A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses.
OBJECTIVE
Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported.


METHODS
Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and trastuzumab-containing regimens were randomized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m(2) days 1-14 of a 21-day cycle or capecitabine 2,500 mg/m(2) on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were assessed.


RESULTS
399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43-0.77; P < 0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55-1.12, P = 0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P = 0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib.


CONCLUSIONS
The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer progressing after treatment with anthracycline-, taxane-, and trastuzumab-based therapy. Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.
Cameron
David
D
University of Leeds, Leeds, England, UK. d.cameron@ncrn.org.uk
Casey
Michelle
M
Press
Michael
M
Lindquist
Deborah
D
Pienkowski
Tadeusz
T
Romieu
C Gilles
CG
Chan
Stephen
S
Jagiello-Gruszfeld
Agnieszka
A
Kaufman
Bella
B
Crown
John
J
Chan
Arlene
A
Campone
Mario
M
Viens
Patrice
P
Davidson
Neville
N
Gorbounova
Vera
V
Raats
Johannes Isaac
JI
Skarlos
Dimosthenis
D
Newstat
Beth
B
Roychowdhury
Debasish
D
Paoletti
Paolo
P
Oliva
Cristina
C
Rubin
Stephen
S
Stein
Steven
S
Geyer
Charles E
CE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000008:administration & dosage*; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D011799:Quinazolines; D000077341:Lapatinib; D003841:Deoxycytidine; D000069287:Capecitabine; D011505:Protein-Tyrosine Kinases; D000068878:Trastuzumab; D005472:Fluorouracil