PRIMARY OBJECTIVE:
I. To evaluate progression-free survival (PFS) of AZD9291 (osimertinib) and bevacizumab
versus AZD9291 (osimertinib) alone as first-line treatment for patients with metastatic
EGFR-mutant lung cancers.
SECONDARY OBJECTIVES:
I. To evaluate overall survival (OS). II. To evaluate overall response rate. III. To evaluate
time to central nervous system (CNS) progression. IV. To evaluate safety/toxicity of the
combination regimen.
CORRELATIVE OBJECTIVES:
I. To characterize mechanisms of resistance to AZD9291 (osimertinib) and AZD9291
(osimertinib) with bevacizumab first-line therapy through post-progression circulating
tumor-derived deoxyribonucleic acid (ctDNA).
II. To assess for ctDNA clearance on study treatment and associate ctDNA clearance with
clinical outcomes.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive osimertinib orally (PO) once daily (QD) on days 1-21. Cycles repeat
every 21 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive osimertinib PO QD on days 1-21 and bevacizumab intravenously (IV)
over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 10 years.
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, G709X, 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. If there is any question as to whether an EGFR mutation is sensitizing,
please contact the primary study team
- Patients that have received prior radiation therapy are eligible. Radiation
(whole-brain radiotherapy [WBRT] or stereotactic radiation) must have been completed
at least two weeks prior to study registration
- 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)
- Women 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
AZD9291 (osimertinib) alone arm
- 4 months after the last dose of protocol treatment for male patients on AZD9291
(osimertinib) alone arm
- 6 months after the last dose of protocol treatment for all patients on AZD9291
(osimertinib) plus bevacizumab combination arm
- 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, or history of
treatment with cardiotoxic agents, 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
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 urine dipstick > 3+) and tumor invading major blood vessels
- Women 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
