lung cancer (NSCLC) and metastatic disease (with or without histological confirmation of metastatic lesions).
* Have confirmation of the presence of common EGFR mutations (exon 19 deletion, L858R/exon 21, or G719X) through any locally and internationally accepted standard tests.
* Have received at least 12 weeks of Osimertinib treatment (with or without the addition of chemotherapy based on FLAURA2 study results after discussion with the investigative team).
* Have a partial response defined by RECIST 1.1 criteria.
* Have a maximum of 5 residual tumor lesions in up to 2 organs suitable for treatment with Stereotactic Ablative Radiotherapy (SABR).
* Have the following imaging and clinical tests within 4 weeks before study entry:
* Contrast-enhanced brain MRI.
* Chest/abdomen/pelvis CT scan, with or without bone scan (at the investigator's discretion) if PET-CT was not performed.
* 18-FDG PET-CT.
* Spinal MRI for patients with vertebral or paravertebral metastases.
* Electrocardiogram (EKG) and transthoracic echocardiogram.
* Complete blood count and standard blood chemistry.
* Negative pregnancy test for fertile women within 4 weeks prior to starting radiotherapy.
* Liquid biopsy for assessment of tumor allelic fraction (baseline).
* ECOG performance status 0-2.
* All sites of oligoresidual disease must be safely treatable according to the following criteria:
* All brain lesions must be treatable with SRS.
* The maximum size for extracranial lesions will be up to 6 cm, with exceptions for bone metastases which may include lesions larger than 6 cm at the discretion of the investigative medical team (e.g., ribs, scapula, or pelvis).
* Life expectancy \>6 months.
* Not eligible for surgical treatment.
* Osimertinib treatment must be suspended 48 hours before the start of ablative therapy and cannot be initiated within 48 hours of receiving the last fraction. In patients receiving SBRT for central lung lesions, the suspension time for Osimertinib may be extended up to 5 days before and after ablative therapy.
* Patients may have previously received treatments such as radiofrequency or microwave ablation for oligoresidual lesions, but imaging must demonstrate that the lesion persists and is treatable with SABR.
* Metastatic tumor lesions that received initial treatment with radiosurgery cannot be included for SABR treatment.
* If initial treatment was conventional radiotherapy, SABR could be considered if safe to administer. In this case, the ablative therapy must be discussed by the investigative team.
* The eligibility and prognosis criteria will be reviewed by the multidisciplinary thoracic tumor board at CTIC Centro de Tratamiento e Investigación Sobre Cáncer Luis Carlos Sarmiento Angulo.

Exclusion Criteria:

* Severe comorbidities contraindicating radiation therapy.
* Bone metastases in the femur with a high risk of fracture.
* Complete response to Osimertinib treatment (no oligoresidual disease for ablative treatment).
* Inability to treat all oligoresidual lesions with ablative intent.
* History of pneumonitis or functionally limiting interstitial lung disease. It may be considered limiting if the patient is unable to perform DLCO maneuvers or if adjusted DLCO is less than 35% of predicted, PaO2 at Bogotá altitude with FiO2 21% is less than or equal to 50 mmHg.
* Clinical or radiological evidence of symptomatic spinal cord compression.
* Dominant brain metastatic disease requiring surgical management (e.g., imminent herniation or hydrocephalus).
* Candidate for a clinical trial with an experimental drug.
* Inability to receive Osimertinib with minimal adherence.
* Oligoresidual involvement in peritoneum, pleura, or bone marrow (non-measurable disease).
* Leptomeningeal involvement (presumed based on imaging findings or confirmed by cerebrospinal fluid cytology).
* Pregnant or breastfeeding women.