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

44s Breast Cancer—HER2/ER
TPS651 General Poster Session (Board #15F), Sat, 8:00 AM-12:00 PM
LUX-breast 2: Phase II, open-label study of oral afatinib in HER2overexpressing
metastatic breast cancer (MBC) patients (pts) who progressed
on prior trastuzumab (T) and/or lapatanib (L). Presenting Author:
Tamas Hickish, Royal Bournemouth Hospital, Bournemouth, United Kingdom
Background: Management of HER2-overexpressing MBC has improved over
the past decade. However, pts still develop resistance to currently available
HER2-targeted therapies and novel effective treatments are increasingly
required as dual targeted combinations are given in early treatment lines
already. Current therapies focus on targeting HER2 and do not inhibit all
relevant ErbB Family dimers. Afatinib is an oral, irreversible ErbB Family
Blocker that inhibits signaling through activated EGFR (ErbB1), HER2
(ErbB2) and ErbB4 receptors and transphosphorylation of ErbB3. Preclinical
studies have demonstrated efficacy in T-sensitive and T-resistant
human BC xenograft models dependent on ErbB signaling. Efficacy of
afatinib in a T-resistant SUM 190 xenograft model has been shown to be
increased by addition of IV vinorelbine (V). Afatinib monotherapy has
shown promising clinical benefit in 46% of HER2-overexpressing MBC pts
who progressed on prior T, with 10% of pts achieving PR. Methods: This
open-label Phase II trial (NCT01271725) investigates efficacy and safety
of afatinib alone (40 mg/d) followed by afatinib ‘beyond progression’ plus
chemotherapy in 120 pts with HER2-overexpressing MBC, who progressed
on prior neoadjuvant and/or adjuvant T and/or L. Pts who progress on
afatinib monotherapy receive afatinib plus either weekly paclitaxel (P) 80
mg/m2 or V 25 mg/m2 . Eligible pts have confirmed HER2-overexpressing
BC, stage IV disease measurable by RECIST 1.1, progressed on T and/or L
therapy in either neoadjuvant and/or adjuvant setting, are eligible for
retreatment with P or V and should not have been pretreated with P (�12
months) or V, respectively. Exclusion criteria: inadequate cardiac, renal,
hepatic and hematological function, pre-existing gastrointestinal dysfunction,
rapidly progressing visceral disease, ILD and active brain metastases.
The primary endpoint is objective response (OR) and secondary endpoints
include best overall response, duration of OR and PFS; safety will be
assessed separately for afatinib mono- and combination therapy. Patient
enrollment began in May 2011 in ~35 sites and 5 countries.
TPS653 General Poster Session (Board #15H), Sat, 8:00 AM-12:00 PM
A combination of pertuzumab, trastuzumab, and vinorelbine for first-line
treatment of patients with HER2-positive metastatic breast cancer: An
open-label, two-cohort, phase II study (VELVET). Presenting Author: Edith
A. Perez, Mayo Clinic, Jacksonville, FL
Background: Pertuzumab (P) is a humanized monoclonal antibody directed
against the dimerization domain of HER2: it prevents HER2 heterodimerization
and thus activation of downstream signaling. Since P targets a
different epitope than trastuzumab (H), a more comprehensive HER2
blockade is achieved by combining the two agents. Data from CLEOPATRA
showed improved efficacy for P and H plus docetaxel. The combination of P
and H has not yet been assessed with other chemotherapy partners in the
metastatic setting. H plus vinorelbine (V) has shown comparable efficacy to
H plus docetaxel but with a superior safety profile. VELVET will assess the
overall response rate (ORR) of P with H�V in first-line patients (pts) with
HER2-positive MBC. Co-administration of P and H within the same
infusion bag will also be investigated as this could increase pt convenience
by reducing administration and observation time. Methods: VELVET is a
multicenter, open-label, two-cohort, Phase II trial. Pts with HER2-positive
LABC or MBC not previously treated in the metastatic setting with
non-hormonal anticancer therapy are eligible. Pts must have an LVEF
�55% at baseline and an ECOG PS of 0 or 1. Study enrollment started in
January 2012. A total of 210 pts will be included. Based on statistical
assumptions, 95 pts must be evaluable per cohort, which assumes a
withdrawal rate around 10%. Pts in Cohort 1 (the first 105 pts enrolled) will
receive P and H sequentially and pts in Cohort 2 (the next 105 pts) will
receive P and H in the same infusion bag at Cycle 2 onwards if drug
administration in Cycle 1 was well tolerated. V will be given in both cohorts.
Treatment duration is until disease progression or unacceptable toxicity.
Study dose: P: 840 mg loading dose, 420 mg q3w (iv); H: 8 mg/kg loading
dose, 6 mg/kg q3w (iv), and V: 25 mg/m2 Day 1 and 8 (first cycle) then
30�35 mg/m2 Day 1 and 8 q3w (iv) (dose escalation at investigator’s
discretion). The primary endpoint is ORR by independent assessment.
