This phase II trial studies how well ponatinib hydrochloride works in treating patients with stage III-IV lung cancer. Ponatinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

This study will look at the safety and effectiveness of the investigational drug ponatinib in lung cancer. The investigators hope that ponatinib will work against tumors that have certain biomarkers. Therefore, the study will pre-screen patients for these certain biomarkers before enrolling them into the main treatment study. Different doses of ponatinib may be tested in this study.

Inclusion Criteria:

• PART A: Patients must have histologically or cytologically confirmed locally advanced (after failure of local therapy) or metastatic lung cancer (any histology, except carcinoid) stage IIIa, IIIb or IV
• PART A: Existing formalin fixed paraffin embedded biopsy of the lung cancer with potentially sufficient material for analysis
• PART A: Non-small cell lung cancer (NSCLC) with adenocarcinoma histology must have been previously tested for both epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements
• PART A: Able (physically and financially) to travel to University of Colorado for clinical trial treatment
• PART B: Patients must have histologically or cytologically confirmed locally advanced (after failure of local therapy) or metastatic lung cancer (any histology, except carcinoid) stage IIIa, IIIb or IV
• PART B: Patients must be proven to meet marker criteria (FGFR1 silver in situ hybridization (SISH) + in situ hybridization (ISH) +, FGFR1 SISH+ ISH negative [-ve], FGFR1 SISH-ve ISH+, FGFR1 SISH-ve ISH-ve [FGFR1 double negative cohort] or ret proto-oncogene [RET] FISH+) prior to enrollment into Part B (treatment); adenocarcinoma patients must be known to not possess either an EGFR mutation or an ALK rearrangement in their tumor (if positive for one, testing for both is not required)
• PART B: Patients must have measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• PART B: Patients may have received any number of lines of prior therapy
• PART B: Life expectancy of >= 3 months
• PART B: Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• PART B: Leukocytes >= 3,000/mcL
• PART B: Absolute neutrophil count >= 1,500/mcL
• PART B: Hemoglobin >= 9 g/dL
• PART B: Platelets >= 100,000/mcL
• PART B: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), unless due to Gilbert's syndrome
• PART B: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
• PART B: Creatinine =< 1.5 X ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• PART B: Serum lipase =< 1.5 X ULN
• PART B: Serum amylase =< 1.5 X ULN
• PART B: Previous treatment related side-effects/adverse events must have resolved to at least grade 1 or, at the discretion of the investigator, select stable grade 2 toxicities (e.g. alopecia or fatigue) may be permissible if unchanging in grade for at least 3 months following discussion with the principal investigator (PI)
• PART B: Patients with central nervous system (CNS) metastases are eligible for enrollment if they have no overt evidence of neurological deficits, and are not requiring anti-epileptics or steroids to control their neurological symptoms; patients with known CNS metastases must have relevant CNS imaging performed approximately coincident with body imaging during response assessments
• PART B: The effects of ponatinib on the developing human fetus are unknown; for this reason women of child-bearing potential must have a negative urine or blood pregnancy test at screening for Part B; women of child-bearing potential and men must also have documented agreement to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of screening until 30 days after the end of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, they should inform the treating physician immediately
• PART B: Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• PART A: Known EGFR mutation and/or ALK rearrangement in NSCLC with adenocarcinoma histology

• PART B: No previous treatment with a standard or investigational anti-cancer agent within predicted 5 half-lives of the agent; or 28 days whichever is the shorter; if the plasma half-life is not known or the previous therapy was a monoclonal antibody then a 28 day washout period will be considered as the default requirement

• PART B: No previous or current exposure to other FGFR inhibitors in the FGFR-selected cohorts, or RET inhibitors in the RET selected cohorts

• PART B: Prior radiotherapy to proposed target lesions is not permitted unless completed more than 4 weeks prior to treatment within the study and that there has been documented progression at these sites; radiotherapy to non-target lesions is permitted within 2 weeks of study entry provided all acute effects of the radiotherapy have resolved to =< grade 1

• PART B: History of allergic or severe reactions attributed to compounds of similar chemical or biologic composition to ponatinib

• PART B: Ponatinib is a substrate for cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5), concurrent use with potent CYP3A4/5 inhibitors or inducers should be undertaken with caution

• PART B: History of clinically significant bleeding disorder

• PART B: History of acute pancreatitis within 1 year of study or history of chronic pancreatitis

• PART B: Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

• PART B: Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection requiring intravenous antibiotics
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Congestive heart failure, unstable angina pectoris, or myocardial infarction within the 3 months prior to enrollment in part B of the study
  • History of clinically significant (as determined by the treating medical doctor [MD]) cardiac arrhythmia (atrial or ventricular)

• PART B: Patients who have had major surgery within 28 days prior to entering the study or those who have not recovered from adverse events > grade 1 relating to the surgery

• PART B: Pregnant or breastfeeding women

• PART B: Patients with inability to take oral medications, or, in the investigator's opinion, gastrointestinal conditions or abnormalities likely to influence the absorption of oral medications

• PART B: Concomitant use of medications known to be associated with torsades-de-pointes