HER2 in Breast Cancer History and Future Directions and Breast Cancer Swain.pdf1 HER2 in Breast Cancer History and Future Directions Sandra M. Swain, M.D. Director, Washington Cancer

1

HER2 in Breast CancerHistory and Future Directions

Sandra M. Swain, M.D.

Director, Washington Cancer Institute

Washington Hospital Center

Professor of Medicine

Georgetown University

Washington DC

Outline

• History

• EGFR/HER2 signaling pathway

• HER2 as a target for anticancer therapy

• Studies targeting HER2

• Metastatic

• Neoadjuvant

• Key messages

2

Milestones of Her2/anti-Her2 therapies in BC

EGFR discovery

Cohen

neu oncogene discovery Weinberg

EGFR MoAb inhibited growth

MendelsohnFDA approves

trastuzumab in adjuvant setting

1982 19851978 1984 1998 2006 2007 2010

Her2 amplification in breast cancer

Aaronson

FDA approves single agent trastuzumab for 2nd line and in combination with paclitaxel for 1st line MBC

FDA approves lapatinib + letrozole

for MBC

FDA approves lapatinib+ capecitabine for MBC

1987

Amplification of Her2/neu correlates with shorter survival

Slamon

MBC : metastatic breast cancerMoAb : monoclonal antibody

Her2 cloned Ullrich and Coussens

1983

EGF Receptor Family

Baselga & Swain. Nat Rev Cancer. 2009 Jul;9(7):463-75

3

Dimerization: Essential for Receptor Activation


HER2 SignalingPathway


4

Potential HER2

targets for anticancer

therapy


* Combined metastatic and adjuvant patients.Slamon et al. Science. 1987;235:177Pauletti et al. J Clin Oncol. 2000;18:3651

Shortened Median Survival*

HER2 positive 3 years

HER2 normal 6–7 years

HER2 positive protein overexpressionIHC

HER2 : Survival in Breast Cancer

HER2 geneamplificationFISH

Key Decision: Target the cell surface “constitutively active”HER2/ErbB2 protein with a monoclonal antibody

5

HER2+ MBC• Occurs in 20%–25% of invasive breast carcinomas

• First-line agents

• Trastuzumab with

• Paclitaxel ± carboplatin

• Docetaxel

• Vinorelbine

• Second-line agents

• Lapatinib + capecitabine

• Trastuzumab + other first-line agents

• Trastuzumab + capecitabine

• Trastuzumab + lapatinib (without cytotoxic therapy)Hudis N Engl J Med. 2007 Jul 5;357(1):39-51.NCCN 2011 V.2

Potential Mechanisms of Action of Trastuzumab

Hudis N Engl J Med. 2007 Jul 5;357(1):39-51.

6

Trastuzumab Added to ChemotherapyImproves Survival in MBC

Slamon et al, N Engl J Med. 2001 Mar 15;344(11):783-92.

No. at RiskChemotherapy plus 235 214 192 165 134 114 96 47 11trastuzumabChemotherapy alone 234 205 160 136 116 97 76 37 13

First Line Therapy HER2+MBC

7

Lapatinib Increases TTP After Trastuzumab

5 patients with risk were censored for purposes of generating the Kaplan-Meier curve.

Geyer N Engl J Med. 2006 Dec 28;355(26):2733-43.Breast Cancer Res Treat. 2008 Dec;112(3):533-43

Lapatinib + Letrozole as 1st Line Therapy for Postmenopausal ER+

HER2+ MBC Patients

• Patients with HR+ HER2- tumors (n = 952) had no improvements in PFS

• Grade 3/4 AEs more common in lapatinib + letrozole arm vs. letrozole + placebo arm, but they were manageable

Lapatinib + Letrozole Letrozole + Placebo

PFS (mos) 8.2 3.0

HR = 0.71

CBR (%) 48 29

OR = 0.4

Johnston et al. J Clin Oncol. 2009 Nov 20;27(33):5538-46

•N = 219•Randomized •Letrozole (2.5 mg/d) + lapatinib (1,500 mg) or letrozole + placebo• Primary end point: PFS

8

Should We Combine Anti-HER2 Drugs?

Blackwell J Clin Oncol. 2010 Mar 1;28(7):1124-30

Lapatinib ± Trastuzumab HER2+ MBC Progressing on Trastuzumab

Phase III

9

HER2 Targeted Agents

VEGFR = vascular endothelial growth factor receptor; HSP90 = heat shock protein 90; IGF-1R = insulin-like growth factor-1 receptor; HDAC = histone deacetylase; PI3K = phosphoinositide 3-kinase; mTOR = mammalian target of rapamycin; T-DM1 = trastuzumab-DM1.Murphy et al, 2010; Alvarez et al, 2010.

