Erlotinib Hydrochloride and Cabozantinib-s-Malate Alone or in Combination as Second or Third Line Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer

Criteria:

   - Tumor with a sensitizing mutation in epidermal growth factor receptor (EGFR), defined
   as follows:

      - EGFR mutation testing of tumor has been performed and did not demonstrate an EGFR
      tyrosine kinase inhibitor sensitizing mutation; at minimum, testing for EGFR exon
      19 deletion and exon 21 L858R mutations must have been included; OR

      - EGFR mutation testing has been attempted and is inconclusive (for example, due to
      lack of sufficient deoxyribonucleic acid [DNA] yield); OR

      - EGFR mutation status is unknown but tumor is positive for at least one
      alternative driver mutation, i.e: Kirsten rat sarcoma viral oncogene homolog
      (KRAS) mutation, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutation,
      human epidermal growth factor receptor 2 (HER2) mutation, ret proto-oncogene
      (RET) rearrangement/fusion, or one not listed following approval by the study
      chair prior to registration

Inclusion Criteria:

   - INCLUSION CRITERIA STEP 1:

   - Cytologically or histologically confirmed non-small cell lung carcinoma (NSCLC)

   - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS]
   are eligible); mixed tumors will be categorized by the predominant cell type; if small
   cell elements are present the patient is ineligible

   - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th
   edition of the lung cancer TNM classification system

   - Patients must have measurable disease as defined by Response Evaluation Criteria in
   Solid Tumors (RECIST) version (v) 1.1 criteria; baseline measurements and evaluation
   of all sites of disease must be obtained within 4 weeks prior to registration

   - Prior to registration, the investigator/site must confirm that sufficient pathology
   material representative of patient's cancer is available for submission for MET
   immunohistochemical (IHC) testing

   - Patients must have received one or two lines of prior chemotherapy (first line
   platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one
   line of therapy); prior adjuvant chemotherapy for early stage disease does not count
   as one line of therapy if 12 months or greater elapsed between completion of adjuvant
   therapy and initiation of first-line systemic therapy; if less than 12 months elapsed,
   adjuvant chemotherapy counts as one line of therapy

   - Any prior chemotherapy (based on administration schedule) must have been completed in
   greater than or equal to the time frames specified in the protocol

   - Patients must have discontinued treatment with any other type of investigational agent
   >= 4 weeks prior to registration

   - Patients must have recovered to baseline or Common Terminology Criteria for Adverse
   Events (CTCAE) v 4.0 =< grade 1 from toxicity due to all prior therapies except
   alopecia and other non-clinically significant adverse events (AEs)

   - Patients with no known brain metastasis at baseline must have baseline brain imaging
   within 12 weeks prior to study registration not demonstrating brain metastases;
   patients with brain metastases at baseline must have baseline brain imagining within 4
   weeks prior to study registration and meet all of the specific criteria for brain mets
   listed in the protocol

   - Radiation related toxicities must have resolved to =< grade 1 prior to registration

   - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
   between 0-2

   - Patients must have an anticipated life expectancy greater than 3 months

   - Acceptable bone marrow, renal and hepatic function within 2 weeks prior to
   registration as defined in the protocol

   - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF)
   =< 500 ms within 28 days before registration

   - Patients must be able to swallow tablets

   - INCLUSION CRITERIA STEP 2:

   - Patients must have met all eligibility requirements for Step 1 at time of registration
   to Step 1 to be eligible for Step 2

   - Patients must have radiographic progressive disease per RECIST v1.1 criteria after >=
   2 courses of therapy on Arm A or Arm B

   - Patients must be registered to Step 2 within 4 weeks of the last dose of treatment
   administration from Step 1

   - Patients must have an ECOG performance status between 0-2

   - Patients must have recovered to baseline (pre-Step 1) or CTCAE version 4.0 <= grade 1
   from toxicity due to all prior therapies except alopecia and other non-clinically
   significant AEs

Exclusion Criteria:

   - EXCLUSION CRITERIA STEP 1:

   - Patients without sufficient pathology material representative of the patient's cancer
   (tumor block or 10 unstained slides)

   - Prior erlotinib, other EGFR tyrosine kinase inhibitor therapy, vascular endothelial
   growth factor receptor (VEGFR) tyrosine kinase inhibitor therapy, Met tyrosine kinase
   inhibitor therapy, or Met monoclonal antibody (MetMAb); prior antibody therapy such as
   bevacizumab or cetuximab is allowed with a washout period depending on dosing interval
   and investigational nature

   - Prior radiation therapy to the thoracic cavity, abdomen, or pelvis within 3 months
   prior to registration, to bone or brain metastasis within 14 days prior to
   registration, or to any other site within 28 days prior to registration

   - History of the following: Clinically-significant gastrointestinal (GI) bleeding within
   6 months prior to registration; Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood
   within 3 months prior to registration; Any other signs indicative of pulmonary
   hemorrhage within 3 months prior to registration

   - Radiographic or other evidence of the following within 28 days prior to registration:
   • Tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or
   anus), or any evidence of endotracheal or endobronchial tumor; Cavitating pulmonary
   lesion(s); Tumor in contact with, invading or encasing any major blood vessels

   - Psychiatric illness/social situations that would limit compliance with study
   requirements

   - History of major thrombotic events (deep vein thrombosis [DVT] or pulmonary embolism
   [PE]) within 6 months prior to registration

   - Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or
   warfarin-related agents, heparin, low molecular weight heparin (LMWH), thrombin or
   Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). (low dose aspirin
   [=< 81 mg/day] and prophylactic LMWH are permitted)

   - Concomitant treatment of strong cytochrome P450 3A4 (CYP3A4) inducers (e.g.,
   dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
   phenobarbital, and St. John's wort)

   - Cardiovascular disorders including: Congestive heart failure (CHF): New York Heart
   Association (NYHA) class III (moderate) or class IV (severe) at the time of screening;

   - Concurrent uncontrolled hypertension; Any history of congenital long QT syndrome; Any
   of the following within 6 months prior to registration:

      - Unstable angina pectoris

      - Clinically-significant cardiac arrhythmias

      - Stroke (including transient ischemic attack [TIA], or other ischemic event)

      - Myocardial infarction

   - GI disorders particularly those associated with a high risk of perforation or fistula
   formation specified in the protocol

   - Other disorders associated with a high risk of fistula formation including
   percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months prior to
   registration

   - Uncontrolled, significant, intercurrent or recent illness

   - Prior malignancy within 2 years prior to registration which required systemic
   treatment or is currently active

   - Pregnant or breast-feeding

   - Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral
   therapy

   - Known chronic active hepatitis B

   - EXCLUSION CRITERIA (STEP 2):

   - Intervening anticancer treatment or major surgical procedure(s) between Step 1 and
   Step 2, except palliative radiation to the bone finishing >= 2 weeks prior to
   registration to Step 2

   - Central nervous system (CNS) progression; patients with stable CNS disease are allowed

   - Intercurrent illness or disease complication that the investigator believes would
   limit the ability to safely tolerate the combination of erlotinib and cabozantinib