Optimizing Treatment for Her 2 Positive Metastatic Breast Cancer Patients
Sunil Verma MD, MSEd, FRCPCMedical Oncologist
Chair, Breast Medical OncologySunnybrook Odette Cancer Centre
Associate Professor, University of Toronto
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)
Ove
rall
surv
ival
(%
)
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– CLEOPATRA
• Chemo + H vs. Chemo +H+P
7
Gelmon et. al ASCO 20128
Gelmon et. al ASCO 20129
CLEOPATRA study design
10HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease
Patients withHER2-positive MBC
centrally 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 .
CLEOPATRA: Significantly higher response rate with pertuzumab and trastuzumab
Patients, n (%)HT
(n = 336) PHT
(n = 343)
Independently reviewed objective response
rate
Difference in response rates (95% CI)
233 (69.3) 275 (80.2)
10.8% points (4.2, 17.5)p = 0.001
Complete response rate 14 (4.2) 19 (5.5)
Partial response rate 219 (65.2) 256 (74.6)
Stable disease 70 (20.8) 50 (14.6)
Progressive disease 28 (8.3) 13 (3.8)
Unable to assess or no assessment 5 (1.5) 5 (1.5)
H, trastuzumab; P, pertuzumab; T, docetaxel Adapted from Baselga J, et al. N Engl J Med 2012; 366:109–119.
Updated Kaplan-Meier curves of investigator-assessed PFS
12D, 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
ssio
n-f
ree
surv
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 .
Kaplan-Meier curves of the confirmatory overall survival analysis
13
Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138D, docetaxel; 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
n at risk
0Ptz + T + D
0Pla + T + D
Time (months)
Ove
rall
surv
ival
(%
)
45 50 55
0
0
9
4
33
22
84
67
143
128
230
198
317
285
342
324
371
350
387
383
402
406
89%
94%
1 year
2 years
69%
81% 3 years
66%
50%
Ptz + T + D: 113 events; median not reachedPla + T + D: 154 events; median 37.6 months
HR=0.6695% CI 0.52−0.84
p=0.0008
Swain et al. SABCS 2012 Poster P5-18-26 .
Breast cancer therapies following discontinuation of study treatment in patients who had withdrawn from study treatment
14
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
15Highlighted 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
16
* In patients with post-baseline assessmentLVEF, 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 maytansineMCC: 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
Lysosomaldegradation
DM1release*
Internalization
Inhibition of tubulin
polymerization
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 STUDYT-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 toT-DM1 (optional)
PDa
T-DM13.6 mg/kg q3w IV
(n=67)
PDa
Hurvitz, et al., JCO, 2013Hurvitz, et al., JCO, 2013
Objective Response by Investigator
Patients With Measurable Disease at BaselineTrastuzumab +
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 SA, et al. Abstract 5.001. ESMO 2011.Hurvitz, et al., JCO, 2013Hurvitz, 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 externallyThis 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)Time (months)
Progression-Free Survival by InvestigatorRandomized Patients
Pro
por
tion
prog
ress
ion
-fre
e P
rop
ortio
n pr
ogre
ssio
n-f
ree
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 200 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 0T-DM1 67 60 51 46 42 35 22 15 6 3 0
Number of patients at risk
T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0Hazard ratio and log-rank P value were from stratified analysis.
Trastuzumab + docetaxel (n=70)T-DM1 (n=67)
Trastuzumab + docetaxel (n=70)T-DM1 (n=67)
Median
PFS, mos
Hazard ratio 95% CI
Log-rank P value
9.2
14.20.59 0.36 –
0.97 0.035
Hurvitz, et al., JCO, 2013Hurvitz, 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 inJuly 2010
Last patient inQ2 2012
T-DM1 ± pertuzumab: blinded, placebo-controlledTrastuzumab + taxane: open-label
SummaryFirst Line• The standard of care should consist of
pertuzumab and trastuzumab along with docetaxel (?other taxane alternative)
• T-DM1 looks very promising in the first line and may be suited for selected patients– Not candidates for chemotherapy– DFI < 6 months– Contraindication to taxanes
24
Future QuestionsFirst Line• Can we combine Pertuzumab and Herceptin
with other partners– Other taxanes– Other chemotherapies (Vinorelbine/Capecitabine)– Other biologics – T-DM1/Bevacizumab
• Developing effective drugs that can target brain metastases
• Duration of targeted therapy for those responding
25
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
28
Trastuzumab and Lapatinib
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
Verma et al NEJM 2012
EMILIA: Overall Survival
EMILIAAdverse Events
Verma et al NEJM 201234
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)
14121086420.0
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).
