Open-label, Multicenter, Randomized Phase II Trial of Treatment With Cisplatin and Pemetrexed or Cisplatin and Oral Vinorelbine in Chemotherapy Naïve Patients Affected by Stage IIIB-IV Non-Squamous Non-Small Cell Lung Cancer With High Thymidylate Synthase Expression

Inclusion Criteria: 1. Patients must have histologically or cytologically Non-squamous NSCLC, (including those with a non-specified tumor type). 2. Metastatic (stage IV, both M1A or M1B) or locally advanced (stage IIIB, with metastasis to supraclavicular nodes) according to TNM VII edition. 3. TS nuclear H-score ≥ 70 or with TS nuclear and cytoplasmatic H-score ≥ 210. 4. Patients at first diagnosis or those with disease recurrence after former surgery are eligible. 5. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan. See section 9.2 and Appendix E for the evaluation of measurable disease. 6. At least one target or non-target lesion not previously irradiated according to RECIST version 1.1 7. Male or Female, aged ≥18 years. 8. Life expectancy greater than 3 months. 9. ECOG performance status ≤2 (see Appendix C). 10. Patients must have normal organ and marrow function as defined below: * leukocytes ≥3,000/µL * absolute neutrophil count ≥1,000µL * platelets ≥100,000/µL * total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) ≤2.5 X institutional upper limit of normal * creatinine within normal institutional limits OR * creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal 11. Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the study and for 3 months thereafter 12. Participant is willing and able to give informed consent for participation in the study. Exclusion Criteria: 1. Prior chemotherapy or therapy with systemic anti-neoplastic therapy for advanced disease. 2. Prior surgery and/or localised irradiation is permitted if delivered outside to the target lesion. 3. Prior adjuvant chemotherapy is permitted if it did not contain vinorelbine and pemetrexed and if administered at least 6 months prior entering the study. 4. Participation in another clinical trial with any investigational agents within 30 days prior to study screening. 5. Patients with symptomatic brain metastasis or spinal cord compression that has not yet been treated with surgery and/or radiation. Patients with CNS metastases or spinal cord compression previously treated with surgery and/or radiation are eligible if they are asymptomatic and do not require escalating high dose steroids (anti-seizure medications are allowed) 6. History of allergic reactions attributed to compounds of similar chemical or biologic composition to pemetrexed, vinorelbine, cisplatin, carboplatin or other agents used in the study. 7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 8. Other known malignant neoplastic diseases in the patient's medical history with a disease-free interval of less than 5 years (except for previously treated basal cell carcinoma and in situ carcinoma of the uterine cervix or surgically resected prostate cancer with normal PSA); 9. NSCLC with EGFR mutation (or not able to use EGFR inhibitor) or with anaplastic lymphoma kinase (ALK) gene translocation (such as EML4-ALK). 10. Has a known allergy, hypersensitivity, or contraindication to cisplatin, pemetrexed, or vinorelbine or any components used in their preparation or has a contraindication specified in section 7.