Dataset Information

Optimizing the treatment of bevacizumab as first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer: an updated meta-analysis of published randomized trials.

ABSTRACT:

Background

Manifold data have demonstrated that the addition of bevacizumab to chemotherapy improved progression-free survival (PFS), while few trials have revealed its significant overall survival (OS) benefit. Furthermore, it still remains suspended how to maximize the benefits of bevacizumab as first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer. We sought to conduct a meta-analysis to assess the benefits of bevacizumab with chemotherapy and to identify the ideal chemotherapy partner of bevacizumab in the first-line setting for HER2-negative advanced breast cancer patients.

Methods

Computerized and manual searches were performed to identify randomized clinical trials evaluating the efficacy of bevacizumab plus chemotherapy versus chemotherapy alone or bevacizumab with different chemotherapy regimens as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer patients. Risk ratios or odds ratios with their 95% CIs were used to estimate the association between multiple combinations of bevacizumab with chemotherapy and various clinical outcomes.

Results

With 7 trials identified, this analysis included 3,984 eligible patients. The addition of bevacizumab to chemotherapy resulted in a statistically significant improvement in PFS (P=0.019) and objective response rate (ORR; P<0.001) rather than in OS (P=0.783) when compared with chemotherapy alone. The greater benefits in PFS and ORR were achieved from bevacizumab plus taxane-based regimens compared with bevacizumab plus capecitabine-based regimens, while bevacizumab plus capecitabine had comparable OS with bevacizumab plus paclitaxel. Additionally, bevacizumab-based triplet therapy failed to improve the clinical outcomes when compared with doublet therapy.

Conclusion

This meta-analysis reveals that the addition of bevacizumab to chemotherapy yielded PFS and ORR benefits in HER2-negative advanced breast cancer. Additional studies are still prompted to further optimize the first-line treatment of bevacizumab.

SUBMITTER: Li C

PROVIDER: S-EPMC5499926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. METHODS:Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10?mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4?weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as "non-progressors" if they had clinical benefit (SD/PR/CR) at 4?months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. RESULTS:Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11?months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4?months in triple-negatives; P?=?0.11). Clinical benefit rate at 2 and 4?months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P?=?0.73). Non-progressors' tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased TREG signatures in gene expression studies in baseline-post-bevacizumab-tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating TREGs in non-progressors. CONCLUSIONS:This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. TRIAL REGISTRATION:(www.clinicaltrials.gov): NCT02802098 . Registered on June 16, 2020.