Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer.
OBJECTIVE
One third of women with advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2-positive brain metastases.


METHODS
Patients had HER-2-positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity.


RESULTS
Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%).


CONCLUSIONS
The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2-positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.
Lin
Nancy U
NU
Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
Carey
Lisa A
LA
Liu
Minetta C
MC
Younger
Jerry
J
Come
Steven E
SE
Ewend
Matthew
M
Harris
Gordon J
GJ
Bullitt
Elizabeth
E
Van den Abbeele
Annick D
AD
Henson
John W
JW
Li
Xiaochun
X
Gelman
Rebecca
R
Burstein
Harold J
HJ
Kasparian
Elizabeth
E
Kirsch
David G
DG
Crawford
Ann
A
Hochberg
Fred
F
Winer
Eric P
EP
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases