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Optimizing Treatment for Her 2 Positive Metastatic Breast Cancer Patients. Sunil Verma MD, MSEd, FRCPC Medical Oncologist Chair, Breast Medical Oncology Sunnybrook Odette Cancer Centre Associate Professor, University of Toronto. Her 2 Story Poor Prognostic Marker. Outline.

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optimizing treatment for her 2 positive metastatic breast cancer patients
Optimizing Treatment for Her 2 Positive Metastatic Breast Cancer Patients

Sunil Verma MD, MSEd, FRCPC

Medical Oncologist

Chair, Breast Medical Oncology

Sunnybrook Odette Cancer Centre

Associate Professor, University of Toronto

outline
Outline

First Line Treatment

Second Line Treatment and Beyond

Individualized Approach

An Algorithm and Concluding Remarks

outline1
Outline

First Line Treatment

Second Line Treatment and Beyond

Individualized Approach

An Algorithm and Concluding Remarks

trastuzumab prolongs overall survival in her2 positive mbc
Trastuzumab prolongs overall survival in HER2-positive MBC

100

Chemotherapy (n = 234)

Chemotherapy + trastuzumab (n = 235)

RR = 0.80 (95% CI = 0.64,1.00)

p = 0.046

80

Overall survival (%)

60

40

Median OS: 20.3 months

Median OS: 25.1 months

20

0

0

5

15

25

35

45

Time (months after enrolment)

Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:783–792.

OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxelOS, overall survival; RR, relative risk of death

first line treatment approach 2001 2011
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
Recent Achievements in Her 2 positive MBC

First Line

  • MA.31
    • Taxane + H vs. Taxane + L
  • CLEOPATRA
    • Chemo + H vs. Chemo +H+P
cleopatra study design
CLEOPATRA study design

PD

Placebo + trastuzumab

n=406

Docetaxel≥6 cycles recommended

Patients withHER2-positive MBCcentrally confirmed

(N=808)

1:1

PD

Pertuzumab + trastuzumab

n=402

Docetaxel≥6 cycles recommended

Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease

Swain et al. SABCS 2012 Poster P5-18-26 .

cleopatra significantly higher response rate with pertuzumab and trastuzumab
CLEOPATRA: Significantly higher response rate with pertuzumab and trastuzumab

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
Updated Kaplan-Meier curves of investigator-assessed PFS

100

Ptz + T + D: median 18.7 months

∆=6.3 months

Pla+ T + D: median 12.4 months

90

80

70

60

Progression-free survival (%)

HR=0.6995% CI 0.58−0.81

50

40

30

20

10

0

0

5

10

15

20

25

30

35

40

45

50

Time (months)

n at risk

Ptz + T + D

402

341

284

218

178

108

67

34

8

0

0

Pla+ T + D

406

329

223

148

110

72

42

26

8

0

0

D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

Swain et al. SABCS 2012 Poster P5-18-26 .

kaplan meier curves of the confirmatory overall survival analysis
Kaplan-Meier curves of the confirmatory overall survival analysis

1 year

94%

100

2 years

90

89%

81%

3 years

HR=0.6695% CI 0.52−0.84

p=0.0008

80

70

66%

69%

60

Overall survival (%)

50

50%

40

30

Ptz + T + D: 113 events; median not reached

20

Pla+ T + D: 154 events; median 37.6 months

10

0

0

5

10

15

20

25

30

35

40

45

50

55

Time (months)

n at risk

Ptz + T + D

402

387

371

342

317

230

143

84

33

9

0

0

Pla+ T + D

406

383

350

324

285

198

128

67

22

4

0

0

Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138

D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

Swain et al. SABCS 2012 Poster P5-18-26 .

slide14
Breast cancer therapies following discontinuation of study treatment in patients who had withdrawn from study treatment

Swain et al. SABCS 2012 Poster P5-18-26 .

adverse events all grades with 25 incidence or 5 difference between arms
Adverse events (all grades) with ≥25% incidence or ≥5% difference between arms

Highlighted are adverse events with ≥5% higher incidence

Swain et al. SABCS 2012 Poster P5-18-26 .

cardiac adverse events
Cardiac adverse events

* In patients with post-baseline assessment

LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction

Swain et al. SABCS 2012 Poster P5-18-26 .

t dm1 mechanism of action
T-DM1Mechanism of Action

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

Cytotoxic agent (DM1)

Stable linker

Emtansine

Antibody (HERCEPTIN)

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.

t dm1 retains activity of herceptinf
T-DM1Retains Activity of Herceptinf

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

KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.

