NOVEDADES EN SABCS EN CANCER DE MAMA HER2+ · PDF fileNOVEDADES EN SABCS EN CANCER DE MAMA HER2+ ... 8Department of Internal Medicine, Korea University Guro Hospital, Korea; 9Taipei-Veterans

NOVEDADES EN SABCS EN

CANCER DE MAMA HER2+

Prof. Miguel Martín

Servicio de Oncología Médica

Hospital General Universitario Gregorio Marañón

Universidad Complutense

Madrid

[email protected]

Mukohara T. Cancer Sci 102:1, 2011


– Impaired access of trastuzumab

to HER2:

– Overexpression of extracellular

domain-truncated HER2 (p95

HER2)

• Overexpression of MUC4


– Activating mutations or

deletions of downstream

proteins

• PI3K

• AKT

• Aberrating downstream

signaling caused by PTEN

loss

Mucohara T. Cancer Sci 102:1, 2011

– Activation of

compensatory pathways

• Other TK receptors:

IGFR1, EGFR, HER3, MET

• ER signaling

Mucohara T. Cancer Sci 102:1, 2011

– Cell cycle related

• Downregulation of p27

• Cyclin E overexpression

Pertuzumab

Mechanism of action

There are four receptors in the HER family

HER2 HER1/EGFR HER4 HER3

Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137 EGFR = epidermal growth factor receptor


• Receptors are able to homo- and heterodimerise

HER2 HER1/EGFR HER4 HER3



• Receptors are able to homo- and heterodimerise • HER2 does not appear to have a direct ligand and HER3 lacks kinase activity

HER2 HER3



• Receptors are able to homo- and heterodimerise • HER2 does not appear to have a direct ligand and HER3 lacks kinase activity • However, HER2 and HER3 are highly complementary to each other

HER2 HER3


Homodimers Heterodimers

HER2:HER3 dimers initiate the strongest mitogenic signalling

HER1:HER1 HER2:HER2

HER3:HER3 HER4:HER4

HER1:HER2 HER1:HER3 HER1:HER4

HER2:HER4 HER3:HER4

Tzahar et al. Mol Cell Biol 1996;16:5276–5287; Citri et al. Exp Cell Res 2003;284:54–65; Huang et al. Cancer Res 2010;70:1204–1214.

HER2:HER3

Homodimers Heterodimers

HER2:HER3 dimers initiate the strongest mitogenic signalling

HER1:HER1 HER2:HER2

HER3:HER3 HER4:HER4

HER1:HER2 HER1:HER3 HER1:HER4

HER2:HER4 HER3:HER4

Tzahar et al. Mol Cell Biol 1996;16:5276–5287; Citri et al. Exp Cell Res 2003;284:54–65; Huang et al. Cancer Res 2010;70:1204–1214.

Signalling activity

+ + + + + + + + + + + + + + + +

+

HER2:HER3

HER2 dimerises preferentially with HER3 to drive downstream signalling

Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137; Graus-Porta et al. EMBO J 1997;1647–1655; Tzahar et al. Mol Cell Biol 1996;16:5276–5287;

Lee-Hoeflich et al. Cancer Res 2008;68:5878–5887.

HER2 HER3


Ligand-activated HER2:HER3 dimer



HER2 HER3


Ligand-activated HER2:HER3 dimer



HER2 HER3

Phosphorylation of the HER3 intracellular domain by HER2

initiates a signalling cascade

P P P P

Please refer to disclaimer on slide 2

Akt

Shc

HER2:HER3 dimerisation initiates multiple signalling pathways,

including increased tumour cell proliferation

Downstream PI3K/Akt signalling is mainly mediated

by HER3 after transphosphorylation by HER2

Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2:127–137; Olayioye et al. EMBO J 2000;19:3159–3167; Kim et al. J Biol Chem 1994;269:24747–24755; Soltoff et al. Mol Cell Biol 1994;14:3550–3558;

