Trial for Local Ablative Treatment (LAT) Optimization in Patients With Advanced Non-Small Cells Lung Cancer (NSCLC) Presenting an Anaplastic Lymphoma Kinase (ALK) Rearrangement Treated by Brigatinib

Inclusion Criteria:

• Age 18 years or older at diagnosis.

• Stage 3 non eligible for chemoradiotherapy or stage 4 NSCLC, histologically orcytologically confirmed NSCLC.

• Tyrosine Kinase Inhibitor (TKI) treatment naïve.

• ALK rearrangements identified by a validated technique (either Immunohistochimy (IHC), fluorescence in situ hybridization (FISH) or Ribonucleic Acid (RNA)seq, intissue or liquid biopsy)

• Stable disease or response after initiation brigatinib treatment (at least 3 to 9months) according to RECIST 1.1

• At least one site of residual site for LAT (ie. participant should not have acomplete response)

• Oligometastatic disease (five metastatic lesions or less and a maximum of twolesions per organ) de novo or induced

• Eligible for local ablative treatment possible (either alone or combined): surgery,minimally invasive form of surgical radiosurgery (Stereotactic Radio Surgery (SRS)) (18 to 20 Gy in single fraction) or radiotherapy (SBRT) (27 to 54 Gy in 3 fractionsor 45 to 50 Gy in 5 fractions), radiofrequency or cryotherapy (=thermoablation)

• An Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2.

• Life expectancy above 12 weeks as assessed by treating investigator.

• Brain metastases at inclusion are allowed if asymptomatic

• No history of other malignant tumor during the previous 5 years, except foradequately treated carcinomas (in situ cervical carcinoma, basal cell carcinoma,squamous cell skin carcinoma) and low-grade localized prostate cancer (Gleason <6).

• Adequate organ function, as demonstrated by laboratory results prior to the firstadministration of study treatment: normal hepatic function (bilirubin ≤1.5 x upperlimit of normal (ULN), alanine aminotransferase (ALA T) and aspartateaminotransferase (ASAT) ≤2.5 x ULN or ≤5 x ULN in case of liver metastases), renalfunction (calculated creatinine clearance (CrCl, using local formula) above 45ml/mn), normal hematological function (absolute neutrophil count

≥1.5 x 109/L and/or platelets ≥100 x 109/L, hemoglobin ≥8 g/dL), normal coagulationfunction (International Normalized Ratio (INR) or prothrombin time ≤1.5 x ULN andactivated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) ≤1.5 x ULN unless the patient is receiving anticoagulant therapy)

• For patients of childbearing potential: Women of childbearing potential should useeffective non-hormonal contraception during treatment with brigatinib and for atleast 4 months following the final dose. Men with female partners of childbearingpotential should use effective contraception during treatment and for at least 3months after the last dose of brigatinib.

• Signed informed consent to participate in the study

• Affiliation with or benefit from French social security

Exclusion Criteria:

• NSCLC without known ALK rearrangements

• Neuroendocrine tumor (even in case of mixed tumors).

• Uncontrolled and untreated superior cava syndrome.

• Unstable symptomatic brain metastases despite corticosteroid

• Leptomeningeal, pericardial, pleural and mesenteric lesions, lymphangitic spread (any tumoral lesions not amenable to definitive local therapy). Peri tumorallymphangitic spread around a tumor, but limited to a lobe, may be treated bysurgery).

• Serious concurrent conditions during the previous 6 months (severe or unstableangina pectoris, coronary or peripheral artery bypass graft of <6 months, class 3or 4 congestive heart failure, ischemic stroke, grade ≥2 peripheral neuropathy,psychiatric or neurological disorders that may interfere with the patient'sunderstanding of the study or with his/her informed consent.

• Severe or non-controlled systemic diseases deemed incompatible with the protocol.

• Severe infections within 4 weeks prior to inclusion, including, but not limited to,hospitalization for complications of infection, bacteremia, or severe pneumonia.

• Psychological, family, social, or geographical factors that may interfere with themonitoring of the patient as defined by the protocol.

• Any protected person (legal person protected by legal protection [guardianship,tutorship], person deprived of liberty, pregnant woman, breastfeeding woman, andminor).

• Patients who participated in other concomitant studies unless observational andreceived study therapy or used an investigational device within 4 weeks prior tostart of study treatment

• Known allergies or adverse reactions to the study drugs

• Lung function not compatible with surgery or radiation