I. To determine the progression-free survival with osimertinib plus bevacizumab compared to osimertinib alone.
I. To assess the safety and tolerability of the combination of osimertinib and bevacizumab.
II. To evaluate the time to progression in the central nervous system (CNS) with osimertinib plus bevacizumab versus single-agent osimertinib.
III. To determine the overall response rate and the intracranial response rate to the combination versus single agent.
IV. To assess the overall survival in patients receiving osimertinib plus bevacizumab compared to osimertinib alone.
I. To investigate mechanisms of sensitivity and resistance to combination osimertinib plus bevacizumab versus osimertinib by molecularly characterizing tumor samples including T790M status.
II. To assess whether circulating tumor deoxyribonucleic acid (DNA) in plasma can be used as an indicator of sensitivity and resistance to treatment.
III. To determine whether an angiogenic signature using a multiplex panel array is associated with benefit from the combination of osimertinib plus bevacizumab.
IV. To investigate angiogenesis, immune and signaling pathway markers in tumor samples to determine biomarkers predictive of benefit from combination therapy.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive osimertinib orally (PO) once daily (QD) on days 1-12 and bevacizumab intravenously (IV) over 30-90 minutes on day 1.
ARM II: Patients receive osimertinib PO QD on days 1-12.
In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for a minimum of 4 weeks.
- Biopsy proven 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); plasma testing for EGFR is a suitable alternative to tissue testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory; AND
- The presence of an EGFR T790M mutation from biopsy from any site of disease (intra- or extra-cranial) after progression on a first- or second-generation EGFR TKI; plasma testing for EGFR T790M is a suitable alternative to tissue testing if performed in a CLIA-certified laboratory; for patients who have disease progression in the CNS only (with otherwise stable disease systemically), T790M positivity is not required
- Patients must have measurable disease, defined as one or more of the following:
- At least one systemic (i.e. non-CNS) lesion that can 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, magnetic resonance imaging (MRI), or calipers by clinical exam; and/or
- At least one brain lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain 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
- Disease progression on a first- or second-generation EGFR TKI (i.e. erlotinib, gefitinib, or afatinib); patient may have also received prior chemotherapy or immunotherapy but this is not required
- The presence of at least one untreated cerebral metastasis that is at least 5 mm but less than 20 mm, that is asymptomatic, and does not require local therapy at the time of enrollment; 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
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Life expectancy of greater than 3 months
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 75,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal if no demonstrable liver metastases or =< 3 x institutional upper limit of normal in the presence of liver metastases or Gilbert's syndrome (unconjugated hyperbilirubinemia)
- Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal if no demonstrable liver metastases or =< 5 x institutional upper limit of normal in the presence of liver metastases
- Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- The use of anti-convulsants in 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
- 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
- Symptomatic brain metastases
- Patients with brain metastases for whom complete surgical resection is clinically appropriate
- Prior treatment with a third-generation EGFR TKI (i.e. rociletinib)
- 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
- Presence of leptomeningeal disease
- 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 2 weeks of the first dose of treatment
- Treatment with an EGFR TKI (i.e. erlotinib, gefitinib or afatinib) within 8 days or approximately 5 x half-life, whichever is longer, of the first dose of study treatment
- 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)
- History of clinically significant interstitial lung disease (ILD) (including drug-induced ILD), radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to 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 using Fredericia's formula
- Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block)
- Any factors that increase the risk of corrected QT (QTc) prolongation or risk of arrhythmic events
- Evidence of bleeding diathesis or coagulopathy (including clinically significant hemoptysis)
- 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 inhibitors of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior)
- 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
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy
|Maximum Eligible Age:||N/A|
|Minimum Eligible Age:||18 Years|