HER2 HER3

GRb2 Sos RAS

PI3K P P

P P PDK1

P P P

RAF

MEK

MAPK P

P

mTOR

Cyclin 01

GSK36

NF B

BAD

p27

Angiogenesis Proliferation

Cell cycle control

Apoptosis

Survival


Pertuzumab is the first in a new class of targeted anticancer

therapeutic agents called HER2 Dimerisation Inhibitors

By blocking HER2 dimerisation, pertuzumab inhibits key HER

signalling pathways that mediate cancer cell proliferation and survival1–

4

Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5

HER2

Dimerisation domain

1. Agus et al. Cancer Cell 2002;2:127–137; 2. Baselga. Cancer Cell 2002;2:93–95; 3. Citri et al. Exp Cell Res 2003;284:54–65. 4. Franklin et al. Cancer Cell 2004;5:317–328;

5. Hughes et al. Mol Cancer Ther 2009;8:1885–1892

HER3






4


HER2

Dimerisation domain



Pertuzumab

HER3






4


HER2

Dimerisation domain



Pertuzumab

HER3

Summary of pertuzumab combination trials in HER2-positive breast cancer

EBC (Neo-adjuvant)

First-line MBC Third-line MBC Second-line MBC

BO17929 cohorts 1+2 (n=66) P+T

BO17929 cohort 3 (n=29) P mono then P+T

NCI study (n=11) P+T

CLEOPATRA (n=800) D+T±P

PHEREXA (n=450)

Capecitabine+T±P

NEOSPHERE (n=400)

D+T vs D+T+P vs T+P vs D+P

TRYPHAENA (n=225)

D+FEC+T+P vs carboplatin+D+T+P

Enrolling Enrolment complete

Data on file. Genentech USA, Inc., CA, USA and F Hoffmann-La Roche Ltd., Basel, Switzerland

D = docetaxel; EBC = early-stage breast cancer; FEC = 5-fluorouracil, epirubicin, cyclophosphamide; MBC = metastatic breast cancer; P = pertuzumab; T = trastuzumab

San Antonio Breast Cancer Symposium – Cancer Therapy and

Research Center at UT Health Science Center – December 6‒10, 2011

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

Neoadjuvant Pertuzumab and Trastuzumab Concurrent

or Sequential with an Anthracycline-Containing or

Concurrent with an Anthracycline-Free Standard

Regimen: A Randomized Phase II Study (TRYPHAENA)

A Schneeweiss,1 S Chia,2 T Hickish,3 V Harvey,4 A Eniu,5 R Hegg,6

C Tausch,7 J-H Seo,8 Y-F Tsai,9 A Ackrill,10 G Ross,10 J Cortés11

1National Center for Tumor Diseases, University Hospital, Heidelberg, Germany;

2British Columbia Cancer Agency – Vancouver Centre, University of British Columbia, Vancouver, Canada; 3Royal Bournemouth Hospital, Bournemouth University, Bournemouth, UK; 4Regional Cancer and Blood Centre, Auckland

City Hospital, Auckland, New Zealand; 5Cancer Institute “I Chiricuta”, Cluj-Napoca, Romania; 6Hospital Pérola Byington, São Paulo, Brazil; 7Breast Center, Zürich, Switzerland;

8Department of Internal Medicine, Korea University Guro Hospital, Korea; 9Taipei-Veterans General Hospital, Taipei, Taiwan;

10Roche Products Limited, Welwyn, United Kingdom; 11Vall d'Hebron University Hospital, Barcelona, Spain




24

Study design

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

Trastuzumab

to complete

1 year

S

u

r

g

e

r

y

• 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


FEC Docetaxel

Carboplatin

Docetaxel

Pertuzumab + trastuzumab C

B

A




25

Study endpoints

• Primary endpoint:

– Cardiac safety

• Symptomatic LVSD (grade ≥3)

• LVEF declines (≥10 percentage points and below 50%)

• Secondary endpoints:

– Toxicity

– pCR (defined as the absence of invasive tumor residues in the breast at surgery; remaining in situ lesions allowed; ypT0/is)

• Study was not powered for formal comparison between arms

– Clinical response rate

– Rate of breast-conserving surgery

– Disease-free survival and overall survival

– Biomarker evaluation

LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; pCR, pathologic complete response




26

Cardiac events during neoadjuvant treatment

FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction;

P, pertuzumab; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab

FEC+H+P x3

T+H+P x3

n = 72

FEC x3 T+H+P x3

n = 75

TCH+P x6

n = 76

Symptomatic LVSD (grade ≥3),

n (%) 0 (0.0) 2 (2.7) 0 (0.0)

