Feasibility trial of letrozole in combination with bevacizumab in patients with metastatic breast cancer.
OBJECTIVE
Preclinical models suggest that the use of anti-vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor-positive metastatic breast cancer (MBC).


METHODS
Patients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease.


RESULTS
Forty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease >or= 24 weeks was noted in 67%. Median PFS was 17.1 months.


CONCLUSIONS
Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503).
Traina
Tiffany A
TA
Breast Cancer Medicine Service, Departments of Radiology, Biostatistics, and Renal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Rugo
Hope S
HS
Caravelli
James F
JF
Patil
Sujata
S
Yeh
Benjamin
B
Melisko
Michele E
ME
Park
John W
JW
Geneus
Stephanie
S
Paulson
Matthew
M
Grothusen
Jill
J
Seidman
Andrew D
AD
Fornier
Monica
M
Lake
Diana
D
Dang
Chau
C
Robson
Mark
M
Theodoulou
Maria
M
Flombaum
Carlos D
CD
Norton
Larry
L
Hudis
Clifford A
CA
Dickler
Maura N
MN
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077289:Letrozole; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage; D011379:Prognosis; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000556:secondary; D015996:Survival Rate; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009570:Nitriles; D014230:Triazoles; D000068258:Bevacizumab; D000077289:Letrozole