
    low recruitement rate
  
['carcinoma, non-small-cell lung', 'secondary', 'advanced stage iiib', 'high thymidylate synthase expression']
['oral vinorelbine', 'cisplatin', 'maintenance with metronomic oral vinorelbine', 'pemetrexed', 'cisplatin', 'maintenance with pemetrexed']

        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.
      