advances in the management of metastatic her 2 positive breast...
TRANSCRIPT
Advances in the Management of
Metastatic Her 2 Positive Breast Cancer
Sunil Verma MD, MSEd, FRCPC
Medical Oncologist
Research Lead, Division of Medical Oncology
Chair, Breast Medical Oncology
Sunnybrook Odette Cancer Centre
Associate Professor, University of Toronto
HER2 overexpression
associated with more
aggressive phenotype4
1987
The Her 2 Journey
1. Ullrich A, et al. Nature 1984; 309:418−4253;
Anti-HER2 monoclonal
mouse antibody
humanised: trastuzumab6
1992
HER2 gene is cloned2
HER2 protein found to be
overexpressed in breast tumours3
1985
HER2/neu
gene identified1
1984
Anti-HER2
monoclonal mouse
antibody
developed5
1989
Trastuzumab
clinical trials begin
1993−1995
3. Sainsbury JR, et al. Lancet 1985; 1:364−366;
5. Huzdiak RM, et al. Mol Cell Biol 1989; 9:1165–1172;
4. Di Fiore PP, et al. Science 1987; 237:178–182
6. Carter P, et al. Proc Natl Acad Sci USA 1992; 89:4285–4289
2. Ishii S, et al. Proc Natl Acad Sci USA 1985; 82:4920–4924
Her 2 Story Poor Prognostic Marker
Outline
• First Line Treatment
• Second Line Treatment and Beyond
• Individualized Approach
• An Algorithm and Concluding Remarks
Outline
• First Line Treatment
• Second Line Treatment and Beyond
• Individualized Approach
• An Algorithm and Concluding Remarks
OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxelOS, overall survival; RR, relative risk of death Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:783–792.
Trastuzumab prolongs overall survival in
HER2-positive MBC
Chemotherapy (n = 234)
Chemotherapy + trastuzumab (n = 235)
Overa
ll s
urv
iva
l (%
)
Time (months after enrolment)
RR = 0.80 (95% CI = 0.64,1.00)
p = 0.046
Median OS:
20.3 months
Median OS:
25.1 months
0
20
40
60
80
100
5 15 25 35 450
First Line Treatment Approach (2001-
2011)
• A number of effective options with chemo and
anti-her2
– Taxanes and Herceptin
– Vinorelbine and Herceptin
– Capecitabine and Anti-Her2
– Doublet chemo with Her 2 generally not used
• Select group of patients may benefit from an
anti-Her2 and anti-estrogen approach
Recent Achievements in
Her 2 positive MBC
First Line
– MA.31
• Taxane + H vs. Taxane + L
– Bolero -1
• Paclitaxel + H vs. Paclitaxel + H +Everolimus
– CLEOPATRA
• Chemo + H vs. Chemo +H+P
8
Gelmon et. al ASCO 20129
Gelmon et. al ASCO 201210
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium – December 9-13, 2014
BOLERO-1/TRIO 019: Study Design
11
Everolimus (10 mg PO daily) +
Paclitaxel2 + Trastuzumab3
Placebo +
Paclitaxel2 + Trastuzumab3
Stratification factors:• Prior neo/adjuvant TRAS
• Visceral metastases
• Primary: PFS (investigator-assessed)
• Overall population and
• HR subpopulation
N = 719
• Locally advanced or metastatic
HER2+ breast cancer
• No prior therapy for advanced or
metastatic disease (except
endocrine therapy)
• Prior (neo)adjuvant TRAS and/or
chemotherapy allowed1
• Measurable disease or presence of
bone lesions (lytic or mixed)
Randomized
2:1
Therapy until disease progression
or intolerable toxicity4
ABC, advanced breast cancer; CBR, clnical benefit rate; ORR, overall response rate; OS, overall survival; PFS, progression free survival.
• Secondary:
• OS, ORR, CBR, Time to response, Safety, Duration of
response
1Discontinued > 12 mo before randomization; 2Paclitaxel: 80 mg/m2 weekly; 3Trastuzumab: 4 mg/kg loading dose on day 1 at cycle 1 followed by 2 mg/kg weekly doses4Patients could discontinue any study treatment due to AEs; other study treatments continued until disease progression or intolerable toxicity
Endpoints
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium – December 9-13, 2014
BOLERO-1/TRIO 019: PFS Full Population(Investigator-assessment)
12
480 416 365 324 289 260 217 178 151 130 122 107 94 80 72 63 58 48 42 35 26 21 17 13 10 5 3 3 0239 221 199 166 144 123 106 91 80 69 53 47 43 38 36 36 31 24 17 15 12 9 7 6 4 3 1 1 0
No. of patients still at risk
EverolimusPlacebo
Pro
bab
ilit
y (
%)
0%
20%
40%
60%
80%
100%
Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56
Hazard Ratio = 0.89; 95% CI [0.73, 1.08]
Median PFS
Everolimus: 14.95 months; 95% CI [14.55, 17.91] (n/N = 271/480)
Placebo: 14.49 months; 95% CI [12.29, 17.08] (n/N = 154/239)
Log rank p value = 0.1166
- One-sided p-value is obtained from the log-rank test stratified by prior use of trastuzumab (Y/N) and Visceral metastasis (Y/N) from IWRS.
Censoring times
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium – December 9-13, 2014
BOLERO-1/TRIO 019: Most Frequent Adverse Events (Safety set) [> 25% in everolimus arm]
13
AE/Grade
EVE + TRAS + PAC
(N = 472)
%
PBO + TRAS + PAC
(N = 238)
%
Any Grade 3 Grade 4 Any Grade 3 Grade 4
Non-hematologic
Stomatitis 67 13 0 32 1 0
Diarrhea 57 9 0 47 4 0
Alopecia 47 <1 0 53 0 0
Rash 40 1 0 21 <1 0
Cough 40 <1 0 33 1 0
Pyrexia 39 2 0 27 1 0
Fatigue 35 5 0 36 3 0
Epistaxis 33 0 0 18 0 0
Peripheral edema 33 1 0 24 <1 0
Nausea 33 1 0 35 1 0
Peripheral neuropathy 29 4 0 24 5 0
Headache 28 1 0 29 1 0
Vomiting 26 1 0 23 3 0
Pneumonitis* 16 4 1 4 <1 0
Hematologic
Neutropenia 38 21 4 25 11 4
Anemia 31 9 1 16 3 0
*AE of clinical importance
EVE, Everolimus; HR, hormone receptor; PAC, Paclitaxel; PBO, Placebo; TRAS, Trastuzumab.
CLEOPATRA study design
14HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease
Patients with
HER2-positive MBCcentrally confirmed
(N=808)
Placebo + trastuzumab
1:1
Randomization was stratified by geographic region and prior treatment status
(neo/adjuvant chemotherapy received or not)
Docetaxel≥6 cycles recommended
n=406
n=402
Pertuzumab + trastuzumab
Docetaxel≥6 cycles recommended
PD
PD
Swain et al. SABCS 2012 Poster P5-18-26 .
Updated Kaplan-Meier curves of
investigator-assessed PFS
15D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
Time (months)
Pro
gre
ss
ion
-fre
e s
urv
ival
(%)
45 50
0
0
0
0
8
8
34
26
67
42
108
72
178
110
218
148
284
223
341
329
402
406
Ptz + T + D: median 18.7 monthsPla + T + D: median 12.4 months
HR=0.6995% CI 0.58−0.81
∆=6.3 months
n at risk
Ptz + T + D
Pla + T + D
Swain et al. SABCS 2012 Poster P5-18-26 .
PFS
primary
analysis
May 2011
Efficacy Analysis Milestones
May 2012
OS
1st interim
analysis
OS
2nd interim
analysis
16
HR 0.64 (p = 0.005)
Δ 6.1 months
HR 0.62 (p < 0.0001)
HR 0.66 (p = 0.0008)*
July 2012
Patients still on
placebo offered
crossover to
pertuzumab
Feb 2014
OS
final analysis
Final OS AnalysisMedian follow-up 50 months (range 0–70 months)
17
ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.
CI, confidence interval; Pla, placebo; Ptz, pertuzumab.17
OS
(%
)
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 7060
Time (months)
HR 0.68
95% CI = 0.56, 0.84
p = 0.0002
Ptz + T + D
Pla + T + D
128104226268318371
02391179230289350
n at risk
Ptz + T + D
Pla + T + D
402
406
40.8
months
56.5
monthsΔ 15.7
months
Cleopatra Overall Survival
Cross over patients (11%) excluded
Swain et. al NEJM 2015
Breast cancer therapies following
discontinuation of study treatment in patients
who had withdrawn from study treatment
20
n (%)
Placebo+ trastuzumab + docetaxel
(n=338)
Pertuzumab+ trastuzumab + docetaxel
(n=298)
Any 260 (76.9) 225 (75.5)
In patients receiving subsequent breast cancer treatment
n=260 n=225
Any HER2-targeted treatment 178 (68.5) 160 (71.1)
Trastuzumab 104 (40.0) 106 (47.1)
Lapatinib 114 (43.8) 93 (41.3)
Trastuzumab emtansine 26 (10.0) 21 (9.3)
Capecitabine 140 (53.8) 113 (50.2)
Vinorelbine 70 (26.9) 51 (22.7)
Cyclophosphamide 43 (16.5) 30 (13.3)
Doxorubicin 46 (17.7) 29 (12.9)
Paclitaxel 32 (12.3) 21 (9.3)
Docetaxel 11 (4.2) 13 (5.8)
Swain et al. SABCS 2012 Poster P5-18-26 .
Adverse events (all grades) with ≥25%
incidence or ≥5% difference between arms
21Highlighted are adverse events with ≥5% higher incidence
n (%)Placebo + trastuzumab + docetaxel
(n=396)Pertuzumab + trastuzumab + docetaxel
(n=408)
Diarrhea 191 (48.2) 278 (68.1)
Alopecia 240 (60.6) 248 (60.8)
Neutropenia 197 (49.7) 216 (52.9)
Nausea 168 (42.4) 179 (43.9)
Fatigue 148 (37.4) 155 (38.0)
Rash 95 (24.0) 149 (36.5)
Decreased appetite 105 (26.5) 121 (29.7)
Mucosal inflammation 79 (19.9) 112 (27.5)
Asthenia 121 (30.6) 110 (27.0)
Vomiting 97 (24.5) 104 (25.5)
Peripheral edema 122 (30.8) 101 (24.8)
Pruritus 40 (10.1) 68 (16.7)
Constipation 101 (25.5) 63 (15.4)
Febrile neutropenia 30 (7.6) 56 (13.7)
Dry skin 23 (5.8) 44 (10.8)
Swain et al. SABCS 2012 Poster P5-18-26 .
Cardiac adverse events
22
* In patients with post-baseline assessment
LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction
n (%)Placebo
+ trastuzumab + docetaxelPertuzumab
+ trastuzumab + docetaxel
Data cutoff date May 2011(n=397)
May 2012(n=396)
May 2011(n=407)
May 2012(n=408)
LVSD (all grades) 33 (8.3) 34 (8.6) 18 (4.4) 22 (5.4)
Symptomatic LVSD 7 (1.8) 7 (1.8) 4 (1.0) 5 (1.2)
LVEF decline to <50% and by ≥10% points from baseline*
25/379 (6.6) 28/378 (7.4) 15/393 (3.8) 18/394 (4.6)
LVEF recovery to ≥50%* 18/25 (72.0) 25/28 (89.3) 13/15 (86.7) 16/18 (88.9)
Swain et al. SABCS 2012 Poster P5-18-26 .
KADCYLA is a HER2-targeted antibody and microtubule inhibitor conjugate
consisting of
• HERCEPTIN, a humanized anti-HER2 IgG1 monoclonal antibody
• DM1, a cytotoxic microtubule inhibitor derived from maytansine
− on average, KADCYLA has 3.5 DM1 molecules per antibody
• MCC, a stable thioether linker, covalently linking HERCEPTIN to DM1
T-DM1Mechanism of Action
Antibody
(HERCEPTIN)
Stable linker
Cytotoxic
agent (DM1)
Emtansine
DM: derivative of maytansine
MCC: 4-[N-maleimidomethyl] cyclohexane-1-
carboxylate
KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.
Swanton C, Johnston SR, editors. Handbook of Metastatic Breast Cancer, 2nd ed. Informa Healthcare, New York, 2012.
In vitro studies in human breast cancer cells that overexpress HER2 have
shown that, like HERCEPTIN, KADCYLA
• Binds subdomain IV of the HER2 extracellular domain
• Inhibits HER2 signaling
• Mediates antibody-dependent cell-mediated cytotoxicity (ADCC)
• Inhibits shedding of the HER2 extracellular domain
T-DM1Retains Activity of Herceptinf
KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.
KADCYLA has the additional MOA of DM1. Upon binding to HER2, KADCYLA undergoes
• Receptor-mediated internalization
• Subsequent lysosomal degradation
• Intracellular release of DM1-containing cytotoxic catabolites
• DM1 binding to tubulin, disrupting microtubule networks in the cell, resulting in cell
cycle arrest and apoptotic cell death
T-DM1Intracellular Delivery of DM1
HER2
Lysosomal
degradation
DM1
release*
Internalization
Inhibition of
tubulin
polymerizatio
n
KADCYLA
*The primary DM1-containing cytotoxic catabolite released is lysine-MCC-DM1.
KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.
LoRousso PM, et al. Clin Cancer Res 2011.