HER1/2 TKI Lapatinib, neratinib (HKI-272), BIBW 2992, PKI-166, EKB-569

Pan HER TKI Canertinib, BMS-599626

HER1/2/VEGFR TKI XL647, AEE788

HER2 dimerization inhibitor Pertuzumab

Bispecific antibody Ertumaxomab

Conjugated antibodies T-DM1, trastuzumab-A-Z-CINN, 310-paclitaxel

HSP90 inhibitors Tanespimycin, alvespimycin, CNF2024, IPI-504, AUY922, SNX5422

IGF-1R inhibitors (MoAb, TKI) CP-751871, EM164, IMC-A12, NVP-ADW742, INSM-18

HDAC inhibitors Vorinostat, LBH589, PXD101, NVP-LAQ824, depsipeptide, CI-994, MS-275

PI3K inhibitors SF1126, BEZ235, XL147, XL765

Akt inhibitors Perifosine, XL418

mTOR inhibitors Rapamycin (sirolimus), temsirolimus, everolimus, deforolimus

Her3/Her2 antibody U3-1287 (AMG 888) , MM-111, MEHD7945A

HER2 vaccines

Neratinib in HER+ MBC

Burstein et al. J Clin Oncol. 2010 Mar 10;28(8):1301-7

Diarrhea % Prior T No prior T

Grade 1/2 97 89

Grade 3/4 30 13

10

Trastuzumab and pertuzumab have synergistic activity

HER2Trastuzumab Pertuzumab

Subdomain IV of HER2

Trastuzumab does not inhibit HER2 dimerization, thus blocking HER2:HER3

Trastuzumab prevents HER2 receptor shedding

Trastuzumab blocks HER2 signaling and flags cells for destruction by the immune system

Pertuzumab inhibits HER2 from forming dimer pairs

Flags cells for destruction by the immune system

Pertuzumab does not prevent HER2 receptor shedding

Dimerization domain of HER2

HER3

Pertuzumab but not Trastuzumab Inhibits Heregulin-Dependent Akt Activation

Agus et al. Cancer Cell. 2002 Aug;2(2):127-37.

11

Pertuzumab prevents ligand-induced HER2-HER3 dimerization

Junttila et al. Cancer Cell. 2009 May 5;15(5):429-40

Pertuzumab Activity in Combination or Monotherapy

With Trastuzumab

n = 66

(%)

With Trastuzumab

n = 11

(%)

Monotherapy

n = 29

(%)

Best Objective Response

CR 8 0 0

PR 17 18 7

SD 6 mos 26 4

ORR 24 18 7

CBR 50 11

Cortes et al, 2009; , Baselga, Gelmon, et al, 2010Portera CC et al. Clin Cancer Res. 2008 May 1;14(9):2710-6

12

CLEOPATRA Study design

MBC, metastatic breast cancer; PD, progressive disease

Patients withHER2-positive MBCcentrally confirmed

(N = 808)

Placebo + trastuzumabn=406

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

• Study dosing q3w:− Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance− Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated

1:1

n=402

Docetaxel*≥6 cycles recommended

PD

Pertuzumab + trastuzumab

Docetaxel*≥6 cycles recommended

PD

* <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion

Baselga, et al NEJM , 2011

Baseline characteristics (I)

Placebo+ trastuzumab + docetaxel

(n = 406)

Pertuzumab+ trastuzumab + docetaxel

(n = 402)

Median age, years(range)

54.0 (27–89)

54.0 (22–82)

Region, n (%)AsiaEuropeNorth AmericaSouth America

128 (31.5)152 (37.4)68 (16.7)58 (14.3)

125 (31.1)154 (38.3)67 (16.7)56 (13.9)

ECOG PS, n (%)01≥2

248 (61.1)157 (38.7)

1 (0.2)

274 (68.2)125 (31.1)

3 (0.7)

Baselga et al, NEJM , 2011

13

Prior therapy for breast cancerPlacebo

+ trastuzumab+ docetaxel

(n = 406)

Pertuzumab+ trastuzumab

+ docetaxel(n = 402)

Prior (neo)adjuvant chemotherapy, n (%)

YesNo

192 (47.3)214 (52.7)

184 (45.8)218 (54.2)

Components of (neo)adjuvant therapy*, n (%)

