Annual Meeting Proceedings Part 1 - American Society of Clinical ...

46s Breast Cancer—HER2/ER
TPS659 General Poster Session (Board #16F), Sat, 8:00 AM-12:00 PM
WJOG6110B (ELTOP): Randomized phase II trial comparing trastuzumab
plus capecitabine (HX) and lapatinib plus capecitabine (LX) in HER2positive
metastatic breast cancer patients previously treated with trastuzumab
and taxanes. Presenting Author: Toshimi Takano, Toranomon
Hospital, Tokyo, Japan
Background: In patients with HER2-positive metastatic breast cancer
(MBC) previously treated with trastuzumab and taxanes, there are now two
standard strategies: trastuzumab beyond progression or switch to lapatinib.
A randomized trial comparing trastuzumab plus capecitabine (HX) and
capecitabine alone (X) after first-line trastuzumab-based chemotherapy
(GBG-26) showed that HX was superior to X in terms of time to progression
(TTP). Another randomized trial comparing lapatinib plus capecitabine
(LX) and X in patients previously treated with anthracyclines, taxanes, and
trastuzumab (EGF100151) showed that LX was superior to X in terms of
TTP. To evaluate which strategy is better, we are conducting an open-label,
randomized phase II trial comparing HX and LX. Methods: Primary endpoint
is progression-free survival, and secondary endpoints are overall response
rate, overall survival, proportion of patients progressing brain metastases as
site of first progression, and safety. Major eligibility criteria include: (1)
HER2-positive MBC, (2) previously treated with taxanes, (3) disease
progression or distant relapse while receiving trastuzumab, (4) previously
untreated with capecitabine, S-1, and anti-HER2 drugs other than trastuzumab,
(5) previously treated with no more than two chemotherapy
regimens for MBC, (6) no symptomatic brain metastases (asymptomatic
brain metastases are allowed), and (7) baseline left ventricular ejection
fraction �50%. Patients in the HX arm receive capecitabine 2,500
mg/m2 /day on days 1 to 14 plus trastuzumab (8 mg/kg loading dose and
6mg/kg thereafter) on day 1 every 3 weeks. Patients in the LX arm receive
capecitabine 2,000 mg/m2 /day on days 1 to 14 plus lapatinib 1250
mg/day on days 1 to 21 every 3weeks. Large-scale biomarker analyses are
also performed to explore predictive factors of trastuzumab or lapatinib
efficacy. We are investigating biomarkers related to HER family and other
receptors, PI3K/Akt pathways, ligands, Fc�R, circulating tumor cells, and
so on. This study has just begun and 7 of planned 170 patients have been
enrolled.
TPS661 General Poster Session (Board #16H), Sat, 8:00 AM-12:00 PM
ALTERNATIVE (EGF114299): A study of lapatinib, trastuzumab, and
endocrine therapy in patients who received neo-/adjuvant trastuzumab (IV)
and endocrine therapy. Presenting Author: William Gradishar, Northwestern
University, Chicago, IL
Background: Approximately 50% of human epidermal growth factor receptor
2 positive (HER2�) breast cancers are also hormone receptor-positive
(HR�). For patients with HER2�/HR� disease, combining the aromatase
inhibitor (AI) letrozole with the dual tyrosine kinase inhibitor lapatinib (L)
has been shown to improve outcomes vs letrozole alone. Similar results
were found for the combination of trastuzumab (T; a humanized monoclonal
antibody targeting HER2) and anastrozole vs anastrozole alone. Finally,
the combination of L and T has been shown to improve outcomes vs L alone.
Methods: This phase III, randomized, open-label, multicenter trial (ALTER-
NATIVE) will enroll postmenopausal female patients with HER2�/HR�
metastatic breast cancer (MBC) who have not received prior treatment for
MBC, have received neo/adjuvant T and endocrine therapy, and are not
candidates for chemotherapy. Patients will be randomized 1:1:1 to 1 of 3
treatment arms: L plus T plus an AI; T plus an AI; or L plus an AI. The AI can
be letrozole, anastrozole, or exemestane, to be selected by the investigator.
The primary objective of ALTERNATIVE is to examine the efficacy of L/T/AI
compared with T/AI alone. The primary efficacy endpoint is overall survival
(OS; time from randomization until death due to any cause) for L/T/AI vs
T/AI. Secondary efficacy objectives include: comparisons of OS between
T/AI and L/AI as well as between T/L/AI and L/AI, comparisons of
progression-free survival, overall response rate, time to response, duration
of response, safety, and tolerability for all 3 treatment groups. The study is
powered to detect a 42% reduction in risk of death (hazard ratio�0.70) in
patients who receive L/T/AI (median 28.5 months) vs T/AI (median 20
months) using a 1-sided test for superiority with ��0.025. The required
number of total events to achieve a power of 80% is 249. Secondary
comparisons are not powered and will be based on the ITT population. This
study is currently recruiting, with a target of 525 patients. If its objectives
are reached, it will provide a valuable, chemotherapy-free treatment option
for HER2�/HR� MBC patients. Clinical trial registry number:
NCT01160211.
