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

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TPS655 General Poster Session (Board #16B), Sat, 8:00 AM-12:00 PM<br />

Docetaxel, carboplatin, trastuzumab, and bevacizumab (TCH�B) for earlystage<br />

HER2/neu(�) breast cancer and bone marrow micrometastases.<br />

Presenting Author: Joseph Baar, Seidman Cancer Center, Cleveland, OH<br />

Background: Bone marrow (BM) micrometastases confer a poor prognosis to<br />

early-stage breast cancer (BC) and HER-2/neu(�) BC is a high-risk<br />

phenotype. We have shown that BM-associated stromal cells support the<br />

survival <strong>of</strong> metastatic BC in microenvironmental niches and this activity is<br />

dependent on VEGF and CXCL-12. Therefore, the growth <strong>of</strong> nascent tumor<br />

cell clusters in BM might be impeded by disrupting stromal cells or their<br />

activating ligands, such as VEGF. There is also a positive association<br />

between HER-2/neu and VEGF expression in BC, thereby implicating VEGF<br />

in the aggressive phenotype <strong>of</strong> HER-2/neu overexpression. These observations<br />

support the use <strong>of</strong> combination therapies directed against both<br />

HER-2/neu and VEGF for the treatment <strong>of</strong> HER-2/neu(�) BC. We therefore<br />

hypothesize that an anti-VEGF agent (bevacizumab) given with docetaxel,<br />

carboplatin and trastuzumab (TCH) will eradicate the BM <strong>of</strong> HER-2/neu(�)<br />

BC micrometastases by disrupting stromal cell support within the micrometastatic<br />

BM niche. Methods: Subjects with AJCC Stage I-III HER2/<br />

neu(�) BC will undergo a single iliac-crest BM aspirate and biopsy. If the<br />

BM is positive for CK� micrometastases, up to 17 patients will receive<br />

TCH�B therapy (docetaxel at 75 mg/m2 IV and carboplatin at AUC 6 IV<br />

given every 3 weeks for 6 cycles; trastuzumab at 4 mg/kg IV loading dose,<br />

then 2mg/kg IV every week; bevacizumab at 15 mg/kg IV every 3 weeks).<br />

Four weeks after the 6th cycle <strong>of</strong> therapy, a repeat BM aspiration and biopsy<br />

will be performed to score for response <strong>of</strong> BC micrometastases to therapy.<br />

Patients with a complete clinical response in BM will continue with<br />

trastuzumab every 3 weeks at 6 mg/kg to a total <strong>of</strong> 1 year. Patients with<br />

persistent micrometastases will receive both trastuzumab and bevacizumab<br />

every 3 weeks to a total <strong>of</strong> 1 year <strong>of</strong> therapy. These patients will then<br />

have a repeat BM aspirate and biopsy at the end <strong>of</strong> the 1 year to score for<br />

final response. The primary objective <strong>of</strong> this clinical trial is to determine<br />

clinical response against BC micrometastases in BM. The second objective<br />

is to investigate the specific contribution <strong>of</strong> VEGF and CXCL-12 signaling to<br />

BM support <strong>of</strong> micrometastatic BC cells.<br />

TPS657 General Poster Session (Board #16D), Sat, 8:00 AM-12:00 PM<br />

A phase III clinical trial to compare trastuzumab (T) given concurrently with<br />

radiation therapy (RT) to RT alone for women with HER2� DCIS resected<br />

by lumpectomy (Lx): NSABP B-43. Presenting Author: Melody A. Cobleigh,<br />

National Surgical Adjuvant Breast and Bowel Project, Rush University<br />

Medical Center, Chicago, IL<br />

Background: Asignificant amount <strong>of</strong> DCIS is ER negative and/or overexpresses<br />

