Bevacizumab plus ipilimumab in patients with metastatic melanoma.
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' Affiliations: Departments of Medical Oncology, Stephen_Hodi@dfci.harvard.edu.
F Stephen
FS
Hodi
Massachusetts General Hospital Cancer Center; Departments of.
Donald
D
Lawrence
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
Cecilia
C
Lezcano
Authors' Affiliations: Departments of Medical Oncology.
Xinqi
X
Wu
Authors' Affiliations: Departments of Medical Oncology.
Jun
J
Zhou
Authors' Affiliations: Departments of Medical Oncology.
Tetsuro
T
Sasada
Authors' Affiliations: Departments of Medical Oncology.
Wanyong
W
Zeng
Biostatistics, and.
Anita
A
Giobbie-Hurder
Lombardi Cancer Center Georgetown University, Washington, District of Columbia; and.
Michael B
MB
Atkins
Authors' Affiliations: Departments of Medical Oncology.
Nageatte
N
Ibrahim
Mount Sinai Medical Center, New York, New York.
Philip
P
Friedlander
Massachusetts General Hospital Cancer Center; Departments of.
Keith T
KT
Flaherty
Pathology and.
George F
GF
Murphy
Pathology and.
Scott
S
Rodig
Tufts University; Miraca Life Sciences, Newton, Massachusetts;
Elsa F
EF
Velazquez
Pathology and.
Martin C
MC
Mihm
Surgery, Brigham and Women's Hospital;
Sara
S
Russell
Imaging, Dana-Farber Cancer Institute;
Pamela J
PJ
DiPiro
Imaging, Dana-Farber Cancer Institute;
Jeffrey T
JT
Yap
Imaging, Dana-Farber Cancer Institute;
Nikhil
N
Ramaiya
Imaging, Dana-Farber Cancer Institute;
Annick D
AD
Van den Abbeele
Authors' Affiliations: Departments of Medical Oncology.
Maria
M
Gargano
Beth Israel-Deaconess Medical Center, Boston;
David
D
McDermott
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000074324:Ipilimumab; D000068258:Bevacizumab