Osimertinib With or Without Bevacizumab in Treating Patients With EGFR Positive Non-small Cell Lung Cancer and Brain Metastases

Inclusion Criteria:

Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
No prior treatment with an EGFR TKI; patient may have received prior chemotherapy for early-stage or advanced disease but this is not required; prior immunotherapy is not allowed
Patients must have at least one measurable CNS lesion that is asymptomatic, untreated, and does not require local therapy at the time of enrollment; measurable CNS disease is defined as a brain metastasis that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain magnetic resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history of previously treated brain metastases is allowed, however any lesion present at the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is new or documented to have progressed unequivocally since treatment
Patients are not required to have measurable systemic (i.e. non-CNS) disease; if present, measurable systemic disease must be able to be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, MRI, or calipers by clinical exam
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Life expectancy of greater than 3 months
The use of anti-convulsants is allowed, as long as the patient is on a stable dose with no seizure activity for at least 2 weeks prior to initiating trial therapy

Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child- bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for the institution
Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
Fertile men should be willing to use barrier contraception during and for 4 months after AZD9291 (osimertinib), and fertile women must agree to use adequate contraceptive measures during and for 6 weeks after AZD9291 (osimertinib); fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

Symptomatic brain metastases or symptomatic leptomeningeal disease; asymptomatic leptomeningeal disease is allowed
Patients with brain metastases for whom complete surgical resection is clinically appropriate
Prior treatment with any EGFR TKI
Prior treatment with agents targeting the VEGF pathway, including bevacizumab
The use of corticosteroids to control cerebral edema or treat neurologic symptoms will not be allowed, and patients who previously required corticosteroids for symptom control must be off steroids for at least 3 days without recurrence of symptoms prior to starting trial therapy; corticosteroids for other indications is allowed
Patients may not be receiving any other investigational agents and may not have participated in a study of an investigational agent or using an investigational device within five half-lives of the compound or 3 months, whichever is greater
Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia and grade 2 platinum-therapy related neuropathy
Concurrent, active malignancies in addition to that being studied (other than cutaneous squamous cell carcinoma or basal cell carcinoma)
Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted medical devices)
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD9291 (osimertinib) or bevacizumab
Urine protein should be screened by urine analysis; if protein is 2+ or higher, 24-hour urine protein should be obtained; patients with 24-hour urine protein >= 1000 mg are excluded
Serious or non-healing wound, ulcer or bone fracture
History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1

Invasive procedures defined as follows:

Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to day 1 therapy
Anticipation of need for major surgical procedures during the course of the study
Core biopsy within 7 days prior to day 1 (D1) therapy
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1

Patients with clinically significant cardiovascular disease are excluded

Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] > 160 mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive medication)
History of cerebrovascular accident (CVA) within 6 months (see additional requirement for adjuvant protocols)
Myocardial infarction or unstable angina within 6 months (see additional requirement for adjuvant protocols)
New York Heart Association grade II or greater congestive heart failure
Serious and inadequately controlled cardiac arrhythmia
Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)
Clinically significant peripheral vascular disease

Any of the following cardiac criteria:

Mean resting corrected QT interval (Fridericia's correction formula [QTcF]) > 470 ms obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived corrected QT (QTc) value
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block)
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval
Evidence of bleeding diathesis or coagulopathy (including clinically significant hemoptysis)
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9291 (osimertinib)
Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
Any evidence of severe or uncontrolled systemic diseases, including, but not limited to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV); screening for chronic conditions is not required
History of hypersensitivity active or inactive excipients of AZD9291 (osimertinib) or drugs with a similar chemical structure or class to AZD9291 (osimertinib)
Absolute neutrophil count < 1.5 x 10^9/L
Platelet count < 100 x 10^9/L
Hemoglobin < 90 g/L
Alanine aminotransferase > 2.5 times upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases; aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases
Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases
Serum creatinine > 1.5 times ULN concurrent with creatinine clearance < 50 mL/min (measured or calculated by Cockcroft and Gault equation)-confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN
Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements