Hans Wildiers University Hospitals Leuven

Belgium

The next wave of successful drug therapy strategies in

HER2-positive breast cancer

Trastuzumab in 1st Line significantly improved the prognosis of HER2-positive MBC

• MBC, metastatic breast cancer • Dawood et al. JCO 2010

Ove

rall

surv

ival

(%

)

Time (months from diagnosis)

HER2-negative HER2-positive with trastuzumab HER2-positive without trastuzumab

0

20

40

60

80

100

0 12 24 36 48 60

OS

Trastuzumab significantly improves overall survival in HER2-positive MBC

18

25 22.7

31.2

Slamon et al.* Marty et al.

Taxanes

Trastuzumab + taxanes MBC, metastatic breast cancer *IHC3+ patients Slamon; Anti-Cancer Drugs 2001 Marty, JCO 2005 Valero et al. JCO 2010; 29(2):149-56

Med

ian

over

all s

urvi

val (

mon

ths)

OS

37.1

Valero et al.

New anti-HER2 drugs

Lapatinib /Neratinib

Baselga & Swain, Nature Reviews Cancer 2009

BO17929: A Phase II study of pertuzumab and trastuzumab in MBC that progressed during trastuzumab-based therapy

HER2 positive MBC progressing on trastuzumab + CT

HER2 positive MBC progressing on trastuzumab + CT

Pertuzumab + trastuzumab

Pertuzumab + trastuzumab Pertuzumab PD PD

PD

• Primary endpoints – Objective response rate – Clinical benefit rate (objective responses plus stable disease at 6 months)

Cohort 1 (n = 24) and Cohort 2 (n = 42)1

17 patients received

PD, progressive disease

1. Baselga J, et al. J Clin Oncol 2010; 28:1138–1144;

2. Cortés J, et al. J Clin Oncol 2012; 30:1594–1600.

Cohort 3 (n = 29, added after protocol amendment) 2

HP median PFS 5.5 months (Cohort 1+2) CR, complete response P, pertuzumab PR, partial response H, trastuzumab SD, stable disease CBR, clinical benefit rate

Pertuzumab and Trastuzumab Phase II Proof of Concept study (BO17929)

1. Baselga et al. J Clin Oncol 2010;28:1138–1144; 2. Baselga et al. SABCS 2009. Abstract 5114

6

18

3

21

26

7

21

0

10

20

30

40

50

60

Cohort 1 +2 (HP)n=66

Cohort 3 (P)n=29

Cohort 3 (P -> HP)n=17

Patie

nts

(%)

CR PR SD

HP CBR: 50%

P CBR: 10.3%

P->HP CBR: 41.2%

1 2 2

Pertuzumab plus trastuzumab demonstrates a more comprehensive block of HER2 signalling compared to monotherapy alone in a mouse model

Scheuer et al. Cancer Res 2009;69:9330–9336 ip = intraperitoneal; SEM = standard error of the mean; aLoading dose

Mea

n tu

mou

r vol

ume

(mm

3 ) ±

SEM

Treatment period (days)

KPL-4 breast cancer xenograft model

Vehicle control Pertuzumab (30a/15 mg/kg/w ip) Trastuzumab (30a/15 mg/kg/w ip) Pertuzumab (30a/15 mg/kg/w ip) + trastuzumab (30a/15 mg/kg/w ip)

0

100

300

400

500

600

0 40 50 60 70 80

200

10 20 30

Single-agent pertuzumab and trastuzumab demonstrate similar efficacy; combination of the two leads to a more comprehensive blockade of HER2 signaling

CLEOPATRA: Combination of pertuzumab with trastuzumab in HER2-positive first-line MBC

MBC, metastatic breast cancer; PD, progressive disease Baselga et al. NEJM 2012

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

Primary endpoint: Independently assessed PFS Secondary endpoints included Overall survival; PFS by investigator assessment; Safety

Patients with HER2-positive first-line MBC

central confirmation

(N=808)

Placebo + trastuzumab

1:1 Docetaxel

≥6 cycles recommended

n=406

n=402

Pertuzumab + trastuzumab

PD

PD

Docetaxel ≥6 cycles recommended

CLEOPATRA : Independently assessed PFS showed significant benefit for pertuzumab arm

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

Prog

ress

ion-

free

sur

viva

l (%

)

Stratified by prior treatment status and region

Baselga et al. SABCS 2011. Oral presentation S5-5 Baselga et al. NEJM 2012;366(2):109-19

PFS

Combination of HER2-targeted therapy significantly improves efficacy in HER2-positive MBC

taxanes

Trastuzumab + taxanes

12.4 mths

18.5mths

MBC, metastatic breast cancer *IHC3+ patients Slamon; Anti-Cancer Drugs 2001 Marty, JCO 2005 Baselga, NEJM 2012

3.0 mths

6.1 mths

7.1 mths

11.7 mths

Slamon et al.*

Marty et al.

Tim

e To

Pro

gres

sion

(mon

ths)

Baselga et al.

