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

14s Breast Cancer—HER2/ER
528 Poster Discussion Session (Board #18), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Results from a phase Ib study of trastuzumab emtansine (T-DM1),
paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic
breast cancer (MBC) previously treated with trastuzumab. Presenting
Author: Shanu Modi, Memorial Sloan-Kettering Cancer Center, New York,
NY
Background: The antibody–drug conjugate T-DM1 has shown single-agent
activity in phase II studies in patients (pts) with HER2–positive MBC.
Preclinical data suggest synergy for T-DM1 combined with taxanes and with
P. Methods: TDM4652g is a phase Ib, open-label, dose-escalation study
evaluating the safety and tolerability of T-DM1 (qw and q3w) � T (qw) � P
(q3w) in pts with HER2-positive MBC previously treated with trastuzumab.
A3�3 dose-escalation scheme is used for T-DM1 � T to determine the
maximum tolerated dose (MTD); P is added at this MTD. Initial restrictive
dose-limiting toxicity (DLT) criteria were modified to establish a more
clinically relevant MTD. Results: We report interim results with T-DM1 (qw
and q3w) � T(�P) using modified DLT criteria. 24 pts have been enrolled
in these cohorts; median age was 53 yrs (range, 23–69)*; median number
of prior systemic therapies in MBC was 7 (range, 2–15)*. See table below.
Conclusions: Data support combining T-DM1 � T � P at the MTD for future
clinical trials. The MTD for weekly T-DM1 � T is 2.4 mg/kg � 80 mg/m2 qw; MTD for weekly T-DM1 � T � P is 2.4 mg/kg � 80 mg/m2 qw � 840
mg LD, 420 mg q3w. Updated results will be presented, including the MTD
for T-DM1 q3w � Tqw� P q3w, outcomes from pts with prolonged
follow-up, and duration of response from an extension trial.
Dosing † DLTs MTD Gr 3/4 AEs* SAEs* Best response*
T-DM1 (1.6–2.4 mg/kg qw) �
T (65–80 mg/m 2 qw)
4 cohorts
n�12
T-DM1 (2.4 mg/kg qw) �
T (80 mg/m 2 qw) �
P (840 mg LD,
420 mg q3w)
1 cohort
n�3
T-DM1 (2.4-3.6 mg/kg q3w) �
T (65-80 mg/m 2 qw)
3 cohorts
n�9
None 2.4 mg/kg qw �
T80mg/m 2 qw
None 2.4 mg/kg qw �
T80mg/m 2 qw �
P (840 mg LD,
mg q3w)
G3 peripheral neuropathy,
G3 neuropathy (n�2),
G3 fatigue (n�2),
G3 neutropenia (n�3),
G3 thrombocytopenia,
G3 sepsis, G3 ulcer
TBD TBD G3 hypokalemia,
G4 febrile neutropenia,
G3 abdominal pain
G3 sepsis, G3 ulcer
SD�6
PR�3
PR
unconfirmed�1
NA�2
NR NR NA�2
G4 febrile neutropenia SD�3
PR
unconfirmed�1
NA�4
*Based on data available from 22 pts as of data cutoff: Jan 24, 2012; NR�none reported; NA�not available. † Pts receiving P
added to T-DM1 q3w � T qw to be enrolled.
