Phase II Study With Cabozantinib in Patients With RET Positive NSCLC

Inclusion Criteria:

1. Locally advanced, relapsed or metastatic non-small cell lung cancer - stage IIIB/IVaccording to 7th International Association for the Study of Lung Cancer (IASLC)classification

2. Ability to understand and willingness to sign informed consent prior to initiation ofany study procedures.

3. Pathologically (histology or cytology) confirmed diagnosis of non- small cell lungcarcinoma.

4. RET gene rearrangement by local laboratory analysis with an approved standard method (FISH or Next Generation Sequencing Panel). An archival tumor sample must be availablefor central laboratory confirmation.

5. Male or female and = 18 years of age

6. Life expectancy = 12 weeks

7. Have progressed after or during at least one standard anticancer treatment

8. Have measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1); clear radiological evidence of disease progression after first-linetherapy must be documented; no previous radiotherapy on the only site of measurable orevaluable disease, unless that site had subsequent evidence of progression

9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1

10. Subjects must have adequate organ function including the following:

• Absolute neutrophil count > 1.5 x 10^9/L

• Platelet count > 100 x 10^9/L

• Haemoglobin > 90 g/L

• ALT < 2.5 times the upper limit of normal (ULN)

• AST < 2.5 times ULN

• Total bilirubin <1.5 times ULN

• Creatinine <1.5 times ULN concurrent with creatinine clearance > 50 ml/min (measured or calculated by Cockcroft and Gault equation, confirmation ofcreatinine clearance is only required when creatinine is > 1.5 times ULN)

• Lipase < 2.0 times the upper limit of normal (ULN)

11. Stable medical condition, including the absence of acute exacerbations of chronicillnesses, serious infections, or major surgery within 4 weeks before registration,and otherwise noted in other inclusion/exclusion criteria

12. Recovered (i.e., = Grade 1 toxicity) from effects of prior anticancer therapy, exceptalopecia

13. No radiologic or clinical evidence of acute or chronic pancreatitis

14. For Females: must be postmenopausal (defined as amenhorrea = 12 consecutive months)before the screening visit, or are surgically sterile. If they are of childbearingpotential, a negative serum pregnancy test obtained within 3 days before startingstudy treatment has to be documented; furthermore, patients must agree to adopt 2effective methods of contraception, at the same time, from the time of signing theinformed consent form (ICF) through 4 months after the last dose of study drug.

15. For Males: even if surgically sterilized (i.e. post-vasectomy status) agree topractice effective barrier contraception during the entire study treatment period andthrough 4 months after the last dose of study drug.

16. Ability to comply with protocol requirement.

Exclusion criteria:

1. Radiation therapy for bone metastasis within 2 weeks, any other external radiationtherapy within 4 weeks before randomization. Systemic treatment with radionuclideswithin 6 weeks before randomization. Subjects with clinically relevant ongoingcomplications from prior radiation therapy are not eligible.

2. Previous treatment with cabozantinib.

3. Gastrointestinal disorders likely to interfere with absorption of the study drug.

4. Subjects with gastrointestinal disorders associated with a high risk of perforation offistula formation.

5. Subjects with active peptic ulcer or with a history of clinically ¿significant GIbleeding within 6 months before the first dose of study treatment.

6. Patients requiring full-dose anticoagulation therapy any time prior to enrollment.

7. Current use of aspirin, clopidogrel, ticlopidine.

8. Patients with tumors invading major pulmonary vessels and/or with cavitating pulmonarylesions.

9. Major surgery within the last four weeks. Complete wound healing from major surgerymust have occurred 1 month before randomization and from minor surgery at least 10days before randomization. Subjects with clinically relevant ongoing complicationsfrom prior surgery are not eligible.

10. Subjects with clinical or radiological signs of pulmonary hemorrhage within 3 monthsbefore the first dose of study treatment.

11. Symptomatic CNS or leptomeningeal lesions, not previously treated with radiotherapy. Untreated central nervous system (CNS) or leptomeningeal metastases are allowed ifasymptomatic. Patients with symptomatic CNS or leptomeningeal lesions will be allowedto participate in this study if previously treated with radiotherapy and on stabledose of corticosteroids and/or anticonvulsants for > 10 days or not requiring suchmedication. Radiotherapy must have been completed a minimum of 4 weeks prior to registration, andpatients must have recovered from AEs related to radiotherapy to < grade 1 (exceptalopecia).

12. History of congenital platelet function defect.

13. Patient unable to swallow tablets

14. Corrected QT interval greater than 500 ms (Fridericia formula)

15. Clinically significant, uncontrolled heart diseases:

• Unstable angina within 6 months prior to screening

• Myocardial infarction within 6 months prior to screening

• History of documented congestive heart failure

• Uncontrolled hypertension defined by a Systolic Blood Pressure , with or withoutantihypertensive medication. Initiation or adjustment of antihypertensivemedication(s) is allowed prior to screening

• Ventricular arrhythmias, Supraventricular and nodal arrhythmias not controlledwith medication

• Congenital history of QT syndrome.

16. Diagnosed with or treated for another malignancy within 3 years before the first doseof study drug, or previously diagnosed with another malignancy and have any evidenceof residual disease. Patients with non-melanoma skin cancer or carcinoma in situ ofany type may be enrolled in the study if they have undergone complete resection and noevidence of active disease is present.

17. Any type of systemic anticancer agent within 3 weeks of first dose of study treatment,or within 5 half- lives of the agent whichever is shorter (subjects on LHRH or GnRHagonists may be maintained on these agents)

18. Any serious and/or unstable pre-existing medical, psychiatric, or other conditionsthat could interfere with subject's safety, provision of informed consent, orcompliance to study procedures.

19. Rare hereditary problems of