AnthracyclineHormonesTaxaneTrastuzumab

164 (40.4)97 (23.9)94 (23.2)41 (10.1)

150 (37.3)106 (26.4)91 (22.6)47 (11.7)


Primary endpoint: Independently assessed PFS

n = 433 PFS events

0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

n at risk

402 345 267 139 83 32 10 0 0Ptz + T + D

406 311 209 93 42 17 7 0 0Pla + T + D

Time (months)

Ptz + T + D: median 18.5 months

Pla + T + D: median 12.4 months

HR = 0.6295% CI 0.51‒0.75

p<0.0001

∆ = 6.1 months

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Stratified by prior treatment status and region


14

808 0.63 0.52‒0.76

432 0.63 0.49‒0.82376 0.61 0.46‒0.81

306 0.72 0.53‒0.97135 0.51 0.31‒0.84114 0.46 0.27‒0.78253 0.68 0.48‒0.95

681 0.65 0.53‒0.80127 0.52 0.31‒0.86789 0.64 0.53‒0.7819 0.55 0.12‒2.54

480 0.62 0.49‒0.8030 0.64 0.23‒1.79261 0.68 0.49‒0.9537 0.39 0.13‒1.18

630 0.55 0.45‒0.68178 0.96 0.61‒1.52

388 0.72 0.55‒0.95408 0.55 0.42‒0.7212 ─

721 0.60 0.49‒0.74767 0.64 0.53‒0.78

n HR 95% CI

All

NoYes

EuropeNorth AmericaSouth America

Asia

<65 years≥65 years<75 years≥75 years

WhiteBlackAsianOther

Visceral diseaseNon-visceral disease

PositiveNegative

Unknown

IHC 3+FISH-positive

0 0.2

ER/PgR status

Disease type

Race

Age group

Region

HER2 status

Prior (neo)adjuvant chemotherapy

0.4 0.6 1 2

Independently assessed PFS in predefined subgroups

ER, estrogen receptor; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; PgR, progesterone receptor;PFS, progression-free survival

Favorsplacebo

Favorspertuzumab

Unstratified analyses

Baselga, NEJM , 2011

Independently assessed PFS by prior trastuzumab therapy in patients with

(neo)adjuvant therapy

Placebo+ trastuzumab

+ docetaxelMedian PFS, months


+ docetaxelMedian PFS, months

Prior (neo)adjuvant trastuzumab treatment(n = 88)

10.4 16.9

No prior (neo)adjuvanttrastuzumab treatment(n = 288)

12.6 21.6


15

Independently reviewed ORIn patients with measurable disease at baseline

Placebo+ trastuzumab




Objective response rate, n (%)

Complete response rate, n (%)

Partial response rate, n (%)

233 (69.3)

14 (4.2)

219 (65.2)

275 (80.2)

19 (5.5)

256 (74.6)

p = 0.0011*

Stable disease, n (%) 70 (20.8) 50 (14.6)

Progressive disease, n (%) 28 (8.3) 13 (3.8)

Unable to assess or no assessment, n (%)

5 (1.5) 5 (1.5)


Overall survival: Predefined interim analysis

Median follow-up: 19.3 months, n = 165 OS events

D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 40 45

0

10

20

30

40

50

60

70

80

90

100

n at risk

Pertuzumab + T + D 402 387 367 251 161 87 31 4 0 0

406 383 347 228 143 67 24 2 0 0Placebo + T + D

Time (months)

Ptz + T + D: 69 events

Pla + T + D: 96 events

HR = 0.64*95% CI 0.47‒0.88

p = 0.0053*

* The interim OS analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p ≤0.0012)

Ove

rall

surv

iva

l (%

)


16

Cardiac tolerability

LVSD was defined as NYHA class III/IV


(n = 397)


(n = 407)

Investigator-assessed

symptomatic LVSD*1.8% 1.0%

Independently adjudicatedsymptomatic LVSD*

1.0% 1.0%

Fall in LVEF to <50% and by ≥10 percentage points from baseline

6.6% 3.8%


Adverse events ≥25% incidence or ≥5% difference between arms

Adverse event, n (%)


(n = 397)


(n = 407)

Diarrhea 184 (46.3) 272 (66.8)

Alopecia 240 (60.5) 248 (60.9)

Neutropenia 197 (49.6) 215 (52.8)

Nausea 165 (41.6) 172 (42.3)

Fatigue 146 (36.8) 153 (37.6)

Rash 96 (24.2) 137 (33.7)

Decreased appetite 105 (26.4) 119 (29.2)