t dm1 intracellular delivery of dm1
T-DM1Intracellular Delivery of DM1

HER2

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

KADCYLA

DM1

release*

Inhibition of tubulin polymerization

Lysosomal

degradation

Internalization

*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

PDa

PDa

PHASE II STUDY T-DM1 vs. Docetaxel and Trastuzumab

T-DM1

3.6 mg/kg q3w IV

(n=67)

HER2-positive, recurrent locally advanced breast cancer or MBC (N=137)

1:1

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)

Hurvitz, et al., JCO, 2013

objective response by investigator patients with measurable disease at baseline
Objective Response by Investigator Patients With Measurable Disease at Baseline

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, et al., JCO, 2013

Hurvitz SA, et al. Abstract 5.001. ESMO 2011.

progression free survival by investigator randomized patients
Progression-Free Survival by InvestigatorRandomized Patients

1.0

0.8

0.6

0.4

0.2

0.0

Trastuzumab + docetaxel (n=70)

T-DM1 (n=67)

Proportion progression-free

0 2 4 6 8 10 12 14 16 18 20

Time (months)

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.

Hurvitz, et al., JCO, 2013

marianne a clinical trial of pertuzumab and t dm1 in first line metastatic breast cancer
MARIANNE: A clinical trial of pertuzumab and T-DM1 in first-line metastatic breast cancer

Pertuzumab + T-DM1

Placebo + T-DM1

HER2-positive, progressive or recurrent, locally advanced or untreated MBC

(N = 1092)

R

Trastuzumab + taxane (docetaxel or paclitaxel)

T-DM1 ± pertuzumab: blinded, placebo-controlled

Trastuzumab + taxane: open-label

2010

2011–2012

2013

Last patient inQ2 2012

First patient in

July 2010

Figure adapted from:

http://clinicaltrials.gov/ct2/show/NCT01120184;

Roche. Data on file

summary first line
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
future questions first line
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

outline2
Outline

First Line Treatment

Second Line Treatment and Beyond

Individualized Approach

An Algorithm and Concluding Remarks

second line 2006 2010
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 mbc1
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
emilia study design
EMILIA Study Design
  • HER2-positive LABC or MBC (N=980)
  • Prior taxane and trastuzumab
  • Progression on metastatic treatment or within 6 months of adjuvant treatment

T-DM1

3.6 mg/kg q3w IV

PD

1:1

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
EMILIA: Overall Survival

Verma et al NEJM 2012

emilia adverse events
EMILIAAdverse Events

Verma et al NEJM 2012

th3resa study schema
TH3RESA Study Schema

HER2-positive (central) advanced BCa

(N=600)

≥2 prior HER2-directed therapies for advanced BC

Prior treatment with trastuzumab, lapatinib, and a taxane

T-DM1

3.6 mg/kg q3w IV

(n=400)

PD

2

Treatment of physician’s choice (TPC)b

(n=200)

1

T-DM1c

(optional crossover)

PD

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.

Stratification factors: World region, number of prior regimens for advanced BC,dpresence of visceral disease

Co-primary endpoints: PFS by investigator and OS

Key secondary endpoints: ORR by investigator and safety

Wildiers H, et al. ECC 2013; Abstract 15LBA.

.

pfs by investigator assessment
PFS by Investigator Assessment

1.0

0.8

0.6

Proportion progression-free

0.4

0.2

0.0

0

2

4

6

8

10

12

14

Time (months)

No. at risk:

TPC

198

120

62

28

13

6

1

0

T-DM1

404

334

241

114

66

27

12

0

Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.

Unstratified HR=0.521 (P<0.0001).

Wildiers H, et al. ECC 2013; Abstract 15LBA.

.

first interim os analysis
First Interim OS Analysis

1.0

Observed 21% of targeted events

0.8

0.6

Proportion surviving

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

Time (months)

No. at risk:

TPC

198

169

125

80

51

30

9

3

0

T-DM1

404

381

316

207

127

65

30

7

0

44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.

Unstratified HR=0.57 (P=0.004).

Wildiers H, et al. ECC 2013; Abstract 15LBA.

.

the pi3k pathway and breast cancer
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.

