The purpose of this study is to assess if the combination of erlotinib and chemotherapy (docetaxel in case of squamous cell NSCLC or pemetrexed in case of other histological types) is superior to erlotinib alone and has acceptable tolerability and safety in the 2nd line treatment of patients with advanced/metastatic non-small cell lung cancer (NSCLC).

Open randomized multicenter phase II study in patients in need of 2nd line treatment for advanced/metastatic NSCLC. Efficacy and safety of monotherapy with erlotinib will be compared with combination therapy of erlotinib and chemotherapy. In recent studies it was established that pemetrexed activity is more pronounced in non-squamous NSCLC in comparison to squamous cell carcinoma. Therefore in patients with non-squamous carcinoma pemetrexed will be used. As in second line treatment of NSCLC docetaxel is registered also for usage in patients with squamous cell carcinoma, docetaxel will be used in patients with squamous histology.

Chemotherapy will be limited to 4 courses. Erlotinib will be continued until disease progression or unacceptable toxicity.

Erlotinib as monotherapy will be administered continuously. In combination with chemotherapy, erlotinib will be given from day 2-16 of every course of 3 weeks.

Inclusion Criteria:

1. Histologically or cytologically confirmed NSCLC, locally advanced and metastatic disease stage IIIB and IV. Evidence of disease progression after one or two cytotoxic treatment regimens which should have included a platinum agent.

2. Complete recovery from prior chemotherapy side effects to < Grade 2.

3. At least one unidimensional measurable lesion meeting RECIST criteria.

4. ECOG PS 0-2.

5. Age > 18 years.

6. Adequate organ function, including:

   • Adequate bone marrow reserve: ANC > 1.5 x 109/L, platelets > 100 x 109/L.
   • Hepatic: bilirubin <1.5 x ULN, AP, ALT, AST < 1.5 x ULN AP, ALT, and AST <5 x ULN is acceptable if the liver has tumor involvement
   • Renal: calculated creatinin clearance > 40 ml/min based on the Cockcroft-Gault formula.

7. Estimated life expectancy >12 weeks.

8. Male and female patients with reproductive potential must use an approved contraceptive method, if appropriate. Female patients with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

9. Signed informed consent.

10. Patient compliance and geographical proximity that allow adequate follow up.

Exclusion Criteria:

1. Pregnant or lactating women.
2. Patients with medical risks because of non-malignant disease as well as those with active uncontrolled infection.
3. Documented brain metastases unless the patient has completed local therapy for central nervous system metastases and has been off corticosteroids for at least two weeks before enrollment.
4. Previous treatment with an EGFR-TKI, or in non-squamous histology earlier treatment with pemetrexed and in squamous earlier treatment with docetaxel.
5. Inability to interrupt aspirin or other non-steroidal anti-inflammatory agents for a 5-day period (5 day period for long-acting agents such as piroxicam).
6. Inability or unwillingness to take folic acid, vitamin B-12 supplementation or dexamethasone.
7. Concomitant treatment with any other experimental drug under investigation.