Mucosal inflammation 79 (19.9) 113 (27.8)

Asthenia 120 (30.2) 106 (26.0)

Peripheral edema 119 (30.0) 94 (23.1)

Constipation 99 (24.9) 61 (15.0)

Febrile neutropenia 30 (7.6) 56 (13.8)

Dry skin 17 (4.3) 43 (10.6)Baselga et al, NEJM , 2011

17

Summary and conclusions

• CLEOPATRA met its primary endpoint and demonstrated a statistically significant improvement in PFS (HR = 0.62) in patients with HER2-positive MBC

• Median PFS increased by 6.1 months

• The combination of pertuzumab and trastuzumab plus docetaxel increased rates of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin

• There was no increase in cardiac adverse events or LVSD


APHINITY: Study Schema

N=3,806SURGERY

Central confirmation

of HER2 status

Randomisationwithin 7 weeks

of surgery

Starttreatment

within1 week

FOLLOWUP

10YEARS

RANDOMIZATION

Chemotherapy plus trastuzumab and pertuzumab

Chemotherapy plus trastuzumab and placebo

Radiotherapy and/or endocrine therapy may be startedat the end of adjuvant chemotherapy

Anti HER2 therapy for a total of 1 year (52 weeks)

18

Should We add anti-VEGF to Anti-HER2 Drugs?

AVEREL Background

• Strong preclinical rationale for combining trastuzumab (H) and bevacizumab (BEV):

• VEGF expression is positively regulated by HER21,2

• VEGF levels correlate with HER2 overexpression3,4

• H and BEV are synergistic in in vivo models5

• Single-arm phase II studies of H + BEV (± chemotherapy) in LR/mBC showed encouraging activity6,7

1. Klos et al. Cancer Res 2008; 2. Loureiro et al. Biochem Biophys Res Comm2005; 3. Yang et al. Cancer 2002

4. Konecny et al. Clin Cancer Res 2004; 5. Pegram et al. SABCS 2004;6. Hurvitz et al. SABCS 2009; 7. Tjulandin et al. ASCO 2011

19

Investigator-assessed PFS (unstratifieda)E

stim

ated

pro

babi

lity

Time (months)0 6 12 18 24 30 36 42 48 54

1.0

0.8

0.6

0.4

0.2

0.0

No. at risk: 208 173 106 65 38 18 10 5 1 0216 192 134 82 48 22 12 8 2 0

13.7 16.5

H + DOC(n=208)

H + DOC + BEV(n=216)

Events, n (%) 154 (74.0) 153 (70.8)Median PFS, months

(95% CI)13.7

(11.4‒16.3)16.5

(14.1‒19.1)HR, unstratified

(95% CI)0.82

(0.65‒1.02)Log-rank p-value 0.0775

aPrimary analysis per protocolGianni L. et al. SABC 2011

PFS according to baseline plasma VEGF-A

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54

PlasmaVEGF-A HR (95% CI)

≤ median 0.83 (0.50‒1.36)

> median 0.70 (0.43‒1.14)

0.2 0.5 1 2 5

H + DOC + BEV better

HR

H + DOC better

Est

imat

ed p

roba

bilit

y

Time (months)

H + DOC low VEGF-A (n=45)

13.68.5

H + DOC high VEGF-A (n=37)

16.5

H + DOC + BEV low VEGF-A (n=36)

16.6

H + DOC + BEV high VEGF-A (n=43)

Gianni L. et al. SABC 2011

20

Perspectives• In AVEREL, exploratory analyses of plasma

VEGF-A suggest a potentially predictive effect (greater benefit with high VEGF-A levels), consistent with observations in HER2-negative LR/mBC

• Global biomarker study GO25632 (MERiDiAN) is planned: BEV + paclitaxel with stratification by plasma VEGF-A level

• The BETH adjuvant trial will provide further data on BEV in patients with HER2-positive breast cancer

Gianni L. et al. SABC 2011

Immunoconjugate/ADC• T-DM1: Trastuzumab Emtansine

– Antibody Drug Conjugate (ADC)

– Trastuzumab is linked to an antimicrotubule drug (maytansine or DM1) for a targeted and antineoplastic effect

– Trastuzumab binds to HER2 cancer cells, is absorbed, and then releases DM1

Burris et al . J Clin Oncol. 2011 Feb 1;29(4):398-405.

