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

TPS655 General Poster Session (Board #16B), Sat, 8:00 AM-12:00 PM
Docetaxel, carboplatin, trastuzumab, and bevacizumab (TCH�B) for earlystage
HER2/neu(�) breast cancer and bone marrow micrometastases.
Presenting Author: Joseph Baar, Seidman Cancer Center, Cleveland, OH
Background: Bone marrow (BM) micrometastases confer a poor prognosis to
early-stage breast cancer (BC) and HER-2/neu(�) BC is a high-risk
phenotype. We have shown that BM-associated stromal cells support the
survival of metastatic BC in microenvironmental niches and this activity is
dependent on VEGF and CXCL-12. Therefore, the growth of nascent tumor
cell clusters in BM might be impeded by disrupting stromal cells or their
activating ligands, such as VEGF. There is also a positive association
between HER-2/neu and VEGF expression in BC, thereby implicating VEGF
in the aggressive phenotype of HER-2/neu overexpression. These observations
support the use of combination therapies directed against both
HER-2/neu and VEGF for the treatment of HER-2/neu(�) BC. We therefore
hypothesize that an anti-VEGF agent (bevacizumab) given with docetaxel,
carboplatin and trastuzumab (TCH) will eradicate the BM of HER-2/neu(�)
BC micrometastases by disrupting stromal cell support within the micrometastatic
BM niche. Methods: Subjects with AJCC Stage I-III HER2/
neu(�) BC will undergo a single iliac-crest BM aspirate and biopsy. If the
BM is positive for CK� micrometastases, up to 17 patients will receive
TCH�B therapy (docetaxel at 75 mg/m2 IV and carboplatin at AUC 6 IV
given every 3 weeks for 6 cycles; trastuzumab at 4 mg/kg IV loading dose,
then 2mg/kg IV every week; bevacizumab at 15 mg/kg IV every 3 weeks).
Four weeks after the 6th cycle of therapy, a repeat BM aspiration and biopsy
will be performed to score for response of BC micrometastases to therapy.
Patients with a complete clinical response in BM will continue with
trastuzumab every 3 weeks at 6 mg/kg to a total of 1 year. Patients with
persistent micrometastases will receive both trastuzumab and bevacizumab
every 3 weeks to a total of 1 year of therapy. These patients will then
have a repeat BM aspirate and biopsy at the end of the 1 year to score for
final response. The primary objective of this clinical trial is to determine
clinical response against BC micrometastases in BM. The second objective
is to investigate the specific contribution of VEGF and CXCL-12 signaling to
BM support of micrometastatic BC cells.
TPS657 General Poster Session (Board #16D), Sat, 8:00 AM-12:00 PM
A phase III clinical trial to compare trastuzumab (T) given concurrently with
radiation therapy (RT) to RT alone for women with HER2� DCIS resected
by lumpectomy (Lx): NSABP B-43. Presenting Author: Melody A. Cobleigh,
National Surgical Adjuvant Breast and Bowel Project, Rush University
Medical Center, Chicago, IL
Background: Asignificant amount of DCIS is ER negative and/or overexpresses
HER2. This provides an opportunity to test molecular therapy in
DCIS. In xenograft models and cell lines, T boosts RT effectiveness. In
T-treated HER2� patients, apoptosis occurs within 1 wk of single agent T
use, with T found in ductal aspirates. Ample safety evidence for T exists. T
given during whole breast irradiation (WBI) may improve results for
Lx-resected HER2� DCIS. A trial to examine this question will enhance the
understanding of breast tumor biology and the prevention of such tumors
and could possibly extend breast-conserving surgery benefits for women
with DCIS. Methods: After Lx for pure DCIS, each patient’s DCIS lesion is
centrally tested for HER2 by IHC analysis. HER2 2� tumors undergo FISH
analysis. HER2 3� or FISH� patients can be randomly assigned to 2 doses
of T, 3 weeks apart during WBI or to WBI alone. Women �18 yrs. with a
margin-clear Lx for pure DCIS, with ECOG status 0/1 who are and clinically
or pathologically node negative are eligible. Centrally tested DCIS must be
HER2 �. ER and/or PR status must be known before randomization.
Primary aims are to determine if T decreases ipsilateral breast cancer
recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary
aims are to determine the benefit of T in preventing regional or distant
recurrence and contralateral invasive breast cancer or DCIS. B-43 will
determine if DFS, recurrence-free interval, and OS can be improved with
the use of T. 2000 patients will be accrued over 7.9 yrs, with a definitive
analysis of primary endpoints performed at163 ipsilateral breast cancer
events (7.5 - 8 yrs. after protocol initiation) with an 80% power to detect a
hazard reduction of 36%, from 1.73 ipsilateral breast cancer events per
100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in
the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of
40% hazard reduction if the compliance were perfect, with a 10%
noncompliance rate. As of 12-31-11, 763 patients have been randomized.
