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J Natl Cancer Inst. 2019 Oct 25. pii: djz211. doi: 10.1093/jnci/djz211. [Epub ahead of print]

A Systematic Review and Meta-analysis of Bevacizumab in First-line Metastatic Breast Cancer: Lessons for the Research and Regulatory Enterprises.

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Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Harvard Center for Bioethics, Harvard Medical School, Boston, MA.
Department of Oncology, Department of Public Health Sciences, and Division of Cancer Care and Epidemiology, Queen's University, Kingston, Ontario, Canada.
Harvard Medical School, Boston, MA.



The FDA's accelerated approval and later withdrawal for bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for ongoing debates about the validity of using progression-free survival (PFS) as a surrogate measure for overall survival (OS) in cancer drug approvals. We systematically reviewed and meta-analyzed the evidence around bevacizumab's regulatory approval and withdrawal in mBC.


We searched for all published phase 2 or 3 clinical trials testing bevacizumab in first-line mBC. Data was extracted on trial demographics, interventions, and outcomes. Descriptive analysis was stratified by whether the trial was initiated prior to, during, or after the accelerated approval. We used a cumulative random effects meta-analysis to assess the evolution of evidence of the effect of bevacizumab on PFS and OS. We estimated the association between the trial-level PFS and OS effect using a non-linear mixed regression model.


Fifty-two studies were included. Trial activity dramatically dropped after the accelerated approval was withdrawn. Eight clinical trials reported hazard ratios (HRs) and were meta-analyzed. The cumulative HR for PFS was 0.72 (95%CI 0.65-0.79), and the cumulative HR for OS was 0.90 (95%CI 0.80-1.01). The regression model showed a statistically non-significant association between PFS benefit and OS benefit (β = 0.43, SE = 0.81).


The FDA's decision-making in this case was consistent with the evolving state of evidence. However, the fact that 7 clinical trials is insufficient to conclude validity (or lack thereof) for a trial-level surrogate suggests that it would be more efficient to conduct trials using the more clinically meaningful endpoints.


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