HER2/HER3

PI3K

Ras

Raf

PIP3

PTEN

PDK1

Akt

TORC2

MEK

Tuberin

Tuberin

Tuberin

Tuberin

Erk

Rheb

Rsk

TORC1

S6K

4EBP1

S6

summary second line and beyond
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
future questions
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?

outline3
Outline

First Line Treatment

Second Line Treatment and Beyond

Individualized Approach

An Algorithm and Concluding Remarks

personalized factors to consider
Personalized Factors to Consider

Hormone Receptor Status

Prior Adjuvant Trastuzumab

CNS Metastases

Biomarkers

cleopatra overall survival in predefined subgroups

Hormone Receptor Status

CLEOPATRAOverall survival in predefined subgroups

Favorspertuzumab

Favorsplacebo

n HR 95% CI

All

808 0.66 0.52‒0.84

NoYes

432 0.66 0.47‒0.93376 0.66 0.46‒0.94

Prior (neo)adjuvant chemotherapy

EuropeNorth AmericaSouth AmericaAsia

306 0.72 0.48‒1.07

135 0.68 0.36‒1.28

114 0.55 0.31‒0.98253 0.64 0.41‒1.00

Region

<65 years≥65 years <75 years≥75 years

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

Age group

WhiteBlackAsianOther

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

Race

Visceral diseaseNon-visceral disease

630 0.57 0.44‒0.74178 1.42 0.71‒2.84

Disease type

388 0.73 0.50‒1.06408 0.57 0.41‒0.79

PositiveNegative

ER/PgR status

IHC 3+

721 0.66 0.51‒0.85

HER2 status

FISH-positive

767 0.67 0.52‒0.86

0

1

2

3

4

5

ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PgR, progesterone receptor

Swain et al. SABCS 2012 Poster P5-18-26 .

emilia overall survival subgroup analyses

Hormone Receptor Status

EMILIAOverall Survival Subgroup Analyses

Hazard ratio

0.2

0.5

1

2

5

aDefined 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

slide47

Prior Trastuzumab

CLEOPATRA: Independently assessed PFS by prior trastuzumab therapy in patients with (neo)adjuvant therapy

CI, confidence interval; PFS, progression-free survival

Adapted from Baselga J, et al. N Engl J Med 2012; 366:109–119.

cleopatra overall survival subgroup analyses

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

Swain et al. SABCS 2012 Poster P5-18-26 .

emilia progression free survival subgroup analyses

Prior Trastuzumab

EMILIA: Progression-Free Survival Subgroup Analyses

Cap + Lap

T-DM1

Baseline characteristic

T-DM1

better

Cap + Lap

better

Totaln

Median,mos

Median,mos

HR(95% CI)

All pts

991

6.4

9.6

0.66 (0.56, 0.78)

Age

<65 yrs

853

6.0

9.8

0.62 (0.52, 0.74)

≥65 yrs

138

8.1

7.0

1.06 (0.68, 1.66)

ER and PR status

ER+ and/or PR+

545

7.1

9.0

0.72 (0.58, 0.91)

ER− and PR−

426

5.6

10.3

0.56 (0.44, 0.72)

Line of therapya

First

118

5.7

10.8

0.51 (0.30, 0.85)

Second

361

6.8

9.6

0.69 (0.53, 0.91)

Third

512

6.5

9.0

0.69 (0.55, 0.86)

0.2

0.5

1

2

5

Hazard ratio

Data cut-off Jan 14, 2012

HRs were from unstratified analysis.

aDefined as any systemic therapy, including endocrine or chemotherapy.

Verma et al. N Eng J Med 2012 (incl. supplementary appendix)

Blackwell et al. ASCO 2012; Abst #LBA1

emilia overall survival subgroup analyses1

Prior Trastuzumab

EMILIA: Overall Survival Subgroup Analyses

Hazard ratio

0.2

0.5

1

2

5

aDefined 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

outline4
Outline

First Line Treatment

Second Line Treatment and Beyond

Individualized Approach

An Algorithm and Concluding Remarks

milestones in the management of her2 positive mbc overall survival
Milestones in the Management of HER2-positive MBCOverall Survival

First Line

Second

Line +

Abbreviations: Ana, anastrozole; Cape, capecitabine; CT, chemotherapy; Doc, docetaxel; Lap, lapatinib; Let, letrozole; OS, overall survival; Pac, paclitaxel; Pert, pertuzumab; T-DM1, trastuzumabemtansine; Tras, trastuzumab.

an algorithm to manage her 2 positive mbc
An Algorithm to Manage Her 2 positive MBC

Verma et. al The Oncologist 2013

an algorithm to manage her 2 positive mbc1
An Algorithm to Manage Her 2 positive MBC

Can we consider

another taxane with

P + H?

Can we consider Pertuzumab for DFI 6m-1year?

Is there still activity of

Trastuzumab/Lapatinib post T-DM1?

Verma et. al The Oncologist 2013

conclusion raising the bar
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!