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

TPS647 General Poster Session (Board #15B), Sat, 8:00 AM-12:00 PM
LUX-breast 3: Randomized phase II study of afatinib alone or with
vinorelbine versus investigator’s choice of treatment in patients (pts) with
HER2-positive breast cancer (BC) with progressive brain metastases (BM)
after trastuzumab or lapatinib-based therapy. Presenting Author: Heikki
Joensuu, Department of Oncology, Helsinki University Central Hospital,
Helsinki, Finland
Background: Approximately 1/3 of pts with HER2-positive, advanced BC
will develop BM with a poor prognosis. Efficacy of systemic therapies is
limited since few drugs can readily cross the blood-brain barrier. BC BM
represents a high unmet medical need for which novel targeted therapies
are needed. Afatinib is a small molecule, irreversible ErbB Family Blocker
that has shown preclinical activity in trastuzumab-resistant cell lines and
HER2-positive tumor xenografts. Its clinical efficacy has been demonstrated
in pts with heavily pre-treated, HER2-positive metastatic BC, who
progressed after trastuzumab therapy, with partial responses in 10% and
clinical benefit in 46% of pts. In a Phase I afatinib trial a sustained PR was
observed in a NSCLC pt with BM, and in a phase II trial in NSCLC, pts with
or without BM achieved comparable outcome on afatinib. The purpose of
this study (NCT01441596) is to investigate whether afatinib alone or in
combination with vinorelbine has any effect on HER2-positive BC with BM
after failure of prior trastuzumab or lapatinib. Methods: Key eligibility
criteria: histologically confirmed HER2-positive BC; recurrent/progressive
BM during/after prior trastuzumab or lapatinib therapy; �1 measurable BM
(�10 mm on T1-weighted, gadolinium-enhanced MRI); extra-CNS lesions
allowed; prior surgery, whole brain radiotherapy or stereotactic radiosurgery
allowed; ECOG 0–2. Eligible pts are stratified by: ECOG score 0–1 vs 2; No
of BM � 3vs�3; prior lapatinib therapy. Pts are randomized to (n �
40/arm): Arm A: afatinib (40 mg/d oral); Arm B: afatinib (40 mg/d oral) �
vinorelbine (25 mg/m2 / week); Arm C: investigator’s choice of medical
treatment approved for metastatic BC. Primary endpoint: pt benefit at 12
weeks (i.e. absence of CNS/extra CNS disease progression as per RECIST
1.1) and no tumour-related worsening of neurological signs/symptoms or
increase in steroid dosage. Secondary endpoints: PFS, OS, safety and
afatinib concentration in plasma/cerebrospinal fluid in �12 pts. The study
began in October 2011 and enrollment is ongoing.
TPS649 General Poster Session (Board #15D), Sat, 8:00 AM-12:00 PM
LUX-breast 1: Randomized, phase III trial of afatinib and vinorelbine versus
trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic
breast cancer (MBC) failing one prior trastuzumab treatment.
Presenting Author: Nadia Harbeck, University of Cologne, Cologne, Germany
Background: Afatinib is an ErbB Family Blocker that irreversibly blocks
signaling from all relevant ErbB Family dimers. Afatinib is being developed
in EGFR (ErbB1)-driven (NSCLC/HNSCC) and HER2 (ErbB2)-driven (breast)
malignancies. In trastuzumab-resistant, HER2-positive (SUM190) xenografts,
afatinib showed antitumor activity which was superior to lapatinib
and increased by addition of IV vinorelbine. Afatinib monotherapy also
demonstrated clinical activity (progression-free survival [PFS] � 15.1 wk;
objective response [OR] � 10%) in an open-label, single-arm, Phase II trial
in patients with HER2-positive MBC after progression on trastuzumab.
Methods: LUX-Breast 1 (NCT01125566) is a Phase III, open-label,
multicenter trial evaluating the efficacy and safety of afatinib � vinorelbine
vs. trastuzumab � vinorelbine in patients with HER2-overexpressing MBC
who progressed on, or after one prior trastuzumab-based treatment regimen.
Patients are randomized 2:1 to afatinib (40 mg/d oral) � vinorelbine
(IV 25 mg/m2 /wk) or trastuzumab (IV 2 mg/kg/wk after 4 mg/kg loading
dose) � vinorelbine (IV 25 mg/m2 /wk). Patients receive continuous
treatment in the absence of disease progression or adverse events. Key
eligibility criteria include histologically-confirmed HER2-positive BC, stage
IV disease; no prior treatment with vinorelbine or HER2-targeted treatment
other than trastuzumab; progression on one prior trastuzumab based
regimen in either the adjuvant (or �12 months after trastuzumab completion)
or first-line (or �6 months after trastuzumab completion) setting;
prior anthracycline and/or taxane chemotherapy; ECOG score 0 or 1. The
primary endpoint is PFS and secondary endpoints include OR, overall
survival and safety. Serum and tissue biomarkers will be assessed on
archival tissue. HER-receptor and HER-ligand reprogramming, putative
resistance markers and EGFR response signature will be explored in fresh
tissue biopsies. Enrollment began in June 2010 and is ongoing, targeting
�240 sites with a recruitment target of 780 patients.
