First-line Immunotherapy-based Standard of Care and Local Ablative Treatments for Oligometastatic Non-small Cell Lung Cancer Patients.

Inclusion Criteria:

• Histologically proven advanced synchronous oligometastatic stage IV NSCLC.

• NSCLC patients eligible first line immunotherapy-based SoC according to the EuropeanMarketing Authorization.

• PDL1 status available.

• Metastases eligible to RLT according to the local multidisciplinary board (MTB): ≤5cm each in CT scan, excluding primary tumour.

• Maximum 5 metastases in 3 organs (EORTC criteria), according to brain MRI andFDG-PET.

• Symptomatic lesions requiring urgent palliative radiation, is permitted prior torandomization. These treated lesions should be counted towards the total number ofmetastases at the time of enrolment.

• Clinically required brain metastases (BM) ablation (surgery and/or SBRT) ispermitted and BM count within the total number of 5 lesions. The patient would thenbe randomized to treatment of their extracranial disease.

• Acceptable organ function for RLT.

• ECOG performance status (PS) 0-1.

• Measurable lesions according to RECIST V1.1 on standard imaging.

• Patient aged 18 or more.

• Woman of childbearing potential must agree to use adequate contraception (implanttype, vaginal ring, contraceptive pill, contraceptive patch, Intrauterine Device (IUD), etc.) for the duration of study participation and up to 6 months aftercompleting treatment/therapy, in addition, male partners use a condom during thissame period. Male patients must agree to use condom for the duration of studyparticipation and up to 6 months after completing treatment/therapy.

• Patients affiliated to the social security system.

• Patient should understand, sign, and date the informed consent form written inFrench prior to any protocol-specific procedures performed.

• Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits, and examinationsincluding follow-up.

Exclusion Criteria:

• Non-squamous NSCLC with targetable tumour mutations and approved first line targetedtherapy (such as EGFR, ALK and ROS1).

• Metastases not eligible to RLT: e.g. brainstem or diffuse serosal metastases (meningeal, pericardial, pleural, peritoneal, mesenteric) or that invades thegastrointestinal tract.

• Brain metastases only, without extra-cerebral metastases.

• Uncontrolled severe comorbidity, symptomatic interstitial lung disease or activeinfection.

• Prior therapy with T-cell costimulation or immune checkpoint-targeted agents within 1 year.

• Uncontrolled concomitant (<1-year) malignancy except adequately treated basal orsquamous cell carcinoma of the skin, or in-situ carcinoma of any organ or in-situmelanoma of the skin.

• Persons deprived of liberty by judicial or administrative decision.

• Persons subject to a legal protection measure (guardianship, curatorship, safeguardof justice).

• Persons not affiliated to a social security system or equivalent.