HER2. This provides an opportunity to test molecular therapy in<br />

DCIS. In xenograft models and cell lines, T boosts RT effectiveness. In<br />

T-treated HER2� patients, apoptosis occurs within 1 wk <strong>of</strong> single agent T<br />

use, with T found in ductal aspirates. Ample safety evidence for T exists. T<br />

given during whole breast irradiation (WBI) may improve results for<br />

Lx-resected HER2� DCIS. A trial to examine this question will enhance the<br />

understanding <strong>of</strong> breast tumor biology and the prevention <strong>of</strong> such tumors<br />

and could possibly extend breast-conserving surgery benefits for women<br />

with DCIS. Methods: After Lx for pure DCIS, each patient’s DCIS lesion is<br />

centrally tested for HER2 by IHC analysis. HER2 2� tumors undergo FISH<br />

analysis. HER2 3� or FISH� patients can be randomly assigned to 2 doses<br />

<strong>of</strong> T, 3 weeks apart during WBI or to WBI alone. Women �18 yrs. with a<br />

margin-clear Lx for pure DCIS, with ECOG status 0/1 who are and clinically<br />

or pathologically node negative are eligible. Centrally tested DCIS must be<br />

HER2 �. ER and/or PR status must be known before randomization.<br />

Primary aims are to determine if T decreases ipsilateral breast cancer<br />

recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary<br />

aims are to determine the benefit <strong>of</strong> T in preventing regional or distant<br />

recurrence and contralateral invasive breast cancer or DCIS. B-43 will<br />

determine if DFS, recurrence-free interval, and OS can be improved with<br />

the use <strong>of</strong> T. 2000 patients will be accrued over 7.9 yrs, with a definitive<br />

analysis <strong>of</strong> primary endpoints performed at163 ipsilateral breast cancer<br />

events (7.5 - 8 yrs. after protocol initiation) with an 80% power to detect a<br />

hazard reduction <strong>of</strong> 36%, from 1.73 ipsilateral breast cancer events per<br />

100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in<br />

the hazard <strong>of</strong> IIBCR-SCR-DCIS on the T arm is based on a projection <strong>of</strong><br />

40% hazard reduction if the compliance were perfect, with a 10%<br />

noncompliance rate. As <strong>of</strong> 12-31-11, 763 patients have been randomized.<br />

NCT00769379 Grant support: PHS NCI-U10-CA-69651, -12027, and<br />

NCI P30-CA-14599 from the US NCI and Genentech, Inc.<br />

Breast Cancer—HER2/ER<br />

45s<br />

TPS656 General Poster Session (Board #16C), Sat, 8:00 AM-12:00 PM<br />

LCCC 1025: A phase II study evaluating the mTOR inhibitor everolimus<br />

with trastuzumab and vinorelbine to treat progressive HER2-positive breast<br />

cancer brain metastases. Presenting Author: Carey K. Anders, University <strong>of</strong><br />

North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center,<br />

Chapel Hill, NC<br />

Background: HER2� breast cancer (BC) is an aggressive subset <strong>of</strong> BC with<br />

high rates <strong>of</strong> brain metastases (BM) and poor survival. A recent study<br />

illustrates activation <strong>of</strong> the PI3K/mTOR pathway in approximately twothirds<br />

<strong>of</strong> BCBM across all subtypes. Everolimus, a novel oral derivative <strong>of</strong><br />

rapamycin that selectively inhibits mTOR, is clinically-active in combination<br />

with trastuzumab (with or without chemotherapy) in advanced HER2�<br />

BC. Everolimus penetrates the blood brain barrier. We are evaluating the<br />

efficacy and safety <strong>of</strong> everolimus plus trastuzumab and vinorelbine in<br />

patients (pts) with HER2� BCBM. Methods: Pts with HER2� BCBM<br />

progressing following cranial radiation and measuring � 0.5cm are eligible<br />

for enrollment. Treatment with prior vinorelbine or mTOR inhibition is<br />

prohibited. Steroid treatment is allowed if stable or decreasing doses �7<br />

days prior to study entry. Pts with leptomeningeal disease are excluded. Pts<br />

receive everolimus (5mg orally daily), trastuzumab 2mg/kg and vinorelbine<br />

25mg/m2 (both IV days 1, 8, 15) <strong>of</strong> a 21 day cycle. Intra- and extracranial<br />

disease is assessed every 9 weeks by gadolinium-enhanced brain MRI and<br />

CT chest/abdomen/pelvis, respectively. The primary endpoint is intracranial<br />

response rate (RR) assessed by modified RECIST. Secondary objectives<br />

include extracranial RR (assessed by RECIST 1.1), intra- and<br />

extracranial time to progression, progression free survival, overall survival,<br />

quality <strong>of</strong> life, and correlative science endpoints. Statistical considerations:<br />

In this two stage design, a sample size <strong>of</strong> 28 evaluable pts (n�11 in<br />

Stage 1) has 80% power to detect a difference between the null (�5%<br />

intracranial RR) and alternative hypothesis (�5%) at a 0.05 significance<br />

level. If 1 pt has a CR, PR or SD for � 3 months in the 1st stage, 17<br />

additional pts will be enrolled. Assuming a 20% drop-out rate, 35 total pts<br />

will be enrolled. Correlative studies: Archival primary and/or metastatic<br />

tissues are required from all pts to evaluate intrinsic BC subtype, protein<br />

(p-AKT, pS6, PTEN) and gene expression to identify biomarkers that may<br />

be predictive <strong>of</strong> response or resistance to this novel combination<br />

(NCT01305941).<br />

TPS658 General Poster Session (Board #16E), Sat, 8:00 AM-12:00 PM<br />

HALT MBC: HER2 suppression with the addition <strong>of</strong> lapatinib to trastuzumab<br />

in HER2-positive metastatic breast cancer (LPT112515). Presenting<br />

Author: Nancy Lin, Dana-Farber Cancer Institute, Boston, MA<br />

Background: Dual blockade <strong>of</strong> HER2 with the combination <strong>of</strong> trastuzumab<br />

(T) and lapatinib (L) enhances antitumor activity in HER2-positive breast<br />

cancer (BC) preclinical models due to the complementary mechanisms <strong>of</strong><br />

action <strong>of</strong> the 2 agents. In patients (pts) with T-treated HER2-positive<br />

metastatic BC (MBC), treatment with the combination was associated with<br />

longer progression-free (PFS) and overall survival (OS) compared with L<br />

alone. In pts with stage II/III BC, preoperative treatment with the combination<br />

plus paclitaxel (P) resulted in significantly higher pathologic complete<br />

response rates compared with P combined with either agent alone. This<br />

evidence supports the concept <strong>of</strong> dual HER2 blockade as a treatment<br />

strategy for HER2-positive MBC. The present study is designed to evaluate<br />

whether the addition <strong>of</strong> L improves PFS among women with HER2-positive<br />

MBC receiving T as maintenance therapy. Methods: In this open-label,<br />

Phase III study, 280 pts will be stratified by line <strong>of</strong> treatment (first/second)<br />

and hormone receptor status (positive/negative), then randomized 1:1 to<br />

receive maintenance treatment with either L (1000 mg qd, continuously) in<br />

combination with T (6 mg/kg once every 3 weeks [q3w]) or T (6 mg/kg q3w)<br />

alone. Pts will receive study treatment until disease progression, death,<br />

discontinuation due to adverse events, or other reasons. The primary<br />

endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and<br />

safety. Key eligibility criteria include pts with HER2-positive MBC who<br />

have completed 12 to 24 weeks <strong>of</strong> first- or second-line treatment with T<br />

plus chemotherapy with an objective response or stable disease at time <strong>of</strong><br />

chemotherapy discontinuation. Pts with stable brain metastases are<br />

eligible if entering the study on second-line treatment. Efficacy endpoints<br />

will be analyzed in the ITT population. A total <strong>of</strong> 193 PFS events is required<br />

to detect a 50% increase in median PFS (hazard ratio�0.67) for L plus T<br />

compared with T alone (median PFS 27 vs 18 weeks, respectively). The<br />

hypothesis will be tested using a 1-sided test with 80% power and a type I<br />

error <strong>of</strong> 0.025. The trial is currently open for accrual in the United States<br />

and Canada.<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

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