530 Poster Discussion Session (Board #20), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase IB/II study of the HSP90 inhibitor AUY922, in combination with
trastuzumab, in patients with HER2� advanced breast cancer. Presenting
Author: Anthony Kong, Churchill Hospital, Oxford University Hospitals
NHS Trust and University of Oxford, Oxford, United Kingdom
Background: AUY922 is a novel HSP90 inhibitor that causes degradation of
oncogenic proteins. A Phase I study in advanced solid tumors gave a
recommended Phase II dose (RP2D) of 70 mg/m2 . In the Phase II part of
the study, single-agent AUY922 showed preliminary activity in HER2�
metastatic breast cancer (mBC) (Schröder et al ASCO 2011). This Phase
Ib/II study assessed safety and efficacy of AUY922 � trastuzumab (T) in
pts with T-refractory HER2� advanced/mBC. Methods: Pts with HER2� BC
(ECOG PS �1) who progressed on 1–2 prior anti-HER2 regimens with at
least 1 T-containing regimen, received weekly AUY922 (55 or 70 mg/m2 ,
IV) � T (2 mg/kg) in a 28-day cycle. The Phase Ib primary objective was to
define a MTD/RP2D of AUY922 combined with T using an adaptive
Bayesian logistic regression model. The Phase II primary objective is to
evaluate preliminary antitumor activity at this dose (ORR). Secondary
objectives included evaluation of PK, safety and preliminary efficacy (PFS,
OS). Results: In the Phase Ib part (11 pts) there was 1 DLT (Grade [Gr] 3
diarrhea), and the full standard single dose of AUY922 was recommended
for use in combination with T. As of 11th January 2012, 31 HER2� BC pts
(median age 51 years [range 29–71]; 84% invasive ductal carcinoma;
52% estrogen receptor-positive; 81% had received �2 prior antineoplastic
regimens) received AUY922 at 55 mg/m2 (n�5) or 70 mg/m2 (n�26) � T.
The most common study drug-related AEs (all Gr) were diarrhea (25 [81%]
pts), visual AEs (e.g. vision blurred, visual impairment, photopsia) (25
[81%] pts), and nausea (11 [35%] pts). Gr 3/4 AEs were rare; most
frequently diarrhea and visual impairment (both 6%). Treatment was
ongoing for 13 (37%) pts at the cutoff date. Preliminary Phase II best
overall response data (RECIST, investigator assessed) was available for 22
pts at AUY922 70 mg/m2 . Any partial responses were reported in 5/22
(23%) pts. Conclusions: The data suggests AUY922 � T is well tolerated.
Common AEs were considered manageable, and eye disorders were
reversible with treatment interruption, dose reduction or discontinuation.
The combination of AUY922 � T is active in pts with HER2� mBC who
progressed on T-based therapy, and the regimen warrants further investigation.
529 Poster Discussion Session (Board #19), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase Ib study of open-label AMG 386 plus paclitaxel (P) and trastuzumab
(T) or capecitabine (C) and lapatinib (L) in patients (pts) with HER2�
locally recurrent or metastatic breast cancer (MBC). Presenting Author:
Hans Wildiers, Universitair Ziekenhuis Gasthuisberg, Department of General
Medical Oncology, Leuven, Belgium
Background: AMG 386, an investigational peptibody, reduces tumor angiogenesis
by blocking interaction of angiopoietins 1 and 2 with the Tie2
receptor. This interim analysis evaluates the tolerability and efficacy of
AMG 386 � P/T or C/L in HER2� MBC. Methods: In part 1, pts in cohorts
A1 and A3 (no prior 1st-line MBC T or L ) received AMG 386 IV QW plus P
80 mg/m2 IV QW and T 8 mg/kg loading dose, then 6 mg/kg Q3W; pts in
cohorts B1 and B3 (history of failed 1st-line MBC T treatment; no prior L or
C) received AMG 386 IV QW plus C 1000 mg/m2 PO Q12 hrs, days 1-14
Q21D and L 1250 mg PO QD. A1 and B1 received AMG 386 at 10 mg/kg;
A3 and B3 received AMG 386 at 30 mg/kg. In part 2, cohorts were
expanded to n � 20 if � 1of6or�2 of 9 pts had dose-limiting toxicities
(DLTs). Primary endpoints were adverse events (AEs) and DLTs; secondary
endpoints included efficacy and pharmacokinetics (PK). Interim results
from A1, A3, and B1 will be presented. Results: 46 pts were enrolled at
interim analysis; all received � 1 dose of study treatment (A1, A3, B1; n �
20, 6, 20). The median follow-up for A1, A3, and B1 was 39.6, 22.7, and
31.3 wks. Across cohorts, there was 1 DLT in A1. AEs � 50% were
peripheral edema, diarrhea, fatigue and alopecia in A1 and A3 combined,
and diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES),
and peripheral edema in B1. AEs grade �3 occurring in � 2 pts were
peripheral neuropathy, peripheral sensory neuropathy, dyspnea (n � 5, 4,
3, respectively, in A1 and A3 combined); PPES, diarrhea, and neutropenia
(n � 6, 5, 3, respectively, in B1). Objective response rates were 80% in A1,
50% in A3, and 50% in B1. Median (95% CI) progression-free survival was
14.5 mo (6.8-20.5) in A1 and 10.1 mo (3.7-14.7) in B1. Median duration
of response (DOR) was 12.6 mo (4.3-20.2) in A1 and 8.5 mo (4.1-not
evaluable) in B1. PFS and DOR were not yet evaluable in A3. No changes
were apparent in any PK parameters in these combinations relative to
within study or historical monotherapy PK data. Conclusions: In this
ongoing phase 1b study of pts with HER2� MBC, interim results suggest
that adding AMG 386 to P/T or C/L is tolerable and has antitumor activity.
