Evaluation of lapatinib and topotecan combination therapy: tissue culture, murine xenograft, and phase I clinical trial data.
OBJECTIVE
Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial.


METHODS
The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2+ BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial.


RESULTS
Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2+ BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21 or 28 days with 3.2 mg/m2 topotecan i.v. on days 1, 8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization.


CONCLUSIONS
The lapatinib/topotecan combination is well tolerated and warrants further study.
Molina
Julian R
JR
Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. molina.julian@mayo.edu
Kaufmann
Scott H
SH
Reid
Joel M
JM
Rubin
Stephen D
SD
Gálvez-Peralta
Marina
M
Friedman
Robert
R
Flatten
Karen S
KS
Koch
Kevin M
KM
Gilmer
Tona M
TM
Mullin
Robert J
RJ
Jewell
Roxanne C
RC
Felten
Sara J
SJ
Mandrekar
Sumithra
S
Adjei
Alex A
AA
Erlichman
Charles
C
D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D000077341:Lapatinib; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D011799:Quinazolines; D000077341:Lapatinib; D019772:Topotecan