CABozantinib in Non-Small Cell Lung Cancer (NSCLC) Patients With MET Deregulation

Inclusion Criteria:

1. Citological or histological diagnosis of non-small-cell-lung cancer (NSCLC) stage IIIB (not suitable for local treatments with curative intent) or stage IV.

2. Tissue samples available for MET analysis (archivial tissue or tissue collected atstudy entry); patients without archival tumor tissue or refusing new biopsy at studyentry, are eligible if MET mutation is detected in cf-DNA

3. Presence of MET mutations (exon 14 skipping mutation ONLY) detected in tissue orcf-DNA at the local lab or in the central lab or MET amplification (MET/CEP7 ratio > 2.2) detected in the central lab ONLY.

4. Measurable disease according to RECIST criteria version 1.1

5. At least 1 prior line of standard therapy (chemotherapy and/ or immunotherapy)

6. Performance status 0-1 (ECOG)

7. Age ≥18 years

8. Patients potentially fertile using adequate methods of contraception in order to avoidchildbearing. Contraceptive methods must be respected by male and female patients andtheir partners during study treatment period and at least 4 months after completingtherapy

9. Adequate hematologic and end organ function, defined by the following laboratoryresults obtained within 14 days prior to enrollment:

10. ANC ≥ 1500 cells/μL without granulocyte colony-stimulating factor support

11. Platelet count ≥ 100,000/μL without transfusion

12. Hemoglobin ≥ 9.0 g/dL Patients may be transfused to meet this criterion

13. AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:

• Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN

• Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN.

5. Serum bilirubin ≤ 1.25 × ULN

6. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN maybe enrolled

7. Calculated creatinine clearance (CRCL) ≥ 45 mL/min or calculated CRCL must be ≥ 60 mL/min

8. Patient compliance to the study procedure

9. Written informed consent

Exclusion Criteria:

1. Tissue sample not available in patients without MET exon 14 skipping mutation detectedin cf-DNA

2. No possibility to assess MET status

3. Absence of any measurable disease according to RECIST criteria

4. Co-existence of driver events, including EGFR mutations, KRAS mutations, ALKrearrangements or ROS-1 rearrangements

5. No prior therapy

6. Concomitant chemotherapy or immunotherapy or radiotherapy

7. Symptomatic brain metastasis

8. Uncontrolled significant inter-current or recent illness, including cardio-vasculardisorders and gastro-intestinal disorders

9. Major surgery within 2 months before first dose of study treatment

10. Concomitant anti-coagulation with oral anti-coagulants or plated inhibitors

11. History of significant bleeding, trachea-bronchial tree/major blood vessels invadingtumors, cavity pulmonary lesions and GI disorders associated with a risk ofperforation or fistula formation

12. Diagnosis of another cancer in the last 3 years, except for in situ carcinoma ofcervix, breast and bladder or skin carcinoma (squamous or basalioid)

13. Pregnancy or breastfeeding