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

532 Poster Discussion Session (Board #22), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Cardiac safety in a phase II study of trastuzumab emtansine (T-DM1)
following anthracycline-based chemotherapy as adjuvant or neoadjuvant
therapy for early-stage HER2-positive breast cancer. Presenting Author:
Chau T. Dang, Memorial Sloan-Kettering Cancer Center, New York, NY
Background: T-DM1 has demonstrated clinical activity as a single agent in
patients (pts) with previously untreated MBC. In a previous phase II
randomized trial of T-DM1 vs trastuzumab � docetaxel, T-DM1 had no
clinically significant cardiac events, no cases of post-baseline left ventricular
ejection fraction (LVEF) �40%, and fewer grade �3 adverse events
(AEs; Hurvitz, ESMO 2011). This phase II study assessed the clinical
safety and feasibility of T-DM1 following anthracycline-based chemotherapy
in the adjuvant or neoadjuvant setting for early-stage HER2positive
breast cancer. Methods: TDM4874g (NCT01196052) is a phase II
single-arm, open-label study of T-DM1 (3.6 mg/kg q3w IV; up to 17 cycles)
following completion of doxorubicin/cyclophosphamide (AC; q2w or q3w
for 4 cycles), or 5-fluorouracil/epirubicin (100 mg/m2 )/cyclophosphamide
(FEC; q3w for 3-4 cycles) chemotherapy in pts with early-stage HER2positive
breast cancer. Pre-chemotherapy LVEF by MUGA/ECHO �55%
was required for enrollment. Co-primary endpoints are safety and rate of
pre-specified cardiac events following initiation of T-DM1 treatment. An
interim analysis was planned for the first 60 pts evaluable for cardiac safety
(received �1 T-DM1 dose). Results: For pts in the interim analysis (20
received AC, 40 FEC), the most common all-grade T-DM1-related AEs were
nausea (n�20), asthenia (n�17), and headache (n�17); 8 pts had grade
3/4 T-DM1-related AEs (including 3 with grade 3 increased aspartate
aminotransferase [AST] and/or alanine aminotransferase [ALT]). No deaths
occurred. Two pts had AEs leading to T-DM1 discontinuation (grade 3 AST
and grade 2 ALT increase; grade 3 thrombocytopenia). No pre-specified
cardiac events occurred; no pts delayed or discontinued T-DM1 due to
cardiac AEs; there were no reports of grade �2 left ventricular systolic
dysfunction, heart failure, or LVEF �50%. Results will be updated with
data from all 153 enrolled pts. Conclusions: T-DM1 following anthracyclinebased
chemotherapy was not associated with cardiac toxicity in pts with
early-stage HER2-positive breast cancer; this study continues without
modification.
534 Poster Discussion Session (Board #24), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase I trial of the IGF-1R antibody IMC-A12 in combination with
temsirolimus in patients with metastatic breast cancer. Presenting Author:
Gini F. Fleming, The University of Chicago Medical Center, Chicago, IL
Background: mTOR plays a critical role in promoting tumor cell growth. In
preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated
by feedback up-regulation of AKT mediated by IGF-1R. We designed a
phase I trial to determine the maximum-tolerated dose (MTD), doselimiting
toxicities (DLT) and pharmacodynamic effects of the IGF-1R
antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts)
with metastatic breast cancer (MBC) where mTOR is frequently activated.
Methods: A3�3 phase I design was chosen. Tem and IMC-A12 were
administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC
refractory to standard therapies. Tumor response was evaluated by RECIST.
Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and
C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion
were compared to baseline (BL) using paired t-test. Results: Of 26 pts
enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid
condition (1). MTD was determined from remaining 22 pts aged 34-72
(median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER�
cancer. Median number of regimens for MBC was 4. Two DLTs at the
starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1),
then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose
escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in
DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue,
neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting �
4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were
significantly elevated on d2 (p �0.002) and d8 compared to BL (p
�0.001), but C-peptide levels were not found to differ from BL. Conclusions:
The MTD for the combination of IMC-A12 and tem in pts with MBC is lower
than that observed for single agents alone. A phase II study is ongoing in
MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM,
N01-CM62205 and N01-CM-2011-00071.
DL Tem (mg) IMC-A12 (mg/kg) No. DLT
1 25 3 3 2: gr 2 mucositis with trt delay
-1 20 3 1 1: gr 3 neutropenia and leukopenia
-2 15 3 6 1: gr 3 mucositis
-2A 15 4 6 0
-2B 15 5 3 1: gr 2 thrombocytopenia with trt delay
1: gr 3 neutropenia with trt delay
Breast Cancer—HER2/ER
15s
533^ Poster Discussion Session (Board #23), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in
patients with HER2-positive metastatic breast cancer in the CLEOPATRA
study. Presenting Author: Michael Ewer, University of Texas M. D.
