This randomized, placebo-controlled, Phase II trial will compare the combination of erlotinib with pazopanib (providing concurrent EGFR and VEGFR inhibition) with erlotinib alone in the second- or third-line treatment of patients with advanced NSCLC. This study will be conducted though the Sarah Cannon Research Consortium, a community-based clinical trial network.

Erlotinib is the current treatment standard for second- or third-line therapy of advanced NSCLC. Since angiogenesis inhibitors have also shown activity in NSCLC, the simultaneous inhibition of the EGFR and VEGF pathway may improve the efficacy of therapy. In a recently reported Phase III trial (Hainsworth et al. 2008), the combination of bevacizumab and erlotinib improved the Progression- Free-Survival (PFS) vs. erlotinib alone when given as second-line therapy in NSCLC (3.4 months vs. 1.7 months, respectively; HR 0.63). Pazopanib also inhibits the angiogenesis pathway, and may have advantages over bevacizumab including: (1) inhibition of other potentially important targets, including PDGFR; and (2) more convenient oral administration.

Inclusion Criteria:

1. Pathologic confirmation of stage IIIB/IV NSCLC (squamous carcinoma, adenocarcinoma, or large cell carcinoma) per the American Joint Committee on Cancer Cancer Staging Manual, 6th edition. Patients with mixed tumors with small- cell elements are ineligible.

2. 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 computerized tomography scan according to the Response Evaluation Criteria in Solid Tumors version 1.1 (Eisenhauer et al. 2009)

3. Failure of at least 1, and no more than 2, prior chemotherapy regimens for advanced disease (either due to progressive disease or toxicity).

4. Recovery from any toxic effects of prior therapy to ≤ grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

5. Completion of radiation therapy at least 28 days prior to the start of study treatment (not including palliative local radiation). Previously irradiated lesions in the advanced setting cannot be included as target lesions unless clear tumor progression has been observed since the end of radiation.

6. ECOG Performance Status of 0-2.

7. Adequate hematologic, hepatic and renal function.

8. A female is eligible to enter and participate in this study if she is of:

   • non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had hysterectomy, bilateral oophorectomy (ovariectomy), bilateral tubal ligation, is post-menopausal
   • childbearing potential, including any female who has had a negative serum pregnancy test within 1 week prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception.

9. Patients entering the study must be willing to provide a serum sample at baseline and at off-study for disease progression for correlative serum proteomic testing.

10. Willingness to provide a plasma sample at baseline, and at off-study for disease progression for correlative testing of circulating plasma biomarkers.

11. Patients entering this study must be willing to provide tissue from a previous tumor biopsy (if available) for correlative tissue testing.

12. Patients must be able to understand the nature of this study, give written informed consent, and comply with study requirements.

Exclusion Criteria:

1. Past or current history of neoplasm (other than the entry diagnosis), with the exception of treated non-melanoma skin cancer or carcinoma in-situ of the cervix, or other cancers cured by local therapy alone, and a disease-free survival ≥3 years.

2. Prior treatment with EGFR tyrosine kinase inhibitors or vascular endothelial factor receptor tyrosine kinase inhibitors for NSCLC. [Note: prior bevacizumab (Avastin®) use is permitted].

3. Prior use of an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.

4. History of any one or more of the following cardiovascular conditions within the past 6 months:

   • Cardiac angioplasty or stenting
   • Myocardial infarction
   • Unstable angina
   • Coronary artery bypass graft surgery
   • Symptomatic peripheral vascular disease
   • Class III or IV congestive heart failure, as defined by New York Heart Association classification

5. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 1 week prior to first dose of study drug. Screening with CNS imaging (CT or magnetic resonance imaging) is required only if clinically indicated or if the subject has a history of CNS metastases.

6. Women who are pregnant or lactating. All females of childbearing potential must have negative serum or urine pregnancy tests within 7 days prior to study treatment.

7. Poorly controlled hypertension [defined as systolic blood pressure of ≥150 mmHg or diastolic blood pressure of ≥90mmHg].

8. Presence of uncontrolled infection.

9. Prolongation of heart rate-corrected QT interval (QTc) ≥480 msec (using Bazett's formula).

10. Use of any of the medications on the prohibited medication list within 14 days of study treatment (with the exception of Amiodarone, which is prohibited from 6 months prior to screening through discontinuation from the study).

11. A serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.

12. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).

13. Minor surgical procedures (with the exception of the placement of portacath or other central venous access) performed less than 7 days prior to beginning protocol treatment.

14. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism (PE), or untreated DVT within the past 6 months.

15. Previous treatment with cetuximab.

16. Patients with hemoptysis or tumor cavitation at baseline.

17. Any prior history of hypertensive crisis or hypertensive encephalopathy.

18. Pulmonary hemorrhage/bleeding event within 6 weeks prior to beginning study treatment.

19. Any other non-pulmonary hemorrhage/bleeding event ≥ grade 3 within 28 days of study treatment.

20. Evidence or history of bleeding diathesis.

21. Serious non-healing wound, ulcer, or bone fracture.

22. Known or suspected allergy/hypersensitivity to any agent given in the course of this trial.

23. Clinically significant gastrointestinal (GI) abnormalities.