Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer.
OBJECTIVE
Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine.


METHODS
Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease.


RESULTS
Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions.


CONCLUSIONS
This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
Lin
Nancy U
NU
Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Diéras
Véronique
V
Paul
Devchand
D
Lossignol
Dominique
D
Christodoulou
Christos
C
Stemmler
Hans-Joachim
HJ
Roché
Henri
H
Liu
Minetta C
MC
Greil
Richard
R
Ciruelos
Eva
E
Loibl
Sibylle
S
Gori
Stefania
S
Wardley
Andrew
A
Yardley
Denise
D
Brufsky
Adam
A
Blum
Joanne L
JL
Rubin
Stephen D
SD
Dharan
Bernie
B
Steplewski
Klaudia
K
Zembryki
Denise
D
Oliva
Cristina
C
Roychowdhury
Debasish
D
Paoletti
Paolo
P
Winer
Eric P
EP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human