Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria:

Provide signed and dated informed consent prior to study-specific screening procedures
Male or female at least 18 years of age
Histologically or cytologically confirmed inoperable locally advanced or metastatic (stage IVA/IVB) NSCLC
Documented KRAS mutation positive status (per Lung Cancer Mutation Consortium [LCMC] guidelines; see www.golcmc.com)
At least one prior chemotherapy regimen for advanced NSCLC
Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
Male or female subjects of child-producing potential must agree to use double barrier contraception, oral contraceptives or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment
Females of childbearing potential must have a negative serum pregnancy test
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with metastatic liver disease
Total bilirubin ≤ 1.5 × ULN
Serum creatinine ≤ 1.5 × ULN
Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
Platelets ≥ 100 x 10^9/L
Hemoglobin ≥ 10 g/dL (transfusion is allowed at least 7 days prior to randomization)
Subjects must agree to allow testing for c-Met status if archival and/or fresh tissue biopsy samples are available.

Exclusion Criteria:

Previous receipt of erlotinib or other epidermal growth factor receptor (EGFR) inhibitors
Previous receipt of any c-MET inhibitor (a receptor tyrosine kinase) or other c-MET-targeted therapy, including ARQ 197, MetMab, crizotinib
Prior receipt of chemotherapy agent selected for administration in this study (e.g., if subject was treated with gemcitabine, he is not eligible to receive gemcitabine in this study but eligible to receive pemetrexed or docetaxel).
Inability or unwillingness to receive ARQ 197, erlotinib, docetaxel, gemcitabine, and/or pemetrexed including contraindications, hypersensitivity, or prior administration
Receipt of any anti-tumor treatment for NSCLC within 3 weeks (2 weeks for radiotherapy) prior to randomization
Pregnant or breastfeeding
Significant gastrointestinal disorder that could, in the opinion of the Investigator, interfere with the absorption of ARQ 197 and/or erlotinib
Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation
Other malignancies within the last three years, with the exception of adequately treated intraepithelial carcinoma of the cervix uteri, prostate carcinoma with a prostate-specific antigen (PSA) value < 0.2 ng/mL or basal or squamous cell carcinoma of the skin
Known human immunodeficiency virus (HIV), or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
Major surgical procedure within 4 weeks prior to randomization
History of cardiac disease: Congestive heart failure defined as Class II to IV per New York Heart Association classification; Active coronary artery disease; Previously diagnosed bradycardia or other cardiac arrhythmia defined as ≥ Grade 2 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension; Myocardial infarction that occurred within 6 months prior to study entry (myocardial infarction that occurred > 6 months prior to study entry is permitted)
Clinically unstable central nervous system metastasis (to be enrolled in the study, subjects must have confirmation of stable disease by MRI or CT scan within 4 weeks of randomization and have central nervous system [CNS] metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications)
Known EGFR-mutation positive status