Breast Cancer—HER2/ER
43s
TPS648 General Poster Session (Board #15C), Sat, 8:00 AM-12:00 PM
BOLERO-1: A randomized, phase III, double-blind, placebo-controlled
multicenter trial of everolimus in combination with trastuzumab and
paclitaxel as first-line therapy in women with HER2-positive (HER2� ),
locally advanced or metastatic breast cancer (BC). Presenting Author: Sara
A. Hurvitz, UCLA Hematology, Oncology and Translational Research in
Oncology (TRIO), Los Angeles, CA
Background: Up to 25% of BCs overexpress human epidermal growth factor
receptor 2 (HER2). Patients with HER2 � disease have a higher rate of
relapse and shorter overall survival (OS). Trastuzumab, a monoclonal
antibody targeting HER2, is the standard of care and improves OS for
HER2 � BC, but acquired resistance is common. The combination of
trastuzumab and paclitaxel has shown good tolerability and excellent
objective response rates (ORR) in up to 84% of patients with HER2 �
metastatic BC (MBC) (Gasparini G, et al. BCRT. 2007;101:355-65).
Everolimus is an orally bioavailable inhibitor of mammalian target of
rapamycin (mTOR), a protein kinase central to multiple protein synthesis
pathways and implicated in trastuzumab resistance. Everolimus-containing
regimens have shown promising results in patients with ER � , HER2 –
advanced BC in phase II/III trials; everolimus plus trastuzumab/paclitaxel
or vinorelbine has shown encouraging ORR with an acceptable safety profile
in phase I/II trials in patients with HER2 � MBC. The present phase III study
was undertaken to assess the effectiveness of adding everolimus to
first-line standard therapy in HER2 � advanced BC. Methods: Women with
HER2 � , locally advanced or metastatic BC who have received no prior
systemic therapy (except endocrine) are eligible. Local disease must not be
amenable to resection with curative intent. Women with a history of central
nervous system metastasis are excluded. Patients are randomized 2:1
(everolimus vs control) to receive standard therapy (paclitaxel and trastuzumab)
plus everolimus (10 mg daily) or placebo. The primary endpoint is
progression-free survival. Secondary endpoints include OS, ORR, and
clinical benefit rate. Additional endpoints are safety, performance status,
and biomarkers. This trial is sponsored by Novartis Pharmaceuticals and is
registered (ClinicalTrials.gov: NCT00876395). Enrollment began September
2009, with a planned accrual of 717. The current accrual is 719, and
the estimated primary completion date is October 2012.
TPS650 General Poster Session (Board #15E), Sat, 8:00 AM-12:00 PM
Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the
treatment of HER2-overexpressing inflammatory breast cancer (IBC).
Presenting Author: Charles Swanton, Translational Cancer Therapeutics
Lab, CR-UK, London, United Kingdom
Background: IBC is an aggressive and rare form of BC (1–6% cases).
Despite recent treatment advances, prognosis remains poor, with 3-yr
survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more
frequently harbour HER2 gene amplification (~40%), and EGFR overexpression
(~30%) associated with poor prognosis. Recent data reported clinical
efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T)
naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family
Blocker with preclinical activity in T-resistant cell lines, HER2-positive
tumor xenografts and HER2-negative SUM 149 xenograft model derived
from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated,
HER2-positive metastatic BC pts who progressed after T, with PR in 10%
and clinical benefit in 46% of pts. The purpose of this biomarker-driven
study is to investigate efficacy and safety of afatinib alone and in
combination with V upon progression on afatinib monotherapy and the
genomic changes that occur through treatment in pts with T pretreated or
naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of
20 pts each: T-naïve and T failure. Key eligibility criteria: histologicallyconfirmed
HER2-positive BC; investigator-confirmed IBC characterized by
diffuse erythema and oedema (peau d’orange) while dermal lymphatic
emboli or palpable mass are not necessary for diagnosis; no prior anti-
HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts
start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon
disease progression, pts may receive afatinib (40 mg/d) � V (IV 25
mg/m2 /week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or
SD) for �6 months. Secondary endpoints: objective response rate, PFS, OS
and safety. Endpoints are assessed separately for Part A and Part B. Fresh
biopsy and blood samples are taken prior to treatment and upon progression
in Part A, to explore predictive markers of response/resistance to
afatinib, to describe the IBC population which may benefit most, and for
next generation sequencing and proteomic analysis. Enrollment ongoing
since Aug 2011.
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