16121086420.0
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=0.0034Efficacy stopping boundary HR<0.363 or P<0.0000013
Wildiers H, et al. ECC 2013; Abstract 15LBA..
The PI3K pathway and Breast Cancer
• Constitutive activation of the PI3K pathway is frequent.
• PI3K pathway activation conveys malignant transformation, cell growth and invasion, tumor neoangiogensis and resistance towards anti-cancer treatments.
• Known mechanisms of PI3K pathway activation include activating mutations of RTKs, gain-of-function mutation of the PIK3CA gene, and loss-of-function mutations of PTEN.
Ras
4EBP14EBP1
Raf
ErkErk
RskRsk
PI3K
TORC1TORC1
S6KS6K
Rheb Rheb
S6S6
PIP3
PIP3
Tuberin
PTEN
TORC2TORC2
MEKMEK
AktPDK1
PDK1
HER2/HER3
TuberinTuberinTuberin
O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.O Regan ASCO 2013
39
O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.O Regan ASCO 2013
40
SummarySecond Line and Beyond• T-DM1 offers significant clinical benefit and superior
toxicity profile and is very 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– ? Biomarkers – p95 still needs to be validated
41
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?
42
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
CLEOPATRAOverall survival in predefined subgroups
45ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PgR, progesterone receptor
808 0.66 0.52‒0.84
432 0.66 0.47‒0.93376 0.66 0.46‒0.94
306 0.72 0.48‒1.07135 0.68 0.36‒1.28114 0.55 0.31‒0.98253 0.64 0.41‒1.00
681 0.70 0.53‒0.91127 0.51 0.27‒0.95789 0.66 0.52‒0.8519 0.72 0.15‒3.50
480 0.70 0.51‒0.9530 0.52 0.14‒1.91261 0.66 0.43‒1.0337 0.29 0.06‒1.43
630 0.57 0.44‒0.74178 1.42 0.71‒2.84
388 0.73 0.50‒1.06408 0.57 0.41‒0.79
721 0.66 0.51‒0.85767 0.67 0.52‒0.86
n HR 95% CI
All
NoYes
EuropeNorth AmericaSouth America
Asia
<65 years≥65 years
<75 years≥75 years
WhiteBlackAsianOther
Visceral diseaseNon-visceral
diseasePositive
Negative
IHC 3+FISH-positive
0 1
ER/PgR status
Disease type
Race
Age group
Region
HER2 status
Prior (neo)adjuvant chemotherapy
2 3 4 5
Favorsplacebo
Favorspertuzumab
Swain et al. SABCS 2012 Poster P5-18-26 .
Hormone Receptor Status
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)
EMILIAOverall 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
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 16.9 0.62(0.35, 1.07)
No prior (neo)adjuvant trastuzumab treatment(n = 288)
12.6 21.6 0.60(0.43, 0.83)
Adapted from Baselga J, et al. N Engl J Med 2012; 366:109–119.
Prior Trastuzumab
CLEOPATRA:Overall survival subgroup analyses
• An exploratory subgroup analysis was performed for patients who had received prior neoadjuvant and/or adjuvant trastuzumab therapy (88 patients).
– The observed hazard ratio of 0.68 (95% CI 0.30−1.55) indicates overall survival benefit in the pertuzumab arm
48Swain et al. SABCS 2012 Poster P5-18-26 .
Prior Trastuzumab
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−
10.89.6
9.0
0.51 (0.30, 0.85)0.69 (0.53, 0.91)
0.69 (0.55, 0.86)
5.76.8
6.5
118361
512
Line of therapya
FirstSecondThird
Age9.87.0
0.62 (0.52, 0.74)1.06 (0.68, 1.66)
6.08.1
853138
<65 yrs≥65 yrs
Median,mos
HR(95% CI)
Median,mos
Totaln
Baseline characteristic
T-DM1better
Cap + Lapbetter
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
EMILIACNS metastases at baseline and Progression
51
CNS Metastases
EMILIAOS Analysis for Patients with CNS mets at baseline
52
CNS Metastases
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
SecondLine +
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/
Lapatinib post T-DM1?
Is there still activity of Trastuzumab/
Lapatinib post T-DM1?
Can we consider
Pertuzumab for DFI 6m-
1year?
Can we consider
Pertuzumab for DFI 6m-
1year?
Can we consider another taxane with
P + H?
Can we consider another taxane with
P + H?
Verma et. al The Oncologist 2013
ConclusionRaising 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!
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