LVSD (all grades), n (%) 4 (5.6) 3 (4.0) 2 (2.6)

LVEF decline ≥10% points and

below 50%, n (%) 3 (4.2) 4 (5.3) 3 (3.9)




27

Pathologic complete response

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

Pa

tho

log

ic c

om

ple

te r

es

po

ns

e (

%)

FEC+H+P x3

T+H+P x3

(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

61.6

66.2

57.3




28

Summary and conclusions

• Results from TRYPHAENA indicate a low incidence of symptomatic and asymptomatic LVSD across all arms

– Concurrent administration of pertuzumab plus trastuzumab with epirubicin resulted in similar cardiac tolerability compared with sequential administration or the anthracycline-free regimen

• Regardless of chemotherapy chosen, the combination of pertuzumab with trastuzumab in the neoadjuvant setting resulted in high pCR rates (57‒66%)

• TRYPHAENA supports the ongoing APHINITY study, a Phase III trial to evaluate pertuzumab and trastuzumab plus standard chemotherapy in the adjuvant setting (poster: OT1-02-04) (NCT01358877)

Original Article Pertuzumab plus Trastuzumab plus Docetaxel for

Metastatic Breast Cancer

José Baselga, M.D., Ph.D., Javier Cortés, M.D., Sung-Bae Kim, M.D., Seock-Ah Im, M.D., Roberto Hegg, M.D., Young-Hyuck Im, M.D., Laslo

Roman, M.D., José Luiz Pedrini, M.D., Tadeusz Pienkowski, M.D., Adam Knott, Ph.D., Emma Clark, M.Sc., Mark C. Benyunes, M.D., Graham

Ross, F.F.P.M., Sandra M. Swain, M.D., for the CLEOPATRA Study Group

N Engl J Med Volume 366(2):109-119

January 12, 2012

CLEOPATRA: Study design

MBC, metastatic breast cancer; PD, progressive disease

Patients with

HER2-positive MBC

centrally confirmed

(N = 808)

Placebo + trastuzumab n=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


Docetaxel* ≥6 cycles recommended

PD

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

Study endpoints

• Primary endpoint

– Independently assessed progression-free survival (PFS)

• Secondary endpoints

– PFS by investigator assessment

– Objective response rate

– Overall survival

– Safety

– Duration of response

– Evaluation of biomarkers and correlation with clinical outcomes

– Time to symptom progression

Baseline characteristics (I)

Placebo

+ trastuzumab + docetaxel

(n = 406)

Pertuzumab


(n = 402)

Median age, years

(range)

54.0

(27–89)

54.0

(22–82)

Region, n (%)

Asia

Europe

North America

South 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 (%)

0

1

≥2

248 (61.1)

157 (38.7)

1 (0.2)

274 (68.2)

125 (31.1)

3 (0.7)

ECOG PS, Eastern Cooperative Oncology Group performance status

Primary endpoint: Independently assessed PFS n = 433 PFS events

D, 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

n at risk

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

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

Time (months)

Ptz + T + D: median 18.5 months

Pla + T + D: median 12.4 months

HR = 0.62

95% CI 0.51‒0.75

p<0.0001

∆ = 6.1 months

Pro

gre

ss

ion

-fre

e s

urv

ival

(%)

Stratified by prior treatment status and region

808 0.63 0.52‒0.76

432 0.63 0.49‒0.82 376 0.61 0.46‒0.81

306 0.72 0.53‒0.97 135 0.51 0.31‒0.84 114 0.46 0.27‒0.78 253 0.68 0.48‒0.95 681 0.65 0.53‒0.80 127 0.52 0.31‒0.86 789 0.64 0.53‒0.78 19 0.55 0.12‒2.54

480 0.62 0.49‒0.80 30 0.64 0.23‒1.79 261 0.68 0.49‒0.95 37 0.39 0.13‒1.18

630 0.55 0.45‒0.68 178 0.96 0.61‒1.52

388 0.72 0.55‒0.95 408 0.55 0.42‒0.72 12 ─

721 0.60 0.49‒0.74

767 0.64 0.53‒0.78

n HR 95% CI

All

No Yes

Europe North America South America

Asia

<65 years ≥65 years

<75 years ≥75 years

White Black Asian Other

Visceral disease Non-visceral disease

Positive Negative

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

Favors placebo

Favors pertuzumab

Unstratified analyses

Independently assessed PFS by prior trastuzumab

therapy in patients with (neo)adjuvant therapy

PFS, progression-free survival

Placebo

+ trastuzumab

+ docetaxel

Median PFS, months

Pertuzumab

+ trastuzumab

+ docetaxel

Median 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)

Independently reviewed objective response In patients with measurable disease at baseline

Placebo

+ trastuzumab

+ docetaxel

(n = 336)

Pertuzumab

+ trastuzumab

+ docetaxel

(n = 343)

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)

* The statistical test result is deemed exploratory

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 0 Placebo + 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)

Overa

ll s

urv

iva

l (%

)

Safety results

Cardiac tolerability

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

Placebo


(n = 397)

Pertuzumab


(n = 407)

Investigator-assessed

symptomatic LVSD* 1.8% 1.0%

Independently adjudicated

symptomatic LVSD* 1.0% 1.0%

Fall in LVEF to <50% and by

≥10 percentage points from

baseline

6.6% 3.8%

* LVSD was defined as NYHA class III/IV

Adverse events (all grades)

≥25% incidence or ≥5% difference between arms

Adverse event, n (%)

Placebo


(n = 397)

Pertuzumab


(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)

Summary and conclusions

• CLEOPATRA met its primary endpoint and demonstrated a statistically

significant and clinically meaningful improvement in PFS (HR = 0.62) in

patients with HER2-positive MBC

– Median PFS increased by 6.1 months from 12.4 to 18.5 months

– The PFS improvement was consistent across subgroups and supported by

the secondary endpoints of ORR and OS (immature)

• The combination of pertuzumab and trastuzumab plus docetaxel increased rates

of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin

– These adverse events were primarily grades 1‒2, manageable, and occurred

during docetaxel therapy

– There was no increase in cardiac adverse events or LVSD

• This new regimen may be practice-changing in HER2-positive

first-line MBC

clinicaloptions.com/oncology

An Update on Metastatic Breast Cancer

Women with previously

untreated HER2-positive

locally recurrent/metastatic

breast cancer

(N = 424)

Trastuzumab 6 mg/kg† +

Docetaxel 100 mg/m2 +

Bevacizumab 15 mg/kg,

all given q3w

(n = 216)

Trastuzumab 6 mg/kg† +

Docetaxel 100 mg/m2,

both given q3w

(n = 208)

Treatment until disease progression

or unacceptable toxicity*

Stratified by previous (neo)adjuvant taxane,

adjuvant trastuzumab, hormone receptor status,

measurable disease

*Planned minimum of 6 docetaxel cycles administered. †Trastuzumab 8 mg/kg loading dose given.

Gianni L, et al. SABCS 2011. Abstract S4-8.

AVEREL: Study Design

Primary endpoint: PFS (investigator assessed)

Secondary endpoints: OS, ORR, duration of response, TTF, safety



AVEREL: PFS, Interim OS Analysis, and

Response

ORR similar between T + Doc + Bev and T + Doc in investigator assessment (74.3% vs 69.9, respectively; P = .3492)

ORR significantly higher with addition of Bev in IRC assessment (76.5% vs 65.9, respectively; P = .0265)

Outcome, Mos T + Doc + Bev

(n = 216)

T + Doc

(n = 208)

HR (95% CI) P Value

Median PFS

(Investigator assessment) 16.5 13.7

0.82

(0.65-1.02) .0775

Median PFS

(IRC assessment) 16.8 13.9

0.72

(0.54-0.94) .0162

Median OS 38.5 38.3

1.01

(0.74-1.38)

(unstratified)

.9543

0.94

(0.68-1.30)

(stratified)

.7078




AVEREL: Conclusions

Addition of bevacizumab to first-line treatment with trastuzumab and docetaxel in patients with HER2-positive advanced breast cancer may prolong PFS

– Findings not significant according to investigator-assessed PFS (primary endpoint; P = .0775)

– Findings significant according to independent review of PFS (exploratory endpoint; P = .0162)

