Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Patient must have a pathologically-confirmed diagnosis of non-squamous, non-small
cell lung cancer (NSCLC)

- Patient must have advanced disease, defined as - either stage IV disease, stage IIIB
disease not amenable to definitive multi-modality therapy, or recurrent disease
after a prior diagnosis of stage I-III disease. All staging is via the American
Joint Committee on Cancer (AJCC)/International Association for the Study of Lung
Cancer (IASLC) 8th edition staging criteria

- Patient must have somatic activating sensitizing mutation in EGFR (e.g. but not
limited to Exon 19 deletion, L858R, E709X, G719X, exon 19 insertions, L861Q, S768I).
Patients with non-sensitizing mutations in EGFR (EGFR exon 20 insertions) are not
eligible. Test results originating from a Clinical Laboratory Improvement Act
(CLIA)-certified or similarly accredited laboratory are acceptable; no specific
assay is mandated. Plasma, cytology, or tumor tissue can be utilized for mutation
testing

- Patient must not have received any prior treatment with an anti-VEGF agent

- NOTE: Prior treatment with an EGFR TKI is not allowed, however if a candidate
for this study has already started osimertinib within 21 days prior to
randomization, the exact osimertinib start date is known, and the patient had
the required study baseline imaging completed prior to the osimertinib start
date, the patient will be eligible

- Patients that have received prior radiation therapy are eligible. Radiation (limited
field stereotactic radiation or conventional radiation) must have been completed at
least one week prior to study drug initiation and more extensive field radiation
(i.e., whole-brain radiotherapy [WBRT]) must have been completed at least two weeks
prior to drug initiation

- Patient must not have any risk factors for anti-VEGF administration, specifically,
hemoptysis, active cardiovascular disease, uncontrolled hypertension, significant
proteinuria (screening urinalysis > 300 mg/dl) and tumor invading major blood
vessels

- Patient must have measurable disease. Baseline measurements of sites of disease must
be obtained within 4 weeks prior to study randomization. If a potential target
lesion is previously irradiated without subsequent growth and/or is radiated after
the imaging from which baseline measurements are obtained, they cannot be included
as target lesions, and additional target lesions are required to meet criteria for
measurable disease

- Patient must not have had any prior systemic treatment for metastatic disease

- Patient must be ≥ 18 years of age

- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 2

- Patient must not be pregnant or breast-feeding due to the potential harm to an
unborn fetus and possible risk for adverse events in nursing infants with the
treatment regimens being used

- All females of childbearing potential must have a blood test or urine study within
14 days prior to randomization to rule out pregnancy

- A female of childbearing potential is defined as any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has achieved menarche at some point, 2) has not undergone a
hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential) for
at least 24 consecutive months (i.e., has had menses at any time in the preceding 24
consecutive months)

- Patient of childbearing potential and sexually active males must not expect to
conceive or father children by using accepted and effective method(s) of
contraception or by abstaining from sexual intercourse for 2 weeks prior to the
start of treatment, while on study treatment, and for

- 6 weeks after the last dose of protocol treatment for female patients on the
osimertinib (AZD9291) alone arm

- 4 months after the last dose of protocol treatment for male patients on
osimertinib (AZD9291) alone arm

- 6 months after the last dose of protocol treatment for all patients on
osimertinib (AZD9291) plus bevacizumab combination arm

- NOTE: Female patients should also not breastfeed while on treatment and for 6
months after the last dose bevacizumab

- Leukocytes >= 3,000/mcL (obtained =< 14 days prior to randomization)

- Absolute neutrophil count >= 1,500/mcL (obtained =< 14 days prior to randomization)

- Platelets >= 100,000/mcL (obtained =< 14 days prior to randomization)

- Hemoglobin >= 9 g/dL (obtained =< 14 days prior to randomization)

- Total bilirubin and creatinine =< 1.5 x institutional upper limit of normal (ULN)
(obtained =< 14 days prior to randomization)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
[SGPT]) =< 2.5 x institutional ULN (obtained =< 14 days prior to randomization)

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated

- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load

- Patients with treated brain metastases are eligible if neurologically stable without
glucocorticoid therapy after the stated washout period from radiation therapy (RT)
or surgery provided the metastatic lesions are non-hemorrhagic

- Patients with untreated brain metastases or leptomeningeal disease are eligible if
the treating physician determines that immediate CNS specific treatment is not
required provided the metastatic lesions are non-hemorrhagic and are neurologically
stable without glucocorticoid therapy

- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial

- Patients with known history or current symptoms of cardiac disease, should have a
clinical risk assessment of cardiac function using the New York Heart Association
Functional Classification. To be eligible for this trial, patients should be class
2B or better

- Patient must have the ability to understand and the willingness to sign a written
informed consent document and comply with study requirements

- Patient must not have had treatment with any investigational drug within five
half-lives or 3 months (whichever is greater), prior to study initiation

- Patient must not be currently receiving (or unable to stop use prior to receiving
the first dose of study treatment) medications or herbal supplements known to be
strong inducers of CYP3A4. For any patient currently receiving such inducers of
CYP3A4, they must discontinue use prior to first dose of study treatment. All
patients must try to avoid concomitant use of any medications, herbal supplements
and/or ingestion of foods with known inducer effects on CYP3A4

- Patient must not have any unresolved toxicities from prior therapy greater than
Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of
randomization, with the exception of alopecia and grade 2 prior
platinum-therapy-related neuropathy

- Patient must not have any evidence of severe or uncontrolled systemic diseases,
including uncontrolled hypertension and active bleeding diatheses, which in the
investigator's opinion makes it challenging for the patient to participate in the
study. Screening for chronic conditions is not required

- Patient must not have refractory nausea and vomiting, chronic gastrointestinal
diseases, the inability to swallow the osimertinib tablets or previous significant
bowel resection that would preclude adequate absorption of osimertinib

- Patient must not have a 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

- Patient must not have a history of hypersensitivity to active or inactive excipients
of osimertinib or drugs with a similar chemical structure or class to osimertinib

- Patient must not have mean resting corrected QT interval (QTc) > 470 msec obtained
from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc
value (using Bazett's correction)

- Patient must not have any clinically important abnormalities in rhythm, conduction
or morphology of resting ECG e.g. complete left bundle branch block, third degree
heart block and second-degree heart block

- Patient must not have any factors that increase the risk of QTc prolongation or risk
of arrhythmic events such as heart failure, electrolyte abnormalities (including:
potassium < lower limit of normal [LLN]; magnesium < LLN; calcium < LLN), 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 and cause torsades de pointes