Anderson Cancer Center, Houston, TX
Background: Addition of trastuzumab (T) to chemotherapy has transformed
outcomes in pts with HER2-positive breast cancer. In pts who had received
anthracyclines (A), T has been associated with cardiac dysfunction.
Monitoring cardiac tolerability of anticancer drugs is important, including
that of a new regimen combining T with a second anti-HER2 antibody that
inhibits HER2 dimerization, pertuzumab (P). In CLEOPATRA, efficacy and
safety of P�T�docetaxel (D) were studied in HER2-positive 1st-line MBC
(Baselga 2012). Methods: CLEOPATRA, a randomized, double-blind,
placebo-controlled, ph III trial, enrolled 808 pts; 804 were included in the
safety population. A baseline (BL) LVEF �50%, no history of congestive
heart failure, and no LVEF decline to �50% during/after prior T were
required. Treatment was administered q3w until disease progression or
unmanageable toxicity (P/placebo [Pla]: 840 mg, followed by 420 mg; T: 8
mg/kg, followed by 6 mg/kg; D [�6 cycles recommended]: 75 mg/m2 ,
escalating to 100 mg/m2 if tolerated). LVEF was assessed by ECHO or
MUGA at BL, every 9 wks during treatment, at discontinuation, and up to 3
yrs thereafter. Adverse events (AE) were monitored continuously and
graded according to NCI-CTCAE v3.0. Results: The incidence of any cardiac
disorder (grade �1) as assessed by the investigators was similar with
Pla�T�D (16.4%) and P�T�D (14.5%). LVSD (grade �1) was the most
frequent cardiac AE and more common with Pla�T�D. At the time of data
cutoff for this analysis, 8/11 symptomatic LVSD events had resolved; none
fatal. All pts who developed symptomatic LVSD had �1 potential cardiac
risk factor (prior A, prior T, radiation, smoking, diabetes, hypertension,
other). Compared to the overall pt population, only prior A and radiation
were higher in pts who developed symptomatic LVSD. Conclusions: CLEO-
PATRA provides evidence that P�T�D does not increase overall cardiac
disorders, specifically symptomatic LVSD, compared to Pla�T�D.
n (%) Pla�T�D(n�397) P�T�D(n�407)
LVSD (grade >1)* 33 (8.3) 18 (4.4)
Symptomatic LVSD (grade >3)* 7 (1.8) 4 (1.0)
LVEF decline to 10% points from BL †
25/379 (6.6) 15/393 (3.8)
* NCI-CTCAE v3.0. † Pts with post-BL LVEF assessment.
535 Poster Discussion Session (Board #25), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Activity of cabozantinib (XL184) in metastatic breast cancer (MBC):
Results from a phase II randomized discontinuation trial (RDT). Presenting
Author: Eric P. Winer, Dana-Farber Cancer Institute, Boston, MA
Background: Dysregulation of MET and VEGF signaling has been implicated
in breast cancer development and progression, including tumor invasion
and dissemination. Cabozantinib (cabo) is an oral, potent inhibitor of MET
and VEGFR2. A RDT evaluated activity and safety in 9 tumor types,
including MBC. Methods: Eligible patients (pts) were required to have
progressive measurable disease per RECIST. Pts received cabo at 100 mg
qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed
q6 wks. Treatment � wk 12 was based on response: pts with PR continued
open-label cabo, pts with SD were randomized to cabo vs placebo, and pts
with PD discontinued. Primary endpoint in the randomized discontinuation
phase was progression-free survival (PFS). Results: Enrollment to this
cohort is complete (n � 45); all pts are unblinded. Baseline characteristics:
median age 56; invasive ductal 86%, invasive lobular 7%; ER� 93%,
HER2� 18%, triple- 5%; visceral disease 91%; bone metastases 73%;
median prior lines of therapy 3 (range 1-8), including 71% with prior
anthracyclines. Median follow-up was 2.9 mos (range 0.1 -16). 21 pts
(47%) completed Lead-in stage with only 9 randomized to continue cabo (n
� 5) or placebo (n � 4). Median PFS from Study Day 1 was 4.1 mos. At wk
12, objective response rate was 14% and disease control rate 48%. Tumor
regression was observed in 25/39 pts (64%) with �1 post-baseline tumor
assessment. 4/10 pts evaluable by bone scan had partial resolution of bone
lesions. Of 12 pts receiving narcotics for bone pain, 5 pts reported
improved pain and 2 pts had decreased narcotics use, per investigator.
4/14 evaluable pts (29%) with bone metastases experienced �50%
decline in serum NTx. Most common Grade 3/4 AEs were palmar-plantar
erythrodyesthesia (13%) and fatigue (11%). One related Grade 5 AE of
respiratory compromise was reported during the Lead-in stage. Conclusions:
Cabo demonstrated a 14% rate of objective tumor regression in heavily
pretreated MBC pts. Observed effects on bone scan and pain are consistent
with those seen in other malignancies. The safety profile of cabo was
comparable to that seen with other VEGFR TKIs.
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