The goal of this clinical trial is to learn if the treatment by systemic Brigatinib (ALUNBRIG®) associated to local ablative therapy (LAT) treatment is improved if administered when the brigatinib works best in participants presenting an advanced non-small cells lung cancer with an ALK gene anomaly (this anomaly produces a defective protein that is responsible for the multiplication of cancer cells).

This clinical trial is expected to involve 45 participants in several sites in France.

Advanced non-small cell lung cancer (NSCLC) participants with ALK rearrangements treated with brigatinib in first line of non-curable setting will be screened.

If the disease assessment done between 3 to 9 months after initiation of brigatinib shows:

• a tumor response or stabilization (according to RECIST 1.1)
• a disease which meets the definition of an oligometastatic disease (five metastatic lesions or less and a maximum of two lesions per organ)
• all tumor targets are accessible to a local ablative therapy (confirmed by an expert panel of clinicians before inclusion): surgery, stereotactic radiosurgery (SRS). For liver, adrenal, or other metastases, percutaneous thermal ablation will be accepted.

Participants will be asked to visit the clinic:

• for eligibility criteria assessment prior to LAT
• for LAT
• every 8 weeks for checkups and tests the first year after LAT
• and then every 12 weeks, for a maximum period of 3 years.

Eligible patients will benefit from local ablative therapy with continuation of brigatinib.

Inclusion Criteria:

• Age 18 years or older at diagnosis.

• Stage 3 non eligible for chemoradiotherapy or stage 4 NSCLC, histologically or cytologically 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, in tissue or liquid biopsy)

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

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

• Oligometastatic disease (five metastatic lesions or less and a maximum of two lesions 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 fractions or 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 for adequately 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 first administration of study treatment: normal hepatic function (bilirubin ≤1.5 x upper limit of normal (ULN), alanine aminotransferase (ALA T) and aspartate aminotransferase (ASAT) ≤2.5 x ULN or ≤5 x ULN in case of liver metastases), renal function (calculated creatinine clearance (CrCl, using local formula) above 45 ml/mn), normal hematological function (absolute neutrophil count

  ≥1.5 x 109/L and/or platelets ≥100 x 109/L, hemoglobin ≥8 g/dL), normal coagulation function (International Normalized Ratio (INR) or prothrombin time ≤1.5 x ULN and activated 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 use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose. Men with female partners of childbearing potential should use effective contraception during treatment and for at least 3 months 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 tumoral lymphangitic spread around a tumor, but limited to a lobe, may be treated by surgery).
• Serious concurrent conditions during the previous 6 months (severe or unstable angina pectoris, coronary or peripheral artery bypass graft of <6 months, class 3 or 4 congestive heart failure, ischemic stroke, grade ≥2 peripheral neuropathy, psychiatric or neurological disorders that may interfere with the patient's understanding 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 the monitoring 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, and minor).
• Patients who participated in other concomitant studies unless observational and received study therapy or used an investigational device within 4 weeks prior to start of study treatment
• Known allergies or adverse reactions to the study drugs
• Lung function not compatible with surgery or radiation