PHASE II STUDY
T-DM1 vs. Docetaxel and Trastuzumab
1:1 HER2-positive,
recurrent locally
advanced breast
cancer or MBC
(N=137)
Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV
+ Docetaxel 75 or 100 mg/m2 q3w
(n=70)
Crossover to
T-DM1
(optional)PDa
T-DM13.6 mg/kg q3w IV
(n=67)
PDa
Hurvitz, et al., JCO, 2013
Objective Response by Investigator Patients With Measurable Disease at Baseline
Trastuzumab +
docetaxel
(n=69)a
T-DM1
(n=67)
Patients with an objective response,b n (%) 40 (58.0) 43 (64.2)
95% CI 45.5–69.2 51.8–74.8
Objective responses, n (%)
Complete response 3 (4.3) 7 (10.4)
Partial response 37 (53.6) 36 (53.7)
Stable disease 23 (33.3) 13 (19.4)
Progressive disease 4 (5.8) 8 (11.9)
Unable to evaluate or missing 2 (2.9) 3 (4.5)
Patients with clinical benefit,c n (%) 56 (81.2) 50 (74.6)
95% CI 70.7–89.1 63.2–84.2 aOne patient was not included in the efficacy analysis due to study site withdrawal.bDefined as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4
weeks apart.cDefined as objective response any time during the study or maintained stable disease for at least 6 months
from randomization.
Hurvitz SA, et al. Abstract 5.001. ESMO 2011.
Hurvitz, et al., JCO, 2013
This presentation contains non-licensed product information and may be subject to local affiliate compliance and / or legal approval before onward internal distribution.
This information is for internal use only and must not be distributed externally
Time (months)
Progression-Free Survival by InvestigatorRandomized Patients
Pro
po
rtio
n p
rog
ressio
n-f
ree
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20
Number of patients at risk
T+D 70 66 63 53 43 27 12 4 2 2 0
T-DM1 67 60 51 46 42 35 22 15 6 3 0
Hazard ratio and log-rank P value were from stratified analysis.
Trastuzumab
+ docetaxel (n=70)
T-DM1 (n=67)
Median
PFS, mos
Hazard ratio 95% CI
Log-rank Pvalue
9.2
14.20.59 0.36 –
0.97 0.035
Hurvitz, et al., JCO, 2013
Figure adapted from:http://clinicaltrials.gov/ct2/show/NCT01120184;
Roche. Data on file
MARIANNE: A clinical trial of pertuzumab and
T-DM1 in first-line metastatic breast cancer
HER2-positive,
progressive or
recurrent, locally
advanced or
untreated MBC
(N = 1092)
Pertuzumab + T-DM1
Trastuzumab + taxane (docetaxel or paclitaxel)
R Placebo + T-DM1
2010 2011–2012 2013
First patient in
July 2010
Last patient in
Q2 2012
T-DM1 ± pertuzumab: blinded, placebo-controlled
Trastuzumab + taxane: open-label
MARIANNEStatistical Analysis
Summary
First Line
• The standard of care should consist of
pertuzumab and trastuzumab along with
docetaxel (? other taxane alternative)
31
Future Questions
First Line• Can we combine Pertuzumab and Herceptin with other
partners
– Other taxanes (PERUSE)
– Other chemotherapies - Vino/Cape (VELVET/PHREXA)
– Other biologics – T-DM1 (MARIANNE negative)
• Developing effective drugs that can target brain
metastases
• Duration of targeted therapy for those responding
• Duration of chemotherapy when receiving dual targeted
therapy
• Combination of endocrine therapy with dual targeted
anti-Her 2 tx for ER+/Her 2 +ve pts32
Outline
• First Line Treatment
• Second Line Treatment and Beyond
• Individualized Approach
• An Algorithm and Concluding Remarks
Second Line
(2006-2010)
• There is continued benefit of trastuzumab
beyond progression
– Capecitabine and Trastuzumab
• There is benefit of Lapatinib in combination with
Capecitabine upon progression on Trastuzumab
Recent Achievements in
Her 2 positive MBC
Second Line and Beyond
– EGF 104900
• L+ H vs L alone
– EMILIA
• T-DM1 vs Cape + L
– Bolero-3
• Vinorelbine + H + Everolimus vs. Vinorelbine
+ H
35
Trastuzumab and LapatinibOverall Survival
EMILIA Study Design
1:1
HER2-positive LABC
or MBC (N=980)
• Prior taxane and
trastuzumab
• Progression on
metastatic treatment
or within 6 months of
adjuvant treatment
PDT-DM1
3.6 mg/kg q3w IV
Capecitabine
1000 mg/m2 PO bid, days 1–14, q3w
+
Lapatinib
1250 mg/day PO qd
PD
Verma et al NEJM 2012
Verma et al NEJM 2012
EMILIA: Progression Free Survival
Verma et al NEJM 2012
EMILIA: Overall Survival
EMILIA
Adverse Events
Verma et al NEJM 201240
2
T-DM1c
(optional
crossover)
TH3RESA Study Schema
• Stratification factors: World region, number of prior regimens for advanced BC,d
presence of visceral disease
• Co-primary endpoints: PFS by investigator and OS
• Key secondary endpoints: ORR by investigator and safety
PD
PDT-DM1
3.6 mg/kg q3w IV(n=400)
Treatment of
physician’s choice
(TPC)b
(n=200)
HER2-positive (central)
advanced BCa
(N=600)
≥2 prior HER2-directed
therapies for advanced BC
Prior treatment with
trastuzumab, lapatinib,
and a taxane
a Advanced BC includes MBC and unresectable locally advanced/recurrent BC.b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with
a chemotherapy, hormonal therapy, or other HER2-directed therapy.c First patient in: Sep 2011. Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive
T-DM1 after documented PD.d Excluding single-agent hormonal therapy.
BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks.
1
Wildiers H, et al. ECC 2013; Abstract 15LBA.
.
PFS by Investigator Assessment
Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.
Unstratified HR=0.521 (P<0.0001).
198 120 62 28 13 6 1 0
404 334 241 114 66 27 12 0
TPC
T-DM1
No. at risk:Time (months)
1412108642
0.0
0.2
0.4
0.6
0.8
1.0
0
Pro
po
rtio
n p
rog
ress
ion
-fre
e
TPC
(n=198)
T-DM1
(n=404)
Median (months) 3.3 6.2
No. of events 129 219
Stratified HR=0.528 (95% CI, 0.422, 0.661)
P<0.0001
Wildiers H, et al. ECC 2013; Abstract 15LBA.
.
First Interim OS Analysis
198
404
169
381
125
316
80
207
51
127
30
65
9
30
0
0
TPC
T-DM1
No. at risk:
3
7
Time (months)
44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.
Unstratified HR=0.57 (P=0.004).
1612108642
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n s
urv
ivin
g
0 14
Observed 21% of targeted events
TPC
(n=198)
T-DM1
(n=404)
Median (months) 14.9 NE
No. of events 44 61
Stratified HR=0.552 (95% CI, 0.369, 0.826); P=0.0034
Efficacy stopping boundary HR<0.363 or P<0.0000013
Wildiers H, et al. ECC 2013; Abstract 15LBA.
.
O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.
O Regan ASCO 201344
O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.
O Regan ASCO 201345
Summary
Second Line and Beyond• T-DM1 offers significant clinical benefit and superior
toxicity profile and is effective for second line Her 2 +
treatment
• Patients progressing on T-DM1 still may derive a benefit
from ongoing systemic tx with chemo with anti-Her 2
approaches
• The role of Lapatinib has evolved and now is generally
considered in third or later lines of treatment. One may
consider earlier use if:
– Progressive brain metastases despite radiation
– Lack of response to first/second line of herceptin based regimen
– ? Biomarkers – p95 still needs to be validated
46
Future Questions
• Is there a benefit of Pertuzumab or T-DM1 (along with
other partners) beyond progression?
• What is the effect on tumor biology once patients
progress on Pertuzumab/T-DM1?
– What are potential targeted agents that may help
overcome resistance?
• What will be the role of PI3K inhibitors in second line +
treatment?
• Who are the ideal patients for dual targeted treatment
alone?
• The Next Generation of anti-Her 2 Drugs….
47
2014
PHEREXA: A clinical trial of pertuzumab
in second-line metastatic breast cancer
2013
Last patient in Q3
HER2-positive MBC
(N = 450)
Arm A:
Pertuzumab + trastuzumab + capecitabine
Arm B:
Trastuzumab + capecitabine
R
Figure adapted from:Muñoz-Mateu M, et al. ASCO 2011 (Abstract TPS118: poster presentation);
Roche. Data on file.
MM-302 is a HER2-targeted antibody-drug conjugated liposomal formulation
Liposome
• Extended half-life
• Stably encapsulates doxorubicin
• Passive accumulation in tissues
possessing leaky vasculature
• Size precludes delivery to cardiac tissue
Lipid
Membrane PEG
75-110 nm
Doxorubicin Crystals• Effective cytotoxic agent in Br Ca
• DNA intercalator, TOP2A inhibitor, free
radical generator
anti-HER2 scFv
• Targets liposome to HER2-overexpressing cells
• Promotes internalization
• Binds to different epitope than trastuzumab
• Does not inhibit HER2 signaling
• No uptake of F5 containing liposomes into
cardiomyocytes
T cell dependent bispecific antibody (TDB) platform
+ =
Hole:
aCD3
Knob:
aTumor antigenFull length
TDB
Ridgeway...Carter. 1996 Prot. Engineering
Atwell...Carter. 1997 J. Mol Biol.