NCT00769379 Grant support: PHS NCI-U10-CA-69651, -12027, and
NCI P30-CA-14599 from the US NCI and Genentech, Inc.
Breast Cancer—HER2/ER
45s
TPS656 General Poster Session (Board #16C), Sat, 8:00 AM-12:00 PM
LCCC 1025: A phase II study evaluating the mTOR inhibitor everolimus
with trastuzumab and vinorelbine to treat progressive HER2-positive breast
cancer brain metastases. Presenting Author: Carey K. Anders, University of
North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center,
Chapel Hill, NC
Background: HER2� breast cancer (BC) is an aggressive subset of BC with
high rates of brain metastases (BM) and poor survival. A recent study
illustrates activation of the PI3K/mTOR pathway in approximately twothirds
of BCBM across all subtypes. Everolimus, a novel oral derivative of
rapamycin that selectively inhibits mTOR, is clinically-active in combination
with trastuzumab (with or without chemotherapy) in advanced HER2�
BC. Everolimus penetrates the blood brain barrier. We are evaluating the
efficacy and safety of everolimus plus trastuzumab and vinorelbine in
patients (pts) with HER2� BCBM. Methods: Pts with HER2� BCBM
progressing following cranial radiation and measuring � 0.5cm are eligible
for enrollment. Treatment with prior vinorelbine or mTOR inhibition is
prohibited. Steroid treatment is allowed if stable or decreasing doses �7
days prior to study entry. Pts with leptomeningeal disease are excluded. Pts
receive everolimus (5mg orally daily), trastuzumab 2mg/kg and vinorelbine
25mg/m2 (both IV days 1, 8, 15) of a 21 day cycle. Intra- and extracranial
disease is assessed every 9 weeks by gadolinium-enhanced brain MRI and
CT chest/abdomen/pelvis, respectively. The primary endpoint is intracranial
response rate (RR) assessed by modified RECIST. Secondary objectives
include extracranial RR (assessed by RECIST 1.1), intra- and
extracranial time to progression, progression free survival, overall survival,
quality of life, and correlative science endpoints. Statistical considerations:
In this two stage design, a sample size of 28 evaluable pts (n�11 in
Stage 1) has 80% power to detect a difference between the null (�5%
intracranial RR) and alternative hypothesis (�5%) at a 0.05 significance
level. If 1 pt has a CR, PR or SD for � 3 months in the 1st stage, 17
additional pts will be enrolled. Assuming a 20% drop-out rate, 35 total pts
will be enrolled. Correlative studies: Archival primary and/or metastatic
tissues are required from all pts to evaluate intrinsic BC subtype, protein
(p-AKT, pS6, PTEN) and gene expression to identify biomarkers that may
be predictive of response or resistance to this novel combination
(NCT01305941).
TPS658 General Poster Session (Board #16E), Sat, 8:00 AM-12:00 PM
HALT MBC: HER2 suppression with the addition of lapatinib to trastuzumab
in HER2-positive metastatic breast cancer (LPT112515). Presenting
Author: Nancy Lin, Dana-Farber Cancer Institute, Boston, MA
Background: Dual blockade of HER2 with the combination of trastuzumab
(T) and lapatinib (L) enhances antitumor activity in HER2-positive breast
cancer (BC) preclinical models due to the complementary mechanisms of
action of the 2 agents. In patients (pts) with T-treated HER2-positive
metastatic BC (MBC), treatment with the combination was associated with
longer progression-free (PFS) and overall survival (OS) compared with L
alone. In pts with stage II/III BC, preoperative treatment with the combination
plus paclitaxel (P) resulted in significantly higher pathologic complete
response rates compared with P combined with either agent alone. This
evidence supports the concept of dual HER2 blockade as a treatment
strategy for HER2-positive MBC. The present study is designed to evaluate
whether the addition of L improves PFS among women with HER2-positive
MBC receiving T as maintenance therapy. Methods: In this open-label,
Phase III study, 280 pts will be stratified by line of treatment (first/second)
and hormone receptor status (positive/negative), then randomized 1:1 to
receive maintenance treatment with either L (1000 mg qd, continuously) in
combination with T (6 mg/kg once every 3 weeks [q3w]) or T (6 mg/kg q3w)
alone. Pts will receive study treatment until disease progression, death,
discontinuation due to adverse events, or other reasons. The primary
endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and
safety. Key eligibility criteria include pts with HER2-positive MBC who
have completed 12 to 24 weeks of first- or second-line treatment with T
plus chemotherapy with an objective response or stable disease at time of
chemotherapy discontinuation. Pts with stable brain metastases are
eligible if entering the study on second-line treatment. Efficacy endpoints
will be analyzed in the ITT population. A total of 193 PFS events is required
to detect a 50% increase in median PFS (hazard ratio�0.67) for L plus T
compared with T alone (median PFS 27 vs 18 weeks, respectively). The
hypothesis will be tested using a 1-sided test with 80% power and a type I
error of 0.025. The trial is currently open for accrual in the United States
and Canada.
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