Bevacizumab-associated AEs led to higher incidence of discontinuation of any study drug


45

A Phase 2, Randomized, Open-label Study of

Neratinib (HKI-272) Versus Lapatinib Plus

Capecitabine for 2nd/3rd-line Treatment of HER2+

Locally Advanced or Metastatic Breast Cancer

Miguel Martin,1 Jacques Bonneterre,2 Charles E. Geyer Jr,3 Yoshinori Ito,4 Jungsil Ro,5 Istvan Lang,6 Sung-Bae Kim,7

Caroline Germa,8,* Jennifer Vermette,9 Marie-Louise Vo Van,8 Kenneth Wang,9,* Kongming Wang,9 Ahmad Awada10

1Hospital Universitario Gregorio Marañón, Madrid, Spain; 2Centre Oscar Lambret, Lille, France; 3University of Texas Southwestern Medical Center, Dallas, TX, USA; 4The Cancer

Institute Hospital of JFCR, Tokyo, Japan; 5National Cancer Center, Goyang, Korea; 6National Institute of Oncology, Budapest, Hungary; 7Asan Medical Center, Seoul, Korea; 8Pfizer Global Research and Development, Paris, France; 9Pfizer Inc, Cambridge, MA, USA; 10Jules Bordet

Institute, Brussels, Belgium.

*This author was employed at Pfizer during the conduct of this study, but has since become employed at another company.

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 authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

46

Phase 2, open-label

trial in HER2+

locally advanced or

metastatic BC

patients

Neratinib

240 mg/day

n = 117

L + C

L 1,250 mg/day + C 2,000 mg/m2 per day

n = 116

R

A

N

D

O

M

I

Z

E

Randomization is stratified based on geographical regions.

Study Design (cont)

● Patients were randomized 1:1 to neratinib or L + C

– Neratinib was administered orally at 240 mg/day continuously

– L 1,250 mg/day was administered orally continuously;

C 2,000 mg/m2 was administered orally on Days 1 to 14 of each

21-day cycle



47

1. Calculated from data published in Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):533-543.

Phase 2 Sample Size Determination

● Non-inferiority design intended to show that neratinib monotherapy

was not inferior to L + C

● Assumption was for non-inferiority in terms of PFS, defined as a

non-inferiority margin of 15% equivalent to retaining 50% of the

benefit demonstrated for L + C over capecitabine monotherapy1

● A total of 163 PFS events were needed for analysis, given the

following assumptions for sample size calculations

– Median PFS of 27.5 weeks for the L + C arm and 33.9 weeks for

the neratinib arm (25% improvement in median PFS; true hazard

ratio = 0.80)

– Enrollment rate of approximately 3 patients per week

– Design based on a 1-sided log-rank test

• Alpha = 0.1; power = 85%; 1-year dropout rate = 20%



48

Baseline Characteristics: ITT Population

Characteristic

Neratinib

(n = 117)

L + C

(n = 116)

Median age (range), y 52 (28–79) 56 (30–79)

Ethnicity, %

White 66 55

Asian 27 40

Other 7 5

ECOG Performance Status, %a

0 60 60

1 37 34

2 3 4

Estrogen receptor–positive, %b 44 40

Progesterone receptor–positive, %c 27 28

No. of prior anti-cancer regimens, %

1 14 14

2 33 33

≥3 53 53

Prior trastuzumab therapy, %

Adjuvant/neoadjuvant settings 20 32

Metastatic setting 79 68 L, lapatinib; C, capecitabine; ECOG, Eastern Cooperative Oncology Group. aECOG information was missing for 1 patient (1%) in the neratinib arm and 3 (3%) patients in the L + C arm. bEstrogen receptor status was unknown for 1 (1%) patient in the neratinib arm and 2 (2%) patients in the L + C arm. cProgesterone receptor status was unknown for 31 (26%) patients in the neratinib arm and 32 (28%) patients in the L + C arm.