21

Phase II Studies of T-DM1 for the Treatment of HER2+ Breast Cancer After Prior HER2-

Directed Therapy• Eligibility: Patients with late stage cancer with PD on trastuzumab, previous

anthracycline, taxane, lapatinib, trastuzumab, capecitabine in TDM 4374g

• Treatment: T-DM1 3.6 mg/kg given IV infusion over 30–90 mins q3wks

ResponseTDM 4258g

(N = 112)

TDM 4374g

(N = 110)

ORR (%)

(95% CI)

CBR

Med Duration Response

Median PFS

ORR retrospective HER 2+

25.9 %

(18.4–34.4%)

39.3 %

NR

4.6 mo

32.1%

32.7 %

48.2 %

NR

6.9 mo

40.3%

Burris et al . J Clin Oncol. 2011 Feb 1;29(4):398-405Krop et al. J Clin Oncol. 2010 Jun 1;28(16):2698-704

Time (months)

TDM4450g: Randomized Phase IIPFS by Investigator

Pro

port

ion

prog

ress

ion-

free

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 0T-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)

MedianPFS, mos

Hazard ratio 95% CI

Log-rank P value

9.214.2

0.5940.364–0.968

0.0353

22

MARIANNE: First Line Metastatic Breast Cancer

Completed ACCRUAL

Trastuzumab + taxane

T-DM1 + pertuzumab

T-DM1 + pertuzumab – placebo

Stratification factors:

World region

Prior (neo) adjuvant tx

Visceral disease

N = 1092

Primary endpoint: PFS by independent review

Secondary endpoints include: RR, OS, safety, PRO

Taxane: docetaxel 75 or 100 mg/m2 q3w or paclitaxel 80 mg/m2 q1wTrastuzumab: 8 mg/kg x 1 then 6 mg/kg q3wT-DM1: 3.6 mg/kg q3wPertuzumab (or placebo): 840 mg x 1 then 420 mg q3w

EMILIAPreviously treated HER2+ MBC

Patients with HER2+ locally advanced or

MBC(Target N = 580)

Trastuzumab-DM1

Continue until disease progression

or unacceptable toxicity occurs

Lapatinib

+

Capecitabine

Continue until disease progression

or unacceptable toxicity occurs

RANDOMIZATION

Available at: http://www.clinicaltrials.gov.

23

March 29, 2012 Genentech Press Release

”EMILIA Study Showed TrastuzumabEmtansine Significantly Extended

the Time People with HER2-Positive Metastatic Breast Cancer Lived without Their Disease Getting

Worse --”

Stratification factors:

– World region (US, Western Europe or Other), number of prior regimens for MBC (2-3 or >3), presence of visceral disease (any or none )

Co-primary endpoints: ORR (IRF) and OS

Key secondary endpoints: PFS, DOR, CBR, landmark survival, safety, PROs

TH3RESA Study Design; Previously treated HER2 + MBC

2:1

HER2-positive(central confirm) recurrent locally advanced BC or MBCN = 795

T-DM13.6 mg/kg Q3W

Treatment of Physician’s Choice

PD

*or unmanageable toxicities

24

Ongoing Phase III Trials in HER2+ MBC

Study Name

Line N Arms Primary endpoint

MARIANE 1st 1092 Trastuzumab + TaxaneT-DM1+ PertuzumabT-DM1 + Placebo

PFS

HALT 1st 276 Lapatinib + TrastuzumabTrastuzumab

PFS

EGF108919 1st 630 (Lapatinib + Taxane) X 24 wk + lapatinib till PD(Trastuzumab + Taxane) X 24 wk + Trastuzumab till PD

PFS

EMILIA >1 991 T-DM1Capecitabine + Lapatinib

PFS/OS

TH3RESA 3rd 795 T-DM1Physician choice

ORR (IRF) & OS

AKT Inhibition and mTORC1 Inhibition Relieve Feedback Suppression of Receptor

Tyrosine Kinase Expression and Activity

Chandarlapaty Cancer Cell. 2011 Jan 18;19(1):58-71.

25

Is there benefit from addition of everolimus?

Study Name

Line N Arms Primary endpoint

BOLERO-1 1st 717 Paclitaxol + Trastuzumab + everolimus or Placebo

PFS

BOLERO-3 >1 572 Trastuzumab + Vinorelbine + Everolimus or Placebo

PFS

Effect of Trastuzumab on Breast Cancer Stem Cells

Trastuzumab reduced the proportion of mammary stem cell, but had no effect on trastuzumab-resistant cell lines. PI3-K inh (LY294002) reduced the proportion stem cells in all cell lines.