Secondary endpoints include investigator assessment of ORR, time to
response, duration of response, PFS, time to progression, overall survival,
safety and tolerability, and QoL.
TPS652 General Poster Session (Board #15G), Sat, 8:00 AM-12:00 PM
A phase II trial of trabectedin (T) in patients with hormone receptorpositive,
HER2-negative advanced breast cancer, according to xeroderma
pigmentosum gene (XPG) expression. Presenting Author: Ahmad Awada,
Institut Jules Bordet, Brussels, Belgium
Background: Hormone receptor-positive, HER2-negative breast cancer (BC)
is currently associated with 3-4 years overall survival in the metastatic
setting and, after �2 relapses, therapeutic approaches are reduced. XPG
expression is frequently modified in BC. T is a cytotoxic agent that forms a
complex with the XPG, inducing cell apoptosis. As a single agent, T has
shown anti-tumor activity in patients with poor prognosis BC, and a better
response to T in BC patients with XPG RNA overexpression has been
observed. Methods: This is an open-label, phase II study of T (1.3 mg/m2 in
3-hour intravenous infusion every 3 weeks) in patients with hormone
receptor-positive, HER2-negative advanced BC, according to their primary
tumor’s XPG expression. Primary endpoint: to evaluate the efficacy of T in
terms of progression free survival rate at 4 months (PFS4) according to the
patient’s XPG expression. Secondary endpoints: Comparison of PFS,
overall response rate, duration of response, overall survival and safety
profile in XPG-high and XPG-low patients. Assignment: BC patients who
have previously received anthracyclins and/or taxanes and who progressed
after 2-5 chemotherapy lines will be assigned according to their XPG
expression from paraffin embedded tumor samples to stratum A (XPG-high
[�3]) or to stratum B (XPG-low [�3]) (threshold was selected from median
XPG expression values observed in a previous trial). Statistical methods: A
two-stage design was chosen: at a first stage 20 patients will be enrolled in
each stratum. A futility analysis (O’Brien Fleming boundary) based on the
primary endpoint (PFS4) will be conducted once 40 evaluable patients
have been recruited. If � 7 out of 20 patients achieve PFS4, recruitment
will continue to a maximum sample size of 50 evaluable patients per
stratum. If � 22 out of 50 patients achieve PFS4, T will be considered
active in this group (alpha error: 0.025, power: 80%). To date, 35 patients
(16 XPG-high and 15 XPG-low) have been enrolled from three countries
and five centers. Recruitment is ongoing.
TPS654^ General Poster Session (Board #16A), Sat, 8:00 AM-12:00 PM
Pertuzumab in combination with trastuzumab plus an aromatase inhibitor
in patients with hormone receptor-positive, HER2-positive metastatic
breast cancer: A randomized phase II study (PERTAIN). Presenting Author:
Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX
Background: Resistance to endocrine therapy in patients (pts) with breast
cancer remains a major clinical concern. Preclinical studies suggest that
complete blockade of the hormone receptor (HR) combined with the
inhibition of HER family members may be necessary to overcome resistance
and improve clinical outcome in HR-positive and HER2-positive
breast cancer (BC). The combination of pertuzumab (P) and trastuzumab
(H) with docetaxel significantly improves patient outcome by blocking,
more efficiently and completely, the HER signalling pathway. This benefit,
however, may be smaller in HR-positive patients. PERTAIN is the first
clinical trial to study whether a more potent blockade of the HER pathway
with P and H in combination with endocrine therapy may restore or enhance
endocrine sensitivity of HER2-positive BC and provide an effective treatment
option in pts with HER2-positive and HR-positive MBC. Methods:
PERTAIN is a multicenter, open-label, Phase II trial for post-menopausal
women with HER2- and HR-positive BC, studying the efficacy of the
combination of P plus H with an aromatase inhibitor (AI) as first-line
therapy for MBC. Pts will be randomized 1:1 to Arm 1 (P: 840 mg loading
dose, 420 mg q3w IV; H: 8 mg/kg loading dose, 6 mg/kg q3w IV; AI
[anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H � AI at same dose
as Arm 1). Pts in either arm may also receive induction chemotherapy
(docetaxel or paclitaxel) for up to 18 weeks at the investigator’s discretion.
Study medication will be administered until disease progression or unacceptable
toxicity. Pts must not have previously been treated with anti-
HER2 agents except H and/or lapatinib in the (neo)adjuvant setting, and
must have no CNS involvement or clinically significant cardiovascular
disease. The primary endpoint is PFS, and secondary endpoints include
overall survival, overall response rate, clinical benefit rate, duration of
response, time to response, safety and tolerability, and quality of life. The
study opened in January 2012 and will recruit 250 pts. Analysis of the
primary endpoint will be performed after 165 PFS events using the
Kaplan-Meier approach.
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