A Phase I/II Study of Ibrutinib in Previously Treated Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed stage IV non-small cell lung cancer, or recurrent non-small cell lung cancer which is not amenable to curative intent therapy.
2. Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors(RECIST) 1.1 criteria
3. For EGFR mutant cohort, patients must have: a) Documented EGFR mutation by Clinical Laboratory Improvement Amendments (CLIA)-certified test b) Documented disease progression on treatment with erlotinib, gefitinib, afatinib, or other EGFR-targeted tyrosine kinase inhibitor c) Tissue available from a biopsy or surgical procedure performed after progression on an EGFR targeted tyrosine kinase inhibitor. If tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy.
4. For HER2 mutant cohort, patients must have: a) Documented EGFR mutation by CLIA-certified test b)Documented disease progression on treatment with erlotinib, gefitinib, afatinib, or other EGFR-targeted tyrosine kinase inhibitor c)Tissue available following progression on most recent systemic therapy. If tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy.
5. Age \>/=18 years
6. Eastern Cooperative Oncology Group (ECOG) performance status \</=2
7. Ability to take pills by mouth
8. Patients must have normal organ and marrow function as defined: leukocytes \>/= 3,000/mcL; absolute neutrophil count \>/= 1,500/mcL; hemoglobin \>/= 9 g/dL; total bilirubin \</= 1.5 x institutional upper limit of normal (ULN); AST(SGOT)/ALT(SGPT) \</= 2.5 × ULN or \</= 5 x ULN if metastases to the liver; creatinine clearance \>/= 45 mL/min
9. Patients with asymptomatic brain metastases are allowed, as long as they are stable and do not require treatment with anticonvulsants or escalating doses of steroids. Maximum daily dose of steroids should be prednisone 20 mg or equivalent. Radiation therapy for brain metastases must be completed at least 14 days prior to treatment on protocol
10. The effects of ibrutinib on the developing human fetus are unknown. Women of child-bearing potential and men must agree to use highly effective contraception (if using hormonal birth control must add a second barrier method; abstinence) prior to study entry, for the duration of study participation as well as for at least 1 month after the last dose of ibrutinib. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use highly effective contraception prior to the study, for the duration of study participation and 3 months after completion of ibrutinib administration.
11. Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

1. Patients who have received EGFR tyrosine kinase inhibitors within 72 hours of initiation of study treatment, or treatment with other anti-cancer agents within 21 days of study treatment
2. Prior treatment with ibrutinib
3. Known hypersensitivity to ibrutinib
4. Concurrent use of agents that strongly inhibit or induce CYP3A unless use is approved by the medical monitor
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
6. Pregnant and nursing women
7. Patients with a history of another active malignancy within the past two years, with the exception of non-melanoma cutaneous malignancy, cervical carcinoma in situ, or ductal carcinoma in situ which has been successfully treated with curative intent therapy
8. Any gastrointestinal disorder expected to limit absorption of ibrutinib
9. Treatment with warfarin or other vitamin K antagonist. Patients with using warfarin who switch to another form of anticoagulation will be eligible
10. Patients with persistent and uncontrolled atrial fibrillation.