• Produced using modular “knobs into holes” technology
• Effector functions removed (E. coli production / N297A)
• Minimal immunogenic potential
• PK is similar to conventional IgG1
T366SL368AY407V T366W
Outline
• First Line Treatment
• Second Line Treatment and Beyond
• Individualized Approach
• An Algorithm and Concluding Remarks
Personalized Factors to Consider
• Hormone Receptor Status
• Prior Adjuvant Trastuzumab
• CNS Metastases
• Biomarkers
CLEOPATRA
PFS in predefined subgroups
54
ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PFS, progression-free survival; PgR, progesterone receptor
808 0.69 0.58‒0.81
432 0.67 0.54‒0.85376 0.70 0.55‒0.90
306 0.70 0.53‒0.91135 0.60 0.40‒0.91114 0.54 0.34‒0.85253 0.81 0.60‒1.10
681 0.72 0.60‒0.87127 0.49 0.31‒0.76789 0.69 0.59‒0.8219 0.62 0.16‒2.40
480 0.65 0.52‒0.8030 0.50 0.16‒1.54261 0.81 0.60‒1.1037 0.47 0.20‒1.10
630 0.63 0.53‒0.76178 0.89 0.61‒1.31
388 0.76 0.60‒0.97408 0.62 0.49‒0.78
721 0.66 0.55‒0.79767 0.70 0.59‒0.83
n HR 95% CI
All
NoYes
EuropeNorth AmericaSouth America
Asia
<65 years≥65 years<75 years≥75 years
WhiteBlackAsianOther
Visceral diseaseNon-visceral disease
PositiveNegative
IHC 3+FISH-positive
0 1
ER/PgR status
Disease type
Race
Age group
Region
HER2 status
Prior (neo)adjuvant chemotherapy
2 3
Favorsplacebo
Favorspertuzumab
Swain et al. SABCS 2012 Poster P5-18-26 .
Hormone Receptor Status
Cleopatra PFS Subgroup Analysis
Cleopatra OS Subgroup Analysis
Cap + Lap T-DM1
Baseline characteristic
Totaln
Median (mos)
Median (mos)
HR(95% CI)
T-DM1Better
Cap + LapBetter
All patients 991 25.1 30.9 0.70 (0.56, 0.87)
Age group
<65 years 853 24.6 30.9 0.66 (0.52, 0.83)
65–74 years 113 27.1 NR 0.74 (0.37, 1.47)
≥75 years 25 NR 11.1 3.45 (0.94, 12.65)
ER and PR status
ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85)
ER– and PR– 426 23.7 27.1 0.75 (0.54, 1.03)
Line of therapya
First-line 118 27.9 NR 0.61 (0.32, 1.16)
Second-line 361 NR 27.1 0.88 (0.61, 1.27)
Third- and later-line 512 23.3 33.9 0.62 (0.46, 0.84)
EMILIA
Overall Survival Subgroup Analyses
Hazard ratio 0.2 0.5 1 2 5aDefined as any systemic therapy including endocrine and chemotherapy.
NR, not reached.
From confirmatory OS analysis; data cut-off July 31, 2012.Verma et al. ESMO 2012; Oral Abstract #LBA12
Hormone Receptor Status
BOLERO-3: PFS Subgroup Analyses by Local Assessment
Favors PBOFavors EVE
Subgroup N
All 569
Age < 65 years 472
≥ 65 97
Region Europe 223
North America 123
Asia 166
Latin America 36
Other 21
Prior lapatinib* Yes 161
No 408
Prior adj/neo trastuzumab** Yes 251
No 318
Baseline ECOG PS 0 3821 or 2 186
Hormonal status ER–/PgR– 250
ER+/PgR+ 317
Visceral involvement Yes 439
No 130
Hazard Ratio [95% CI]
0.78 [0.65-0.95]
0.77 [0.62-0.95]
0.93 [0.56-1.57]
0.72 [0.53-0.99]
0.86 [0.55-1.32]
0.83 [0.59-1.18]
0.61 [0.27-1.38]
1.28 [0.48-3.45]
0.79 [0.56-1.11]
0.78 [0.62-0.99]
0.65 [0.48-0.87]
0.92 [0.71-1.18]
0.79 [0.63-1.00]
0.75 [0.53-1.05]
0.65 [0.48-0.87]
0.93 [0.72-1.20]
0.89 [0.72-1.10]
0.48 [0.30-0.76]
58
Abbreviations: CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group
performance status.
O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.
