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
- 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 have measurable disease. Baseline measurements of sites of disease must
be obtained within 4 weeks prior to study registration. 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 have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 2
- All females of childbearing potential must have a blood test or urine study within 14
days prior to registration 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 registration)
- Absolute neutrophil count >= 1,500/mcL (obtained =< 14 days prior to registration)
- Platelets >= 100,000/mcL (obtained =< 14 days prior to registration)
- Hemoglobin >= 9 g/dL (obtained =< 14 days prior to registration)
- Total bilirubin and creatinine =< 1.5 x institutional upper limit of normal (ULN)
(obtained =< 14 days prior to registration)
- 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 registration)
- 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
Exclusion Criteria:
- Patient must not have received any prior treatment with an EGFR TKI or with an
anti-VEGF agent
- 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 not have had any prior systemic treatment for metastatic disease
- 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
- 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 registration,
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 Bezet'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
