The purpose of this multicenter, Phase II trial is to examine the role of a well-tolerated novel agent, panitumumab, in combination with a modern platinum doublet regimen using carboplatin and pemetrexed, in patients with advanced non-squamous wild type K-ras non-small-cell lung cancer (NSCLC). If this treatment proves to be well tolerated and associated with efficacy, this would provide rationale for further randomized studies.

Inclusion Criteria:

1. Age ≥18 years.

2. Histologically confirmed non-squamous NSCLC (squamous cell histology is ineligible). Cytologic specimens obtained by brushings, washings or needle aspiration of the defined lesion are acceptable. Sputum cytology alone is not acceptable. Mixed tumors with small cell elements are not eligible.

3. Newly diagnosed unresectable stage IIIB or stage IV disease. Patients with stage IIIB disease should be ineligible for combined modality therapy (i.e., pleural effusions, pericardial effusions, etc.).

4. At least one unidimensionally measurable lesion definable by magnetic resonance imaging (MRI) or computed tomography (CT) scan. Measurable disease is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

5. Demonstration of K-ras wild type in archived tumor tissue. Tissue must be available for testing or results from previous K-ras testing must be available at the time of registration.

6. No prior antineoplastic chemotherapy for metastatic lung cancer. Patients may have received adjuvant treatment for stage I, II or III disease.

7. For patients who have had previous radiotherapy as definitive therapy for locally advanced NSCLC, recurrence must be outside of the original radiation therapy port. Radiation therapy must have been completed more than four weeks prior to study entry. Previous radiation must have covered < 30% of marrow bearing area.

8. Full recovery from surgery for patients who have undergone thoracotomy. Patients cannot start protocol treatment until at least three weeks after an operative procedure.

9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

10. Life expectancy ≥ 12 weeks.

11. Normal bone marrow function within 7 days prior to initial treatment as defined by:

    • absolute neutrophil count (ANC) ≥1500/µL
    • platelets ≥100,000/µL
    • hemoglobin ≥8.0 g/dL. Patients may receive transfusions or erythropoietin to maintain or exceed this level.

12. Normal hepatic function as defined by:

    • bilirubin ≤1.5 x institutional upper limit of normal (ULN).
    • transaminases ≤2.5 x institutional ULN. In the presence of known hepatic metastases, transaminases may be ≤5 x institutional ULN.

13. Normal renal function within 7 days prior to initial treatment as defined by:

    • serum creatinine <2.0 mg/dL
    • estimated creatinine clearance (CrCl) ≥ 45 mL/min calculated by the Cockcroft-Gault method.

14. Normal metabolic function as follows:

    • Magnesium ≥ institutional lower limit of normal (LLN)

15. The ability to take folic acid, vitamin B12, and dexamethasone according to the protocol.

16. The ability to interrupt non-steroidal anti-inflammatory drugs (NSAIDs) 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed.

17. Negative serum or urine pregnancy test within 7 days prior to initial study treatment.

18. Agreement of women of child-bearing potential (WOCBP) and men to use adequate contraception (hormonal or barrier method of birth control; abstinence) to prevent contraception during treatment and for a minimum of 6 months after the last study treatment.

19. Willingness and ability to comply with study and follow-up procedures.

20. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

1. NSCLC with squamous cell histology.
2. History of any invasive cancer treated within the previous 5 years with the exception of the disease under study, curatively treated non melanoma skin cancer or carcinoma in situ of the cervix.
3. Prior therapy which specifically and directly targets the EGFR pathway (e.g., cetuximab, gefitinib, erlotinib, lapatinib).
4. Active brain or meningeal metastases. Patients must have completed any previous radiotherapy at least four weeks prior to study entry and recovered from any toxicity associated with radiotherapy. Patients must have no on-going requirement for and must have discontinued corticosteroids.
5. Pregnancy or breast-feeding.
6. A serious active infection at the time of treatment or other serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
7. Acute hepatitis or known human immunodeficiency virus (HIV) infection.
8. Presence of third space fluid which is clinically significant and cannot be controlled by drainage.
9. History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis or any evidence of interstitial lung disease on baseline chest CT scan).
10. History of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with the study participation or investigational product(s) administration or may interfere with the interpretation of the results.
11. Prior severe infusion reaction to a monoclonal antibody or history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study (e.g., carboplatin, pemetrexed).