Hormone Receptor Status
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium – December 9-13, 2014
BOLERO-1/TRIO 019: PFS HR– Subpopulation (Investigator Assessment)
59
• HR=0.66 [0.48, 0.9], p = 0.0043• Sensitivity analysis without censoring patients at the start of new antineoplastic therapy:
• Median PFS and 95% CIs– 20.27 mo (14.82, 24.08) for everolimus [n = 102]
– 12.88 mo (10.94, 16.56) for placebo [n = 68]
208 183 166 151 138 125 100 84 73 64 62 55 49 40 35 32 30 24 21 19 15 11 10 7 5 2 1 1 0103 96 83 68 58 49 43 34 32 28 24 21 20 19 19 19 17 13 7 6 5 4 2 1 1 0 0 0 0
No. of patients still at risk
EverolimusPlacebo
Hazard Ratio = 0.66; 95% CI [0.48, 0.91]
Median PFS
Everolimus: 20.27 months; 95% CI [14.95,24.08] (n/N = 97/208)
Placebo: 13.08 months; 95% CI [10.05,16.56] (n/N = 66/103)
Log rank p value = 0.0049
Pro
bab
ilit
y (
%)
0%
20%
40%
60%
80%
100%
Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56
- One-sided p-value is obtained from the log-rank test stratified by prior use of trastuzumab (Y/N) and Visceral metastasis (Y/N) from IWRS.
Censoring times
CI, confidence interval; PFS, progression-free survival
CLEOPATRA: Independently assessed
PFS by prior trastuzumab therapy in
patients with (neo)adjuvant therapy
HTMedian PFS, months
PHTMedian PFS, months
Hazard ratio(CI)
Prior (neo)adjuvant trastuzumab treatment(n = 88)
10.4 16.90.62
(0.35, 1.07)
No prior (neo)adjuvant trastuzumab treatment(n = 288)
12.6 21.60.60
(0.43, 0.83)
Adapted from Baselga J, et al. N Engl J Med 2012; 366:109–119.
Prior Trastuzumab
Cleopatra OS Subgroup Analysis
EMILIA: Progression-Free Survival Subgroup Analyses
ER and PR status9.0
10.3
0.72 (0.58, 0.91)
0.56 (0.44, 0.72)
7.1
5.6
545
426
ER+ and/or PR+
ER− and PR−
10.8
9.6
9.0
0.51 (0.30, 0.85)
0.69 (0.53, 0.91)
0.69 (0.55, 0.86)
5.7
6.8
6.5
118
361
512
Line of therapya
FirstSecond
Third
Age9.8
7.0
0.62 (0.52, 0.74)
1.06 (0.68, 1.66)
6.0
8.1
853
138
<65 yrs≥65 yrs
Median,
mos
HR
(95% CI)
Median,
mos
Total
n
Baseline
characteristic
T-DM1
better
Cap + Lap
better
0.2 0.5 1 2 5
9.6 0.66 (0.56, 0.78)6.4991All pts
HRs were from unstratified analysis.aDefined as any systemic therapy, including endocrine or chemotherapy.
T-DM1Cap + Lap
Hazard ratio
Verma et al. N Eng J Med 2012 (incl. supplementary appendix)
Blackwell et al. ASCO 2012; Abst #LBA1
Data cut-off Jan 14, 2012
Prior Trastuzumab
Cap + Lap T-DM1
Baseline characteristic
Totaln
Median (mos)
Median (mos)
HR(95% CI)
T-DM1Better
Cap + LapBetter
All patients 991 25.1 30.9 0.70 (0.56, 0.87)
Age group
<65 years 853 24.6 30.9 0.66 (0.52, 0.83)
65–74 years 113 27.1 NR 0.74 (0.37, 1.47)
≥75 years 25 NR 11.1 3.45 (0.94, 12.65)
ER and PR status
ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85)
ER– and PR– 426 23.7 27.1 0.75 (0.54, 1.03)
Line of therapya
First-line 118 27.9 NR 0.61 (0.32, 1.16)
Second-line 361 NR 27.1 0.88 (0.61, 1.27)
Third- and later-line 512 23.3 33.9 0.62 (0.46, 0.84)
EMILIA: Overall Survival Subgroup Analyses
Hazard ratio 0.2 0.5 1 2 5aDefined as any systemic therapy including endocrine and chemotherapy.
NR, not reached.
