Phase I/II study of sorafenib with anastrozole in patients with hormone receptor positive aromatase inhibitor resistant metastatic breast cancer.
We evaluated the use of sorafenib to overcome resistance to aromatase inhibitors (AIs) in patients with metastatic breast cancer who had disease recurrence or progression while on AIs. We performed a multi-institution phase I/II study of sorafenib and anastrozole 1 mg daily in 35 postmenopausal females with hormone receptor positive metastatic breast cancer resistant to AIs. Primary objectives were to determine the dose of sorafenib in conjunction with anastrozole and the clinical benefit rate (CBR) (complete response [CR], partial response [PR], or stable disease [SD] ≥ 24 weeks). Secondary objectives were to determine toxicity and to evaluate if response was associated with change in number of circulating endothelial cells or circulating endothelial progenitor cells. Based on the phase I portion, sorafenib 400 mg twice daily was selected as the phase II dose. Among 35 patients, 7 had SD ≥ 24 weeks, 1 had PR ≥ 24 weeks, and 14 had progressive disease (PD) ≤ 24 weeks, corresponding to a CBR of 23%. The most common adverse events (all; Grade 3/4) were fatigue (66%; 17%), diarrhea (63%; 6%), nausea (60%; 9%), and hand-foot syndrome (57%; 34%). Dose reduction occurred in 77% of the patients and 31% came off study due to toxicity. The combination of sorafenib and anastrozole demonstrated a 23% CBR in patients with hormone receptor positive, AI-resistant metastatic breast cancer, which may be attributable to the restoration of sensitivity to AIs. Toxicities occurred frequently resulting in a high rate of discontinuation.
Isaacs
Claudine
C
Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, Washington, DC 20057, USA. isaacsc@georgetown.edu
Herbolsheimer
Pia
P
Liu
Minetta C
MC
Wilkinson
Mary
M
Ottaviano
Yvonne
Y
Chung
Gina G
GG
Warren
Robert
R
Eng-Wong
Jennifer
J
Cohen
Philip
P
Smith
Karen L
KL
Creswell
Karen
K
Novielli
Antonella
A
Slack
Rebecca
R
D000328:Adult; D000368:Aged; D000077384:Anastrozole; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D001557:Benzenesulfonates / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D009570:Nitriles / Q000008:administration & dosage; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis*; D000077157:Sorafenib; D013234:Stem Cells / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage; D014481:United States
D047072:Aromatase Inhibitors; D001557:Benzenesulfonates; D009570:Nitriles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D009536:Niacinamide; D000077384:Anastrozole; D000077157:Sorafenib