optimizing treatment for her 2 positive metastatic breast cancer patients sunil verma md, msed,...

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

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


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


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)


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)


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)


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


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


EMILIA: Overall Survival

EMILIAAdverse Events


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


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


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


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


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


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


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!

optimizing treatment for her 2 positive metastatic breast cancer patients sunil verma md, msed,...

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