This phase III trial compares the effect of bevacizumab and AZD9291 (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.
Name: Bevacizumab
Name: Osimertinib
Description: 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%.
Measure: Progression-free survival (PFS) Time: 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 yearsDescription: 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.
Measure: Overall survival (OS) Time: From randomization to death from any cause, assessed up to 10 yearsDescription: 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.
Measure: Overall response rate Time: Up to 10 yearsDescription: Time to CNS progression will be estimated using competing risks methodology, adjusting for death and progression as competing events. Regular CNS imaging will occur when patients are on treatment. After they discontinue study treatment, CNS imaging will be symptom-prompted during follow up. Will be analyzed using Wilcoxon rank sum test, and multivariable linear regression models may be used to adjust for multiple associations with outcome.
Measure: Time to central nervous system (CNS) metastases Time: Up to 10 yearsDescription: 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.
Measure: Incidence of adverse events Time: Up to 30 days after the last administration of investigational agentDescription: Preliminary analyses of these data will utilize tests for association comparing the frequency of a particular genomic aberration at baseline and at progression (for example, using McNemar's test) and association between alterations and baseline characteristics (for example, using Fisher's exact test). More sophisticated analyses may include multivariable logistic regression modeling and/or competing risks analysis.
Measure: Mechanisms of resistance to AZD9291 (osimertinib) and AZD9291 (osimertinib) with bevacizumab first-line therapy through post-progression circulating tumor-derived deoxyribonucleic acid (ctDNA) Time: Up to 10 yearsDescription: Will assess ctDNA clearance on study treatment and associate ctDNA clearance with clinical outcomes. Cox regression analysis will be used to assess whether EGFR ctDNA clearance is an independent predictor for PFS (and OS), adjusted by treatment effect, the presence of brain metastasis (yes versus [vs.] no), EGFR exon 19 deletion/L858R vs other, Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2) and other possible clinical and biological risk factors.
Measure: ctDNA clearance on study treatment Time: Up to 10 yearsAllocation: Randomized
Parallel Assignment
There are 3 SNPs
Cox regression analysis will be used to assess whether EGFR ctDNA clearance is an independent predictor for PFS (and OS), adjusted by treatment effect, the presence of brain metastasis (yes versus [vs.] no), EGFR exon 19 deletion/L858R vs other, Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2) and other possible clinical and biological risk factors.. 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. --- L858R ---
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). --- L858R ---
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). --- L858R --- --- L861Q ---
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). --- L858R --- --- L861Q --- --- S768I ---