49

Incidences of Diarrhea and PPE:

Safety Population

0

20

40

60

80

100

Neratinib L + C

Pa

tie

nts

wit

h d

iarr

he

a (

%)

P = 0.002

85% all grades

28% grade 3/4

68% all grades

10% grade 3/4

n = 116 n = 115

Neratinib L + C

Grade 1/2 Grade 1/2

Grade 3/4 Grade 3/4

0

20

40

60

80

100

Neratinib L + C

Pa

tie

nts

wit

h P

PE

(%

)

P <0.001

5% all grades

0% grade 3/4

65% all grades

14% grade 3/4

n = 116 n = 115

PPE, palmar-plantar erythrodysesthesia syndrome; L, lapatinib; C, capecitabine.



50

Treatment Modifications, Discontinuations,

and Deaths Due to Adverse Events

Modification, %

Neratinib

(n = 116)

L + C

(n = 115)

Dose reduction 19 53

Dose delay 32 74

Treatment discontinuationsa 6 17

Diarrhea 2 4

Nausea 0 2

Stomatitis 0 2

PPE 0 4

Dizziness 0 2

Deaths 0 0

L, lapatinib; C, capecitabine; PPE, palmar-plantar erythrodysesthesia syndrome. aAdverse events leading to 2 discontinuations are listed in the table.



51

0 30 5 10 15 20 25

0

10

20

30

40

50

60

70

80

90

100

PFS: ITT Population

n Median PFS 95% CI P value

Neratinib 117 4.5 mo 3.1–5.7 mo 0.231

L + C 116 6.8 mo 5.9–8.2 mo

L, lapatinib; C, capecitabine; PFS, progression-free survival; CI, confidence interval.

Time since randomization (mo)

Pro

bab

ilit

y o

f P

FS

(%

) Neratinib

L + C



52

Analysis of Non-inferiority

ITT population PP populationa

Non-inferiority margin

1 1.15

HR (Ner/L + C)

1.19 0.89 1.60

Neratinib better

1

Non-inferiority margin

1.15

1.14

L + C better

0.84 1.55

HR (Ner/L + C)

● Non-inferiority of treatment with neratinib versus L + C

could not be demonstrated

Neratinib better

L + C better

ITT, intent-to-treat; PP, per protocol; HR, hazard ratio; L, lapatinib; C, capecitabine. aPP protocol population included patients who were randomized and received at least 1 week of study treatment, incurred no major

protocol violations, and had tumor assessments at screening and at least 1 valid post-baseline tumor assessment.



53

Best Overall Response: ITT Population

Modification, %

Neratinib

(n = 117)

L + C

(n = 116)

Complete response 2 4

Partial response 27 36

Stable disease ≥24 weeks 15 23

Stable disease <24 weeks 29 24

Progressive disease 17 7

Unknown/missing 9 5

L, lapatinib; C, capecitabine.

● The ORR was 29% in the neratinib arm compared with

40% in the L + C arm



54

Conclusions

● Neratinib did not demonstrate non-inferiority versus L + C in terms of PFS

● In addition, the antitumor activity of neratinib

monotherapy in heavily pretreated patients with

advanced or metastatic HER2+ BC was robust (ORR

of 29%)

● Diarrhea was the most frequently reported adverse

event, but was typically transient and manageable

● These findings support the continued development

of neratinib as monotherapy and in combination with

other agents for treatment of recurrent HER2+ BC

1. Burstein HJ, et al. J Clin Oncol. 2010;28(8):1301-1307.



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 authors/presenter. Contact them at [email protected] for permission to reprint and/or distribute.

Results of the TEACH Trial Lapatinib in Women With Early-Stage HER2-Overexpressing Breast Cancer

A Double-blind, Placebo-controlled, Phase III Trial

Paul Goss1, Ian Smith2, Joyce O’Shaughnessy3, Bent Ejlertsen4, Manfred Kaufmann5, Frances Boyle6, Aman Buzdar7, Pierre Fumoleau8, William Gradishar9, Miguel Martin10, Beverly Moy1, Martine Piccart-Gebhart11, Kathleen I. Pritchard12, Deborah Lindquist13,

Gursel Aktan14, Erica Rappold14, Lisa Williams14, Dianne Finkelstein1

1Massachusetts Gen Hosp, Boston MA; 2Royal Marsden Hosp, London, UK; 3Baylor Sammons Cancer Ctr and US Oncology, Dallas TX; 4Rigshospitalet, Copenhagen, Denmark; 5JW Goethe-Universität, Frankfurt, Germany; 6Mater Hosp, Sydney, Australia; 7UT MD Anderson Cancer Ctr, Houston TX; 8Centre GF Leclerc, Dijon, France; 9Northwestern Univ, Chicago IL; 10Hospital Universitario Gregorio Maranon, Madrid, Spain; 11Jules Bordet Inst, Brussels, Belgium; 12Sunnybrook Odette Cancer Ctr, Toronto, Ontario; 13Arizona Oncology and US Oncology, Sedona, AZ; 14GlaxoSmithKline, Collegeville PA and Uxbridge, UK.