TPS660 General Poster Session (Board #16G), Sat, 8:00 AM-12:00 PM
The PERSEPHONE trial: Duration of trastuzumab with chemotherapy in
women with HER2-positive early breast cancer. Presenting Author: Helena
Margaret Earl, Department of Oncology, University of Cambridge, and
NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
Background: Persephone is a phase III randomised controlled trial comparing
six months of trastuzumab to the standard 12 month duration in
patients with HER2 positive early breast cancer in respect of disease free
survival, safety and cost-effectiveness. A Persephone sister study, the
PHARE trial run by the National Institute for Cancer, successfully closed to
recruitment in 2010. A prospective meta-analysis is planned once each
trial has reported individually. Methods: A total of 4000 patients will be
randomised into each of the two treatment groups. The power calculations
assume that the disease-free survival (DFS) of the standard treatment of 12
months trastuzumab will be 80% at 4 years. On this basis, with 5% 1-sided
significance and 85% power, a trial randomising 2000 in each arm will
have the ability to prove non-inferiority of the experimental arm defining
non-inferiority as ‘no worse than 3%’ below the control arm 4 year DFS.
Primary outcome is disease-free survival non-inferiority (equivalence) of 6
months trastuzumab compared with 12 months in women with early breast
cancer. Secondary outcomes are overall survival non-inferiority (equivalence);
expected incremental cost effectiveness; cardiology function and
analysis of predictive factors for development of cardiac damage. Two
mandatory sub-studies are: Tumour block collection to discover molecular
predictors of survival with respect to duration of trastuzumab treatment and
blood sample collection, used to discover single nucleotide polymorphisms
(SNPs) as genetic/pharmaco-genetic determinants of prognosis, toxicity
and treatment outcome. A third optional sub-study is the quality of life
questionnaires. Results: Persephone opened to recruitment in October
2007. To date, 1847 patients (46%) of its total have been randomised
from 147 UK sites. Recruitment is due to complete by December 2013 and
the first planned interim analysis of the primary outcome will be mid-2016.
The IDSMC last reviewed the trial in June 2011 and congratulated the Trial
Management Group on the conduct of the trial and the quality of the data.
No safety concerns were identified, and the IDSMC proposed that the trial
continue to planned recruitment.
TPS662 General Poster Session (Board #17A), Sat, 8:00 AM-12:00 PM
HIT: A multicenter phase I-II study of trastuzumab administered by
intrathecal injection for leptomeningeal meningitis of HER2� metastatic
breast cancer. Presenting Author: Maya Gutierrez, Hôpital René Huguenin/
Institut Curie, Saint-Cloud, France
Background: Leptomeningeal metastases (LM) are commonly associated
with breast cancer (BC), announcing short term prognosis that intrathecal
(IT) chemotherapy poorly modifies. Incidence is particularly marked in
HER2� tumours. With the better control of extra-cerebral disease and
prolonged survival yielded by intra-venous (IV) trastuzumab (T), the main
hypothesis is that intra-cerebral recurrences are not reached by this high
molecular weight (148 kD) monoclonal antibody. Analyses performed in
cerebrospinal fluid (CSF) following IV T have shown low T levels, suggesting
that LM of HER2� BC would remain potentially sensitive to anti-HER2
agents as long as they could by-pass the meningeal blood brain barrier.
Intraventricular (via Ommaya port) or IT administration of T would allow
keeping control on LM progression through high T therapeutic concentrations
in CSF. This prospective trial is the first phase I-II study sponsored by
Institut Curie to investigate the safety and efficacy of the IT administration
of T for HER2� LM BC. Methods: Eligible patients must be 18�, have a
diagnosis of LM either on CSF with HER2� cytology or on clinical/MRI
pictures of meningitis, and normal end-organ functions. The phase I cohort
investigates the maximum tolerated dose (MTD) and recommended dose of
T given weekly IT (or via Ommaya port) � hemisuccinate hydrocortisone 25
mg, while aiming at yielding a T target-concentration in CSF close to the
plasma one (30 �g/mL) obtained with standard IV schedule. The MTD is
defined as the highest dose level (DL) tested with �2 dose-limiting toxicity
(DLT, any grade �3 NCI CTCAE v4.0 attributed to T) observed in �6
patients (3�3 Fibonacci dose escalation design, 4 DL 30-150 mg) with a
maximum of 24 patients. The phase II cohort will investigate the efficacy of
the recommended dose (DLMTD-1) defined in cohort I on neurological
progression-free survival at 2 months, in �19 patients. Secondary endpoints
include CSF and MRI response, quality of life, FCGR3A influence,
and comparative CSF/plasma pharmacokinetics. Since study activation in
May 2011, 5 patients have been included at DL1, 3 being evaluable for
DLT. DL2 is now open for accrual.
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