Updated data will be presented.
531 Poster Discussion Session (Board #21), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A randomized phase II study (VEG108838) of lapatanib plus pazopanib
(L�P) versus lapatanib (L) in patients with ErbB2� inflammatory breast
cancer (IBC). Presenting Author: Massimo Cristofanilli, Fox Chase Cancer
Center, Philadelphia, PA
Background: ErbB2 amplification is frequently reported in IBC and there is
evidence of positive association between ErbB2 and VEGF expression. We
evaluated the combination of anti ErbB2 and VEGF therapy in ErbB2� IBC.
Methods: We conducted a multicenter, randomized clinical trial for patients
(pts) with relapsed ErbB2� IBC. Cohort 1: Pts stratified (prior trastuzumab;
cutaneous disease only vs systemic) and randomized 1:1 to receive
L 1500 mg � placebo or L 1500 mg � P 800 mg, QD. Due to high
incidence of Grade 3/4 diarrhea in pts treated with L 1500 mg� P 800 mg
in another study, Cohort 1 was closed after 76 pts randomized. Cohort 2
(87 pts ): Pts were stratified (prior trastuzumab) and randomized 5:5:2 to
receive L 1500 mg � placebo or L 1000 mg � P 400 mg (double-blind) or
P 800 mg (open-label), respectively, QD. Treatment continued until PD,
unacceptable toxicity or death. Primary endpoint was ORR. Secondary
endpoints included PFS, OS, and safety. Results: Cohort 1: 76 pts were
randomized and treated: L, n�38; L�P, n�38. ORR was 29% for the L
arm, and 45% for the L�P arm. Median PFS was 16.1 and 14.3 wks,
respectively, for the L and L�P arms. The most frequent Grade �3 AEs
were diarrhea (0% vs 18%) vomiting (0% vs 8%), ALT increased (0% vs
8%), neutropenia (3% vs 13%), and bilirubin increased (0% vs 5%). Dose
reductions due to AE were 3% and 21% and dose interruptions due to AE
were 11% and 55% in the L and L�P arms, respectively. Cohort 2: 88 pts
were randomized (87 treated): L, n�36; P, n�14; L�P, n�38. The ORR
was 47%, 31%, and 58% for the L, P, and L�P arms, respectively. Median
PFS was 16.0, 11.4, and 16.0 wks for the L, P, and L�P arms,
respectively. The most frequent Grade �3 AEs were ALT increased (0%,
0%, 21%), AST increased (0%, 0%, 18%), diarrhea (3%, 8%, 8%), and
fatigue (3%, 8%, 8%). Dose reductions due to AE occurred in 0%, 0%, and
13% of pts and dose interruptions due to AE occurred in 22%, 23%, and
39% of pts in the L, P, and L�P arms, respectively. Conclusions: This
prospective, randomized study confirmed the clinical activity of lapatinib
single agent in metastatic ErbB2� IBC. Furthermore, we demonstrated
increased toxicity associated with the combination without a clinically
meaningful improvement in efficacy.
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