From confirmatory OS analysis; data cut-off July 31, 2012.Verma et al. ESMO 2012; Oral Abstract #LBA12
Prior Trastuzumab
EMILIA
CNS metastases at baseline and
Progression
64
CNS Metastases
EMILIA: Outcomes of patients with
CNS mets at Baseline
65
A. PFS Independent Assessment
B. PFS Investigator Assessment
D. Overall Survival
Krop et. al Annals of Oncology 2014
66
BIOMARKERS
67
68 | BGT226A2101 – CONFIDENTIAL
INFORMATION, NOT TO BE
DISTRIBUTED
Alterations in PI3K Pathway Signaling
Components Are Frequent in HER2+ Breast
Cancer
20%
10%
PI3K Pathway “activation status” Predicts
Response to Trastuzumab
Bernard R et al Cancer Cell. 2007 Oct;12(4):395-402
pCR and PIK3CA Status by Treatment Arm in NEO-ALTTO
• For each treatment arm, the pCR rate was lower in tumors with a PIK3CA mutation
• The difference was statistically significant in the combination arm
p=0.012
70124 112 119N=Baselga AACR 2013
PIK3CA Mutation Associated With Poorer Prognosis on Both Arms of Cleopatra Study
Baselga et al, SABCS 2012
Lap + Cap T-DM1
PIK3CA
mutation
status n
Median
(months) n
Median
(months)
Hazard
ratioa 95% CI
Mutated 39 4.3 40 10.9 0.45 0.25–0.82
Wild type 87 6.4 93 9.8 0.74 0.50–1.10
Lap + Cap (Mutated) 39 28 22 9 5 3 2 1 0 0 0 0 0 0 0
Lap + Cap (Wild type) 87 69 55 31 21 16 13 10 7 4 4 3 2 1 0
T-DM1 (Mutated) 40 31 26 18 15 12 8 6 6 5 2 2 1 0 0
T-DM1 (Wild type) 93 82 66 42 36 24 19 15 12 9 6 3 2 1 0
Lap + Cap (PIK3CA mutated)
Lap + Cap (PIK3CA wild type)
T-DM1 (PIK3CA mutated)
T-DM1 (PIK3CA wild type)
Pro
po
rtio
n p
rogr
ess
ion
-fre
e
Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
0.0
0.2
0.4
0.6
0.8
1.0
No. at risk:
aHazard ratios are based on unstratified analyses.
EMILIA Biomarker Analysis:
PFS by PIK3CA Mutation Status and Treatment Arm
Baselga et al, SABCS 2013
Lap + Cap T-DM1
PIK3CA
mutation
status n
Median
(months) n
Median
(months)
Hazard
ratioa 95% CI
Mutated 39 17.3 40 NE 0.26 0.12–0.57
Wild type 87 27.8 93 NE 0.68 0.40–1.15
aHazard ratios are based on unstratified analysesNE, not estimable.
39 34 32 31 28 27 22 17 14 10 8 6 4 3 2 0 0 0 0Lap + Cap (Mutated)
87 83 77 74 68 66 57 44 38 32 28 26 20 14 11 6 4 3 2Lap + Cap (Wild type)
40 40 40 40 38 37 36 34 27 25 21 14 12 7 4 4 3 2 2T-DM1 (Mutated)
93 91 89 86 82 78 69 52 44 37 30 27 21 17 12 7 5 3 2T-DM1 (Wild type)
Pro
po
rtio
n s
urv
ivin
g
Time (months)
0.0
0.2
0.4
0.6
0.8
1.0
Lap + Cap (PIK3CA mutated)Lap + Cap (PIK3CA wild type)T-DM1 (PIK3CA mutated)T-DM1 (PIK3CA wild type)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
No. at risk:
EMILIA Biomarker Analysis:
OS by PIK3CA Mutation Status and Treatment Arm
Outline
• First Line Treatment
• Second Line Treatment and Beyond
• Individualized Approach
• An Algorithm and Concluding Remarks
HISTORY – 30 YEARS IN THE MAKING
Milestones in the Management of HER2-positive MBCOverall Survival
Verma et. al The Oncologist 2013Abbreviations: Ana, anastrozole; Cape, capecitabine; CT, chemotherapy; Doc, docetaxel; Lap, lapatinib; Let, letrozole; OS, overall survival; Pac, paclitaxel; Pert, pertuzumab; T-DM1, trastuzumab emtansine; Tras, trastuzumab.
First Line
Second
Line +
An Algorithm to Manage Her 2 positive MBC
Verma et. al The Oncologist 2013
An Algorithm to Manage Her 2 positive MBC
Is there still activity of Trastuzumab/Lapatini
b post T-DM1?
Can we consider
Pertuzumabfor DFI 6m-
1year?
Can we consider another taxane with
P + H?
Verma et. al The Oncologist 2013
Beyond Breast Cancer
Development of Targeted Therapy
2000 2020201520102005
Conclusion
Raising the Bar
• The outcome of patients with Her 2 positive
breast cancer has significantly improved in the
past two decades
• Novel targeted drugs are improving survival and
reducing toxicity for patients with advanced
breast cancer
• The future looks quite bright as we can now
envision a total targeted approach for some of
these patients…..and an overall survival in
excess of five years for some of our patients!