TEACH Trial

Placebo

qd × 1 yr

Lapatinib

1500 mg qd × 1 yr

Stratification

• Time from diagnosis ≤4 vs >4 yrs

• Lymph node +ve vs -ve

• ER+ and/or PgR+ vs ER–/PgR–

4 yr

Eligibility

• HER2+ Local IHC3+ or FISH +ve

•Resected Stage I-IIIc primary BRCA

•No prior trastuzumab

•Neo-/adjuvant chemotherapy (CMF,

anthracycline, or taxane)

•Appropriate endocrine therapy

1 yr

<1 yr only if unable or did

not receive trastuzumab N=3147

Aug 2006-May 2008

33 countries

R

A

N

D

O

M

I

Z

E

59

Diagnosis




TEACH Trial Objectives Primary

• Disease-free survival (DFS): • local, regional, distant recurrence, contralateral BRCA

• other 2nd primary cancers

• death from any cause

Secondary • Recurrence-free survival

• Distant recurrence-free survival

• Overall survival (OS)

• Rate of CNS recurrences and recurrence-free survival

• DFS in key-defined subgroups, including all strata

• Health-related quality of life

• Compliance and treatment exposure

• Safety, including cardiac and liver abnormalities 60




TEACH: ITT and Confirmed FISH+ Patient Population

61

0

25

50

75

100

N. America/Canada(n=473)

Latin America(n=344)

Europe(n=1235)

Asia Pacific

(n=863)

Central FISH+ 79% Confirmed

Confirmed FISH+

Ce

ntr

all

y C

on

firm

ed

FIS

H P

ati

en

t

Po

pu

lati

on

by

Re

gio

n (

%)




0.0

TEACH Primary Endpoint: K-M Plot of DFS in ITT Population—Time From Randomization

62 ap value based on 2-sided stratified log-rank test

Lapatinib

Placebo HR 0.83 (0.70-1.00); p=0.053a

Median Follow up: 4 years

Number of patients at risk

Lapatinib 1500 mg 1571 1431 1349 1293 1233 1168 1001 661 299

Placebo 1576 1487 1412 1343 1295 1247 1048 706 327




TEACH: K-M Plot of DFS in Confirmed FISH+ Population—Time From Randomization

0.0

63

Lapatinib

Placebo

HR 0.82 (0.67-1.00); p=0.04a

ap value based on 2-sided stratified log-rank test.


Lapatinib 1500 mg 1230 1137 1069 1026 980 934 810 533 245

Placebo 1260 1186 1125 1075 1035 993 840 578 275




TEACH Common AEs: Maximum NCI CTC Toxicity Grades

64 NCI=National Cancer Institute; CTC=Common Toxicity Criteria.




TEACH Conclusions

• Although DFS did not reach statistical significance in the overall patient population enrolled over a broad time frame, in centrally confirmed FISH+ tumors, DFS improvement reached statistical significance

• In the overall patient population, DFS improvement was significant in key prespecified subgroups – ER/PgR-ve patients

– Patients ≤ 1 year from diagnosis

• Predominantly low grade diarrhea and skin rash affect compliance, but no new or unexpected serious safety concerns were found

65

T-DM1: A novel antibody−drug conjugate

T-DM1

Monoclonal antibody: trastuzumab

Target expression: HER2

Highly potent chemotherapy (DM1, a tubulin destabiliser)

Cytotoxic drug: DM1

Systemically stable

Linker


TDM4450g Phase II Study: T-DM1 vs Trastuzumab

+ Docetaxel in HER2-Positive MBC

Multicenter, randomized study

Primary end points

– PFS by INV

– Safety

Secondary end points

– Overall survival (OS), ORR, CBR, duration of response, duration of survival, pharmacokinetics, time-to-treatment failure (TTF)

• HER2-positive,

recurrent, LABC

or MBC (N=137)

• No prior therapy for

advanced breast cancer

or MBC

Trastuzumab (8-mg/kg loading dose,

then 6 mg/kg) + docetaxel

(75 or 100 mg/m2) q3w

T-DM1 3.6 mg/kg q3w until

PD/unnacceptable toxicity

or study termination

Cross-

over

to T-DM1 PD

1:1

PD, progressive disease.