Korkaya Oncogene. 2008 Oct 16;27:6120-30

26

Adjuvant Therapy

Phase II Trial of Adjuvant TC (Docetaxel/Cyclophosphamide) Plus

Trastuzumab (HER TC) in HER2 Positive Early Stage Breast Cancer Patients

Steve Jones, MD1,2; Rufus Collea, MD1,3; Devchand Paul, DO, PhD1,4; Ruth Ortiz, MD1,5; Scot Sedlacek, MD1,4; Anne Favret, MD1,6; Ira Gore, Jr, MD1,7; Deborah Lindquist, MD1,8; Frankie

Ann Holmes, MD1,9; Mary Ann K. Allison, MD10; Michael S. Steinberg, MD1,11; Christopher Stokoe, MD1,12; Raul M. Portillo, MD1,13; Maria W. Crockett, CCRP1; Yunfei Wang, MS1;

Lina Asmar, PhD1; Nicholas Robert, MD1,6; Joyce O’Shaughnessy, MD1,2

1US Oncology Research, McKesson Specialty Health, The Woodlands, TX; 2Texas Oncology, Baylor-Sammons Cancer Center, Dallas TX ; 3New York Oncology Hematology,

Albany, NY; 4Rocky Mountain Cancer, Denver CO; 5New York, NY; 6Virginia Cancer Specialists, PC, Fairfax, VA; 7Birmingham Hematology and Oncology, Birmingham, AL; 8Arizona Oncology Associates,

Sedona AZ; 9Texas Oncology, Houston, TX; 10Comprehensive Cancer Center, Henderson, NV; 11Virginia Oncology Associates, Virginia Beach, VA, 12Texas Oncology, Plano, TX,

13Texas Oncology, El Paso, TX

This study was supported by sanofi.

Poster #PD07-03, San Antonio Breast Cancer Symposium; December 6–10, 2011, San Antonio, TX, USA

27

Results

San Antonio Breast Cancer Symposium-Cancer Therapy and Research Center at UT Health Science Center, December 6-10, 2011

This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.

In 486 patients, there were 14 cases of recurrent breast cancer (local 5, or local/distant 9), which resulted in a 3-year disease-free survival of 96.3%.

No. Patients DFS (%)2-Year

DFS (%)3-Year

OS (%)2-Year

OS (%) 3-Year

486 safety population 97.8 96.3 99.4 98.5 101 node positive 96.9 91.9 100 96.5 385 node negative 98.1 97.7 99.2 99.2 94 <1.0-cm node-ve

100 100 100 100

DFS by Nodal Status



0 12 24 36 48

0.5

0.6

0.7

0.8

0.9

1.0

Months

Dis

ease

-fre

e P

robability

Node negativeeNode positiveEvent indicator

28

OS by Nodal Status

0 12 24 36 48

0.5

0.6

0.7

0.8

0.9

1.0

Months

Surv

ival P

robabili

ty

Node negativeNode positiveEvent indicator



Use of Pegfilgrastim by Cycle

Use of Pegfilgrastim by Cycle of Treatment Based on

Clinical Judgment

Cycle Total

n=486 (%)

1 151 (31.1) 2 223 (45.9) 3 203 (41.8) 4 190 (39.1)

Total 291 (59.9)*

*percentage of patients who received pegfilgrastim for at least one cycle.



29

Conclusion

1) 486 patients with HER2+ ESBC in a Phase II, non-comparative, open-label study received HER TC as adjuvant chemotherapy with trastuzumab.

2) DFS was 96.3% and OS was 98.5% at 3 years.

3) In comparison with other published regimens at 2-3 years, HER TC appears to be effective.



Conclusions continued

4) Toxicity was as expected for this combination and was mainly hematologic with a low rate of cardiac dysfunction, mainly reversible.

5) The HER TC regimen is an option for patients with lower risk HER2+ ESBC.


30

Neoadjuvant Studies

29% 30%

0%

10%

20%

30%

40%

50%

60%

DocetaxelTrastuzumab

PaclitaxelTrastuzumab

25%

NeoSp NeoAL NeoAL NeoSp

PaclitaxelLapatinib

Single Agent HER2 Targeted Therapy: pCR

24%

DocetaxelPertuzumab

31

50.4% 51%

0%

10%

20%

30%

40%

50%

60%

EC-DocTrastuzumab

DocetaxelTrastuzumabPertuzumab

46%

Outcomes HER 2 + : pCR

PaclitaxelTrastuzumabLapatinib

GepQ NeoAL NeoSp NeoSp

17%

TrastuzumabPertuzumab

Rate of pCR by ER statusNEOALLTO

Baselga et al. Lancet. 2012 Jan 16.

