The purpose of this multi-center Phase II trial is to examine the impact of pemetrexed/carboplatin in the preoperative treatment of patients with select stage IB, II,and III non-squamous NSCLC. Because patients with non-squamous type NSCLC have been shown to have better survival rates than patients with squamous tumors when given pemetrexed with a platinum agent, only patients with non-squamous NSCLC (adenocarcinoma, large cell, and undifferentiated), not including squamous histology, will be allowed to participate in this study. If this novel regimen proves to be safe and active in this setting, it will provide rationale for further investigation in a larger, prospective, randomized trial.

Inclusion Criteria:

1. Histologically-confirmed NSCLC (adenocarcinoma, large cell, and undifferentiated). Patients with squamous histology are not eligible.

2. Life expectancy of at least 12 weeks.

3. Patients with the following stages of NSCLC:

   • T2 N0 tumors: Limited to tumors >=4 cm.
   • T1-2 N1 tumors.
   • T3 N0-1 tumors (excluding superior sulcus tumors): Including tumors involving the chest wall, proximal airway, or mediastinal pleura where preoperative radiotherapy is not planned.
   • T1-2 N2 tumors: For patients with N2 disease involving one zone (Upper zone (R), AP zone (L), subcarinal zone, or lower zone) and nodes <=2cm in diameter.
   • T4 N0-1 tumors (excluding superior sulcus tumors): T4 lesions other than malignant effusions where radiotherapy is not planned.

4. Patients with clinical N2 involvement must have histologic confirmation by mediastinoscopy (or alternate biopsy procedure).

5. Tumors should be considered potentially resectable.

6. No evidence of extrathoracic metastatic disease.

7. Patients must have measurable disease by RECIST criteria.

8. Patients must be candidates (medically) for chemotherapy followed by surgical resection.

9. Adequate recovery from recent surgery. At least 1 week must have elapsed from the time of a minor surgery; at least 3 weeks must have elapsed from the time of a major surgery.

10. Laboratory values as follows:

    • Absolute neutrophil count (ANC) >=1500/μL
    • Hemoglobin (Hgb) >=10 g/dL
    • Platelets >=100,000/uL
    • AST/SGOT and ALT/SGPT within normal limits (WNL)
    • Total bilirubin within normal limits (WNL)
    • Calculated creatinine clearance >=45 mL/min

11. ECOG Performance Status grade 0 or 1.

12. The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Alimta.

13. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.

14. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately.

15. Patient must be accessible for treatment and follow-up.

16. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry.

Exclusion Criteria:

1. Patients with the following stages are excluded:

   • T1 N0;
   • T2 N0, with primary tumor <4 cm;
   • T1-2 N2, with multiple zones of N2 involvement;
   • T3-4 N2;
   • Any N3;
   • Any TxNxM1 disease; or
   • Any stage where surgery and/or chemoradiotherapy is the preferred initial approach in management, as deemed by the treating physician.

2. Squamous or predominant squamous mixed histologies.

3. Mixed small-cell and non-small cell histologies.

4. Pulmonary carcinoid tumors.

5. Presence of third space fluid which cannot be controlled by drainage.

6. Use of erythropoietin as a hematopoietic growth factor is not allowed.

7. Cardiac disease, including: congestive heart failure (CHF) > Class II per New York Heart Association (NYHA) classification; unstable angina (anginal symptoms at rest) or new-onset angina (i.e., began within the last 3 months), or myocardial infarction within the past 6 months; symptomatic CHF, unstable angina pectoris, cardiac arrhythmia, or cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

8. Women who are pregnant (positive pregnancy test) or lactating.

9. Use of any non-approved or investigational agent within 30 days of administration of the first dose of study drug.

10. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

11. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.

12. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.

13. History of hypersensitivity to active or inactive excipients of any component of treatment.

14. Inability to comply with study and/or follow-up procedures.