Transcript HER2-positive breast cancer

Updates from the San Antonio Breast
Cancer Symposium 2013
HER2+ Breast Cancer
Julie R. Gralow, M.D.
Director and Jill Bennett Professor of Breast Medical
Oncology
Professor of Global Health
University of Washington School of Medicine
Fred Hutchinson Cancer Research Center
Seattle Cancer Care Alliance
HER-2 Over-Expressing Breast Cancer
HER-2 Oncogene: amplified and overexpressed in 2025% of breast cancer
Pertuzumab
Anti-HER-2 Antibody
HER-2
Trastuzumab
Anti-HER-2 Antibody
cancer cell
nucleus
T-DM1
Antibody-Drug
Conjugate
Lapatinib
Dual HER-1/HER-2
Tyrosine Kinase Inhibitor
cell division
2
APT Study: Phase II Study of Paclitaxel +
Trastuzumab as Adjuvant Therapy for
Small, Node-negative HER2+ Breast Cancer
Tolaney SM et al, SABCS 2013, abstract #S1-04
• Randomized adjuvant HER2+ trials included few
small, lymph node negative breast cancers
• Patients: 406 pts with node-negative, HER2+ breast
cancer, < 3 cm
– 2/3 ER+, 20% < 0.5 cm
• Treatment: Paclitaxel and trastuzumab weekly x 12,
followed by 9 months of single agent trastuzumab
• Results: 3.6 years median follow-up
– 10 recurrences/deaths (2.5%): 2 distant, 4
locoregional, 3 contralateral breast cancers, 1 nonbreast cancer death (ovarian ca)
– 3 year DFS 98.7%
APT Study: Phase II Study of Paclitaxel +
Trastuzumab as Adjuvant Therapy for
Small, Node-negative HER2+ Breast Cancer
Tolaney SM et al, SABCS 2013, abstract #S1-04
• Toxicity:
– 2 symptomatic CHF (resolved on stopping
trastuzumab)
– 13 asymptomatic declines in LVEF (able to resume
trastuzumab in 11)
• Conclusion: Paclitaxel plus trastuzumab can be
considered a reasonable approach for majority of
patients with small, lymph node negative, HER2+
breast cancer
HER2 Therapy Combinations
Neo ALTTO: Preop HER2+
Baselga J et al, Lancet 379:633-640, 2012
Invasive,
operable
HER2+ breast
cancer
T > 2 cm
N=450
R Lapatinib 1500 mg/d
A
paclitaxel
S
N
80 mg/m2
U
D
O Trastuzumab weekly R
G
M
paclitaxel
E
I
R
Z
E Lapatinib 1000 to 750 Y
trastuzumab
paclitaxel
pCR
lapatinib
F
E
C
trastuzumab
X
3
lapatinib
trastuzumab
Neo ALTTO: Survival Follow-up Analysis
Piccart M et al, SABCS 2013 abstract #S1-01
Lapatanib +
Trastuzumab
Trastuzumab
Lapatinib
84%
78%
78%
HR+
83%
80%
86%
HR-
86%
72%
70%
3 yr OS (all)
95%
90%
93%
HR+
97%
94%
93%
HR-
93%
87%
93%
3 yr EFS (all)
None statistically significant
Neo ALTTO: EFS and OS by pCR
Piccart M et al, SABCS 2013 abstract #S1-01
Neo ALTTO Survival Follow-up
Analysis: Conclusions
• Underpowered to detect moderate EFS and OS
differences, await results of ALTTO adjuvant trial
• Patients who achieved pCR had significantly better
EFS and OS compared with no pCR
• HER2+/ER- disease different from HER2/ER+ disease
Combined HER-2 Targeted Therapy
BIG 2.06/N063D Adjuvant HER2+ Trial
(ALTTO) – Soon to Report
PIs: M Piccart, E Perez
HER2+ BC
Tumors 1
cm after
completion
of
anthracycline
based
therapy with
LVEF 50%
N= 8,000
R
A
N
D
O
M
I
Z
E
(paclitaxel) trastuzumab (trast for 1 yr)
(paclitaxel) lapatinib (lap for 1 yr)
(paclitaxel) trastuzumab+ lapatinib
(trast + lap for 1 yr)
(paclitaxel) trastuzumab (12 weeks),
6-week wash out , lapatinib (34 weeks)
TRIO Trial: Phase II Trial of Preoperative
Trastuzumab, Lapatinib or Combination
Hurvitz S et al, SABCS 2013, abstract #S1-02
HER2+
invasive
breast
cancer
Stage IIII
N=130
Trastuzumab
1 dose
TCH x 6 cycles
Lapatinib
21 days
TCL x 6 cycles
Lapatinib
21 days
Trastuzumab
1 dose
TCHL x 6 cycles
biopsy
surgery
TRIO Trial: Phase II Trial of Preoperative
Trastuzumab, Lapatinib or Combination