32

Copyrights for this presentation are held by the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6‒10, 2011

63

Study design: TRYPHAENA

AUC, area under the plasma concentration-time curve; EBC, early breast cancer; FEC, 5-fluorouracil, epirubicin, cyclophosphamide

HER2-positive EBC

centrally confirmed(n = 225)

FEC

Surgery

• All 3 arms were experimental

• Study dosing q3w:− FEC: 500 mg/m2, 100 mg/m2, 600 mg/m2

− Carboplatin: AUC 6− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance− Pertuzumab: 840 mg loading dose, 420 mg maintenance− Docetaxel: 75 mg/m2 (escalating to 100 mg/m2 if tolerated, in Arms A and B only)

Docetaxel

Cycles 1‒3 4‒6


Pertuzumab + trastuzumab

FECDocetaxel

Carboplatin

Docetaxel

Pertuzumab + trastuzumabC

B

A



64

Pathologic complete response

FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab

Pat

ho

log

ic c

om

ple

te r

esp

on

se (

%)

FEC+H+P x3→ T+H+P x3

(n = 73)

FEC x3→ T+H+P x3

(n = 75)

TCH+P x6(n = 77)

ypT0/is100

90

80

70

60

50

40

30

20

10

0

61.666.2

57.3

33



65

0

10

20

30

40

50

60

70

80

90

100

Pathologic complete response

FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab

Pat

ho

log

ic c

om

ple

te r

esp

on

se (

%)


(n = 73)

FEC x3→ T+H+P x3

(n = 75)

TCH+P x6(n = 77)

50.7

45.3

51.9

ypT0/is ypT0 ypN0

61.666.2

57.3



66

0

10

20

30

40

50

60

70

80

90

100

Pathologic complete response by hormone receptor status

ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; PR, progesterone receptor; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab

Pat

ho

log

ic c

om

ple

te r

esp

on

se (

%)

ER- and PR-negative ER- and/or PR-positive

79.4

65.0

46.2 48.6

83.8

50.0

ypT0/is


(n = 73)

FEC x3→ T+H+P x3

(n = 75)

TCH+P x6(n = 77)

34

Reactivation of HER2 Receptor activity

Wang et al. Breast Cancer Res. 2011 28;13:R121.

HER2-Positive, ER and/or PgR-Positive Invasive Breast CancerDiagnosed by Core Needle Biopsy with Palpable Breast Mass ≥ 2.0

cm

RANDOMIZATION

Arm 1

TCHevery 21 days x 6 cycles

+Pertuzumab

every 21 days x 6 cycles

Arm 2TCH

every 21 days x 6 cycles+

Pertuzumabevery 21 days x 6 cycles

+Estrogen Deprivation

SURGERY (lumpectomy or mastectomy) and axillary staging

TCHP with or without Estrogen Deprivation Therapy

35

Key Messages• Large number of active agents

• TKIs (HER2 and/or others)

• MoAbs

• T-DM1

• HSP90 inhibitors

• AKTi (PI3Ki, mTORi, etc…)

• Resistance to HER2 therapy an important area of investigation

• ER positive

• Stem cells

Everolimus for postmenopausal women with advanced breast cancer:

updated results of the BOLERO-2 trial

G. N. Hortobagyi, M. Piccart, H. Rugo, H. Burris, M. Campone, S. Noguchi, M. Gnant, K. I. Pritchard, L. Vittori, P.

Mukhopadhyay, T. Sahmoud, D. Lebwohl, J. Baselga

On behalf of the BOLERO-2 Investigators

Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 70

36

Neoadjuvant (Ph II): Letrozole ± Everolimus

RR = response rate.

Baselga J, et al. JCO. 2009;27:2630-2637

Primary endpoint: RR at 16 weeks (palpation)

Postmenopausal women with ER+ early BC

Everolimus 10 mg/day +Letrozole 2.5 mg/day

Placebo +Letrozole 2.5 mg/day

Surgery

RANDOMIZE

• Higher RR: 68% vs 59% (P = 0.062)• Greater antiproliferative response: Ki67 by 57% vs 30% (P < 0.01)

71

TAMRAD (Phase II): Tamoxifen ± Everolimus in Advanced BC

72

• 111 patients randomized phase 2 in postmenopausal women with ER+ advanced breast cancer previously treated with an AI

Bourgier C., et al. ECCO/ESMO 2011 (Abstract #5005)

