Bevacizumab plus ipilimumab in patients with metastatic melanoma.

Abstract

Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.

• Authors: F Stephen Hodi, Donald Lawrence, Cecilia Lezcano, Xinqi Wu, Jun Zhou, Tetsuro Sasada, Wanyong Zeng, Anita Giobbie-Hurder, Michael B Atkins, Nageatte Ibrahim, Philip Friedlander, Keith T Flaherty, George F Murphy, Scott Rodig, Elsa F Velazquez, Martin C Mihm Jr, Sara Russell, Pamela J DiPiro, Jeffrey T Yap, Nikhil Ramaiya, Annick D Van den Abbeele, Maria Gargano, David McDermott
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 2 Issue 7 Pg. 632-42 (Jul 2014) ISSN: 2326-6074 [Electronic] United States
• PMID: 24838938 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibodies, Neoplasm
• Ipilimumab
• Bevacizumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Antibodies, Neoplasm (biosynthesis)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Bevacizumab
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Ipilimumab
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Male
• Melanoma (blood supply, drug therapy, immunology, pathology, secondary)
• Middle Aged
• Neoplasm Staging
• Neovascularization, Pathologic (immunology, prevention & control)
• Treatment Outcome