Perez et al. UPDATE FROM ESMO 2010. Abstract/oral presentation LBA3.

68

Selected Patient Demographic and Baseline

Characteristics

Trastuzumab + docetaxel

(n=70)

T-DM1

(n=67)

Median age, y (range) 52.0 (33–75) 55.0 (27–82)

World region, %

US

Non-US 28.6

71.4

31.3

68.7

ECOG PS 0, %

ECOG PS 1, % 63.8a

36.2a

65.7

34.3

HER2-positive status by central lab, %b

85.2 85.2

ER+ and/or PR+, %

ER– and PR–, %

ER and PR unknown, %

54.3

41.1

4.3

49.3

47.8

3.0

Lung or liver involvement, %

Yes

No

Unknown

67.1

31.4

1.4

71.6

26.9

1.5

Disease-free interval, %

<24 months

>24 months 64.3

35.7

59.7

40.3

aECOG PS data were available for 69 patients in the trastuzumab + docetaxel arm. bCentral testing for HER2 status was performed for 61 patients in the trastuzumab + docetaxel arm and 61 patients in the

T-DM1 arm.

69

Time (months)

Progression-Free Survival by Investigator Randomized Patients

Pro

po

rtio

n p

rog

ressio

n-f

ree

1.0

0.8

0.6

0.4

0.2

0.0 0 2 4 6 8 10 12 14 16 18 20


T+D 70 66 63 53 43 27 12 4 2 2 0

T-DM1 67 60 51 46 42 35 22 15 6 3 0

Hazard ratio and log-rank P value were from stratified analysis.

Trastuzumab

+ docetaxel (n=70)

T-DM1 (n=67)

Median

PFS, mos

Hazard

ratio

95% CI

Log-rank

P value

9.2

14.2

0.594

0.364–

0.968

0.0353

70

Cardiac Safety

• Cardiac function was assessed locally and centrally based on cardiac ECHO/MUGA

• Prior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectively

• Asymptomatic LV dysfunction

• There were no clinically significant cardiac events reported

LVEF assessment Trastuzumab +

docetaxel T-DM1

Local assessment

Patients assessed 65 67

Patients with post-baseline LVEF ≤40% 2a 0

Central assessment

Patients assessed 60 65

Patients with post-baseline LVEF ≤40% 1b 0

aBoth patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the

adjuvant setting. bThis patient did not receive prior treatment with an anthracycline.

71

Summary and Conclusions

•This is the first randomized study to evaluate an antibody-drug

conjugate for HER2-positive MBC

•First-line treatment of HER2-positive MBC with T-DM1,

compared with trastuzumab + docetaxel was associated with:

–A significant improvement in PFS (14.2 vs 9.2 mos; HR=0.594; P

value=0.0353)

–A lower rate of grade ≥3 AEs (46.4% vs 89.4%)

•T-DM1 is being evaluated in phase III randomized clinical trials

for HER2-positive MBC

CONCLUSIONES

-Pertuzumab en asociación con trastuzumab incrementa

significativamente la actividad de éste sin apenas añadir

toxicidad

-TDM-1 posee una gran actividad antitumoral en tumores

HER2+

-El papel del lapatinib como adyuvancia tardía está

pendiente de definir

-El neratinib parece poseer una interesante actividad en

cáncer de mama HER2+

-El bloqueo dual del receptor de HER2 se traduce de

nuevo en un beneficio clínico

Documents

NOVEDADES EN SABCS EN CANCER DE MAMA HER2+ · PDF fileNOVEDADES EN SABCS EN CANCER DE MAMA HER2+ ... 8Department of Internal Medicine, Korea University Guro Hospital, Korea; 9Taipei-Veterans