Cabozantinib-S-Malate and Erlotinib Hydrochloride in Treating Patients With Previously Treated Metastatic Non-Small Cell Lung Cancer

The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment

Prior treatment with XL184 (cabozantinib) or other MET/hepatocyte growth factor (HGF) inhibitor

The subject has received radiation therapy:

* To the thoracic cavity, abdomen, or pelvis within 2 weeks before the first dose of study treatment, or has ongoing complications, or is without complete recovery and healing from prior radiation therapy

* To bone or brain metastasis within 14 days before the first dose of study treatment

* To any other site(s) within 28 days before the first dose of study treatment

The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment; prior erlotinib is required and does not require a 14-day wash out

The subject has received any other type of investigational agent within 28 days before the first dose of study treatment

The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =\< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)

The subject has a primary brain tumor

The subject has active brain metastases or epidural disease; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility

The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test \>= 1.3 x the laboratory ULN within 14 days before the first dose of study treatment

The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=\< 81 mg/day), low-dose warfarin (=\< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted

Strong cytochrome P450 (CYP)3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

The subject has experienced any of the following:

* Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment

* Hemoptysis of \>= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment

* Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment

Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder or coagulopathy

The subject has radiographic evidence of cavitating pulmonary lesion(s)

The subject has tumor in contact with, invading or encasing any major blood vessels

The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib

The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

* 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 defined as sustained blood pressure (BP) \> 140 mm Hg systolic, or \> 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment

* Any history of congenital long QT syndrome

* Any of the following within 6 months before the first dose of study treatment:

* Unstable angina pectoris

* Clinically-significant cardiac arrhythmias

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

* Myocardial infarction

* Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

* Any of the following within 28 days before the first dose of study treatment

* Intra-abdominal tumor/metastases invading GI mucosa

* Active peptic ulcer disease

* Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis

* Malabsorption syndrome

* Any of the following within 6 months before the first dose of study treatment:

* Abdominal fistula

* Gastrointestinal perforation

* Bowel obstruction or gastric outlet obstruction

* Intra-abdominal abscess; note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment

* Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy

* Other clinically significant disorders such as:

* Active infection requiring systemic treatment within 28 days before the first dose of study treatment

* Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment

* History of organ transplant

* Concurrent uncompensated hypothyroidism or thyroid dysfunction within 14 days before the first dose of study treatment

* History of major surgery as follows:

* Major surgery within 8 weeks of the first dose of cabozantinib, with complete wound healing; (patients with ongoing wound healing or other complications will be excluded)

* Minor surgery within 4 weeks of the first dose of cabozantinib; Pleurx catheter placement within 7 days of the first dose of cabozantinib

The subject is unable to swallow tablets

The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms within 28 days before treatment; note: if initial QTcF is found to be \> 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =\< 500 ms, the subject meets eligibility in this regard

The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment

History of allergic reactions attributed to compounds of similar chemical or biologic composition to XL184 (cabozantinib) or erlotinib

Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with XL184 (cabozantinib); these potential risks may also apply to other agents used in this study

Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

What this study is about