1.0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Pro

bab

ilit

y o

f P

rog

res

sio

n

TAM: 4.5 mosTAM + EVE: 8.6 mos

Months

HR = 0.54Log-rank P = 0.002

37

BOLERO-2 (Ph III): Everolimus in Advanced BC

EVE 10 mg daily+

EXE 25 mg daily (n = 485)

Placebo+

EXE 25 mg daily (n = 239)

R

• Endpoints• Primary: PFS (local assessment)• Secondary: OS, ORR, QOL, safety, bone markers, PK

2:1

N = 724• Postmenopausal ER+

• Unresectable locally advanced or metastatic BC

• Recurrence or progression after letrozole or anastrozole

Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases

Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 73

PFS = progression free survival; OS = overall survival; ORR, overall response rate; QOL = quality of life; PK = pharmacokinetics.

BOLERO-2: Prior Therapy Everolimus + Exemestane(n = 485), %

Placebo +Exemestane(n = 239), %

Sensitivity to prior hormonal therapy 84 84

Last treatment: LET/ ANA 74 75

Last treatment

Adjuvant 21 15

Metastatic 79 85

Prior tamoxifen 47 50

Prior fulvestrant 17 16

Prior chemotherapy for metastatic BC 26 26

Number of prior therapies: ≥3 54 53LET: letrozole, ANA: anastrozole

74Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7)

38

BOLERO-2 (12 mo f/up): PFS Local


0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Time (weeks)

Pro

bab

ilit

y (%

) o

f E

ven

tHR = 0.44 (95% CI: 0.36-0.53)Log rank P value: <1 x 10-16

EVE + EXE: 7.4 monthsPBO + EXE: 3.2 months

EVE + EXE (E/N = 267/485)PBO + EXE (E/N = 190/239)

Everolimus

Placebo

Number of patients still at risk

485 436 365 303 246 188 136 96 64 45 34 21 13 9 2 2 0

239 190 131 95 63 45 29 19 12 8 6 6 4 2 0 0 0

BOLERO-2 (12 mo f/up): Response and Clinical Benefit

76

P < 0.0001

Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7)

Per

cen

t

39

BOLERO-2 (12 mo f/up): Most Common Adverse Events

Everolimus + Exemestane (n = 482), %

Placebo + Exemestane (n = 238), %

All Grades Grade 3 Grade 4

All Grades Grade 3 Grade 4

Stomatitis 59 8 0 11 <1 0

Rash 39 1 0 6 0 0

Fatigue 36 4 <1 27 1 0

Diarrhea 33 2 <1 19 <1 0

Appetite decreased 30 1 0 12 <1 0

Nausea 29 <1 <1 28 1 0

Weight decreased 25 1 0 6 0 0

Cough 25 <1 0 12 0 0


BOLERO-2 (12 mo f/up): Bone Markers


% C

han

ge

fro

m B

asel

ine

–5.6

–20.3

–6.3–3.6

–26.7

–0.4

20.9

35.529.5

18.1

40.7 40.3

-40

-30

-20

-10

0

10

20

30

40

50BSAP P1NP CTX BSAP P1NP CTX

6 weeks 12 weeks

EVE + EXE

PBO + EXE

∆27% ∆56% ∆36% ∆22% ∆67% ∆41%

40

BOLERO-2 (12 mo f/up): Summary

• Addition of everolimus to exemestane prolongs PFS in patients with ER+ HER2- breast cancer refractory to non-steroidal aromatase inhibitors

– Local: median 7.4 vs 3.2 months, HR = 0.44, P < 1 x 10-16

– Bone resorption and formation markers increased in the exemestane arm, and decreased in the combination arm

– Toxicities: Mucositis and pneumonitis


BOLERO-2 (12 mo f/up): Summary

• Time to deterioration of QOL was similar in the two arms

• Bone resorption and formation markers increased in the exemestane arm, and decreased in the combination arm

• Adverse events are consistent with previous experience with everolimus


41

Individualized Therapy Decision

Support SystemClinically and MolecularlyAppropriate

TherapyMultidisciplinary Genomics Rounds

Molecular Pathway Knowledge Mining

Informed Consent on USON IRB-approved protocol

N=1 CLIA

CLIAvalidation

Identifying Therapeutic Targets on WGS of mTNBC Cancer

Integrated Analysis Tumor DNA/RNAand germline DNA

Life SOLiD 4

O’Shaughnessy SABCS 2011

42

Documents

HER2 in Breast Cancer History and Future Directions and Breast Cancer Swain.pdf1 HER2 in Breast Cancer History and Future Directions Sandra M. Swain, M.D. Director, Washington Cancer