Osimertinib With or Without Bevacizumab as Initial Treatment for Patients With EGFR-Mutant Lung Cancer

Study Overview
=================
Brief Summary
-----------------
This phase III trial compares the effect of bevacizumab and osimertinib combination vs. osimertinib alone for the treatment of non-small cell lung cancer that has spread outside of the lungs (stage IIIB-IV) and has a change (mutation) in a gene called EGFR. The EGFR protein is involved in cell signaling pathways that control cell division and survival. Sometimes, mutations in the EGFR gene cause EGFR proteins to be made in higher than normal amounts on some types of cancer cells. This causes cancer cells to divide more rapidly. Osimertinib may stop the growth of tumor cells by blocking EGFR that is needed for cell growth in this type of cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with bevacizumab may control cancer for longer and help patients live longer as compared to osimertinib alone.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To evaluate progression-free survival (PFS) of osimertinib (AZD9291) and bevacizumab versus osimertinib (AZD9291) alone as first-line treatment for patients with metastatic EGFR-mutant lung cancers. SECONDARY OBJECTIVES: I. To evaluate overall survival (OS). II. To evaluate best objective response rate and duration of objective response. III. To evaluate time to central nervous system (CNS) progression and CNS PFS. IV. To evaluate toxicity of the combination regimen. CORRELATIVE OBJECTIVES: I. To characterize mechanisms of resistance to osimertinib (AZD9291) and osimertinib (AZD9291) 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. Patients undergo echocardiography (ECHO), multigated acquisition scan (MUGA), computed tomography (CT) and may undergo magnetic resonance imaging (MRI) and blood sample collection on study. After completion of study treatment, patients are followed up every 3 months for 10 years.

Official Title
-----------------
Randomized Phase III Study of Combination Osimertinib (AZD9291) and Bevacizumab Versus Osimertinib (AZD9291) Alone as First-Line Treatment for Patients With Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

Conditions
-----------------
Advanced Lung Non-Squamous Non-Small Cell Carcinoma, Metastatic Lung Non-Squamous Non-Small Cell Carcinoma, Recurrent Lung Non-Squamous Non-Small Cell Carcinoma, Stage IIIB Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8

Intervention / Treatment
-----------------
* Biological: Bevacizumab
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Procedure: Echocardiography
* Procedure: Magnetic Resonance Imaging
* Procedure: Multigated Acquisition Scan
* Drug: Osimertinib


Participation Criteria
=================
Eligibility 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 EGFR TKI or with an anti-VEGF agent 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 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 not have had any prior systemic treatment for metastatic disease 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 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 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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (osimertinib)<br>Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, MUGA, CT and may undergo MRI and blood sample collection on study. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Osimertinib<br>* Given PO<br>* Other names: Mereletinib;|
| Experimental: Arm B (osimertinib, bevacizumab)<br>Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, MUGA, CT and may undergo MRI and blood sample collection on study. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Osimertinib<br>* Given PO<br>* Other names: Mereletinib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. PFS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 2.5%. | From randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first, assessed up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. OS will be tested at the one-sided 10% level. | From randomization to death from any cause, assessed up to 10 years | 
| Best objective response rate | Best objective response will be evaluated via RECIST 1.1 criteria. Will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. | Up to 10 years | 
| Time to central nervous system progression | Will be estimated using competing risks methodology, adjusting for death and progression as competing events. Regular central nervous system imaging will occur when patients are on treatment. After they discontinue study treatment, central nervous system imaging will be symptom-prompted during follow up. | From study randomization to evidence of central nervous system progressive disease, with death and progression as competing events, assessed up to 10 years | 
| Central nervous system progression-free survival | Will be estimated using the Kaplan-Meier method. | From study randomization to evidence of central nervous system progressive disease or death from any cause, whichever occurs first, assessed up to 10 years | 
| Incidence of adverse events | Toxicity will be determined using the Common Terminology Criteria for Adverse Events (CTCAE). Will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. | Up to 30 days after the last administration of investigational agent |