Hurvitz S et al, SABCS 2013, abstract #S1-02
TRIO Trial: Phase II Trial of Preoperative
Trastuzumab, Lapatinib or Combination
Hurvitz S et al, SABCS 2013, abstract #S1-02
• pCR similar in TCH and TCHL arms
– Differs from other preop studies
– Numbers in each arm very small
• Addition of lapatinib increased toxicity, limiting ability
of patients to receive planned therapy
• Molecular analyses ongoing
to evaluate profiles of nonresponders
BETH: Randomized Phase III Trial of
Adjuvant Bevacizumab in HER2+ Breast
Cancer
Slamon D et al, SABCS 2-13, abstract #S1-03
Node positive or high-risk node negative
HER2+
Cohort 2
Anthracycline
Cohort 1
Non-Anthracycline
N= 278
N= 3231
TCH
Arm 1A
TCH
TH
H
Arm 1B
H
TCHBev
HBev
Arm 2A
TH
FEC
H
FEC
H
Arm 2B
THBev
FEC HBev
BETH: Randomized Phase III Trial of
Adjuvant Bevacizumab in HER2+ Breast
Cancer
Slamon D et al, SABCS 2-13, abstract #S1-03
Median Follow-up 38 months
IDFS
OS
No Bevacizumab
92%
96%
+ Bevacizumab
92%
97%
1 year of adjuvant bevacizumab added to chemo and
trastuzumab does not improve IDFS or OS
BETH: Randomized Phase III Trial of
Adjuvant Bevacizumab in HER2+ Breast
Cancer
Slamon D et al, SABCS 2-13, abstract #S1-03
Adverse Events (grade 3, 4)
Chemo/Trastuzumab Chemo/Trastuzumab
/Bevacizumab
Hypertension
4%
19%
Thromboembolic
event
Bleeding
2%
3%
<1%
2%
CHF
<1%
2.1%
1 event
11 events
GI perforation
TH3RESA Trial: T-DM1 in Later Line
Metastatic Disease
Wildiers H et al, European Cancer Congress 2013,
Abstract LBA15
• HER2+ MBC
• Prior anthracycline,
taxane,
capecitabine,
lapatinib,
trastuzumab
• Progression on at
least 2 HER2 Rxs
• N=795
• 2:1 randomization
T-DM1 q3wks
R
Physician’s Choice
TH3RESA Trial: T-DM1 in Later Line
Metastatic Disease
Wildiers H et al, European Cancer Congress 2013, Abstract
LBA15
Metastatic T-DM1 and Pertuzumab
CLOSED: MARIANNE Phase III 1st-Line
HER2+ Metastatic Breast Cancer
HER2+ recurrent locally
advanced or untreated
MBC
Trastuzumab + Taxane
T-DM1 + Pertuzumab
n=1092
Primary endpoint: OS
T-DM1 + Placebo
Rx until progressive disease
Adjuvant Pertuzumab
CLOSED: APHINITY Trial Phase III Trial of
Adjuvant Pertuzumab added to Standard
Chemo and Trastuzumab
• N=4800
• Operable
HER2+
breast
cancer
• Primary
endpoint:
IDFS
Standard chemotherapy (6-8 cycles) +
Trastuzumab q3 wks x 52 weeks
+ Pertuzumab q3 wks x 52 weeks
R
Standard chemotherapy (6-8 cycles) +
Trastuzumab q3 wks x 52 weeks
+ Placebo q3 wks x 52 weeks
Adjuvant Pertuzumab and T-DM1
SOON TO OPEN: KAITLIN Study
Phase III Trial of Adjuvant Trastuzumab +
Pertuzumab + Taxane vs TDM1 + Pertuzumab in
HER2+ Breast Cancer
HER2+, nonmetastatic breast
cancer
(n=2500)
Co-Primary
endpoints: invasive
DFS & OS
T-DM1 + Pertuzumab
Anthracyclinebased regimen
Taxane +
Trastuzumab +
Pertuzumab
Residual Disease after Preop Therapy
OPEN KATHERINE Trial: Phase III Trial of T-DM1
vs Trastuzumab in Patients with HER2+ Breast
Cancer with Residual Disease after Preop Therapy
HER2+, nonmetastatic
breast cancer
T1-4, N0-3 at
presentation
(n=1484)
Primary
endpoints:
invasive DFS
Preop
Therapy:
At least 6
cycles,
including at
least 9 weeks
of taxane and
trastuzumab
Surgery:
Residual
tumor in
breast or
axilla
T-DM1 q3 wks x
14
Trastuzumab
q3 wks x 14
Adjuvant HER2 Therapy Low HER2 Expression Tumors
ONGOING NSABP B-47: Adjuvant Trastuzumab in
Breast Cancer with Normal HER2 Expression
N= 3,260
Primary Breast Cancer
HER2 IHC 1+ or 2+
FISH Negative
Randomization
Docetaxel +
Cyclophosphamide x 6
or
AC x 4 + Paclitaxel x 12
(MD Choice)
Docetaxel +
Cyclophosphamide x 6
or
AC x 4 + Paclitaxel x 12
(MD Choice)
+
Trastuzumab x 1 yr