Pertuzumab + trastuzumab + taxanes

+ 6.1 months PFS

TTP

Kaplan-Meier curves of the definitive confirmatory overall survival analysis showed significant benefit for pertuzumab arm

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

0 Ptz + T + D

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

HR=0.66 95% CI 0.52−0.84

p=0.0008

Swain et al. SABCS 2012

OS

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

Highlighted are adverse events with ≥5% higher incidence

n (%) Placebo + trastuzumab + docetaxel

(n=396) Pertuzumab + trastuzumab + docetaxel

(n=408)

Diarrhea 191 (48.2) 278 (68.1)

Alopecia 240 (60.6) 248 (60.8)

Neutropenia 197 (49.7) 216 (52.9)

Nausea 168 (42.4) 179 (43.9)

Fatigue 148 (37.4) 155 (38.0)

Rash 95 (24.0) 149 (36.5)

Decreased appetite 105 (26.5) 121 (29.7)

Mucosal inflammation 79 (19.9) 112 (27.5)

Asthenia 121 (30.6) 110 (27.0)

Vomiting 97 (24.5) 104 (25.5)

Peripheral edema 122 (30.8) 101 (24.8)

Pruritus 40 (10.1) 68 (16.7)

Constipation 101 (25.5) 63 (15.4)

Febrile neutropenia 30 (7.6) 56 (13.7)

Dry skin 23 (5.8) 44 (10.8)

Swain et al. SABCS 2012

Grade ≥3 adverse events (incidence ≥5%)

n (%)

Placebo + trastuzumab + docetaxel

(n=396)

Pertuzumab + trastuzumab + docetaxel

(n=408)

Neutropenia 182 (46.0) 200 (49.0)

Febrile neutropenia 30 (7.6) 56 (13.7)

Leukopenia 59 (14.9) 50 (12.3)

Diarrhea 20 (5.1) 37 (9.1)

Swain et al. SABCS 2012

Patients with adverse event, n (%) Placebo + trastuzumab

(n=255) Pertuzumab + trastuzumab

(n=298) Hypertension 3 (1.2) 5 (1.7)

Diarrhea 0 (0.0) 3 (1.0)

LVSD 5 (2.0) 2 (0.7)

Fatigue 3 (1.2) 2 (0.7)

Neutropenia 4 (1.6) 0 (0.0)

Grade ≥3 adverse events after docetaxel discontinuation

There is no evidence that pertuzumab increases the incidence of cardiac adverse events

* In patients with post-baseline assessment LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction

n (%) Placebo

+ trastuzumab + docetaxel Pertuzumab

+ trastuzumab + docetaxel

Data cutoff date May 2011 (n=397)

May 2012 (n=396)

May 2011 (n=407)

May 2012 (n=408)

LVSD (all grades) 33 (8.3) 34 (8.6) 18 (4.4) 22 (5.4)

Symptomatic LVSD 7 (1.8) 7 (1.8) 4 (1.0) 5 (1.2)

LVEF decline to <50% and by ≥10% points from baseline*

25/379 (6.6) 28/378 (7.4) 15/393 (3.8) 18/394 (4.6)

LVEF recovery to ≥50%* 18/25 (72.0) 25/28 (89.3) 13/15 (86.7) 16/18 (88.9)

Swain et al. SABCS 2012

15

Phase 2 EORTC Elderly trial (ML28116): 1st line trial

HER2 + MBC "elderly“ patients

(n=80)

pertuzumab + trastuzumab

Primary endpoint: - progression free survival at 6 months

Secondary endpoints: - Overall survival - Breast cancer specific survival - Tumour Response rate as measured by RECIST 1.1 - Evolution of HRQoL assessed by EORTC QLQ-C30 and ELD 15 - Evolution of geriatric assessment - If T-DM1 after progression: PFS after starting T-DM1

T-DM1 (offered, but

not mandatory) PD

pertuzumab + trastuzumab + metronomic chemotherapy**

R

**cyclophosphamide 50 mg/d p.o. continuously

NCT01597414

NeoSphere: Study design and objectives

S

U

R

G

E

R

Y

• Phase II design

• Primary endpoint: Comparison of pCR rates TH vs THP TH vs HP THP vs TP

• Secondary endpoints: Clinical response DFS Breast conservation rate Biomarker evaluation

Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417)

Study dosing: q3w x 4

THP (n=107) docetaxel (75®100 mg/m2) trastuzumab (8®6 mg/kg) pertuzumab (840®420 mg)

HP (n=107) trastuzumab (8®6 mg/kg) pertuzumab (840®420 mg)

TP (n=96) docetaxel (75®100 mg/m2) pertuzumab (840®420 mg)

TH (n=107) docetaxel (75®100 mg/m2) trastuzumab (8®6 mg/kg)

Gianni L, et al. Lancet Oncol 2011 DOI:10.1016/S1470-2045(11)70336-9

NeoSphere: Primary endpoint – pCR (pathologic complete response in ITT population)

H, trastuzumab; P, pertuzumab; T, docetaxel p values from Cochran-Mantel-Haenszel test and adjusted for multiplicity

p=0.0198

TH THP HP TP

p=0.0141 50

40

30

20

10

0

pCR,

% ±

95%

CI

p=0.003

29.0

45.8

16.8 24.0

Gianni L, et al. Lancet Oncol 2011 DOI:10.1016/S1470-2045(11)70336-9

pCR

HER2-positive EBC

(N = 225)

Pertuzumab + trastuzumab (Cycles 1–6) + FEC (Cycles 1–3) + docetaxel (Cycles 4–6)

FEC (Cycles 1–3) ® pertuzumab + trastuzumab + docetaxel (Cycles

4–6)

Pertuzumab + trastuzumab + docetaxel + carboplatin (Cycles 1–6)

Trastuzumab to complete

1 year

S

U

R

G

E

R

Y

All three arms are experimental

FEC, 5-fluorouracil, epirubicin, cyclophosphamide

Schneeweiss A, et al. SABCS 2011 (Abstract S5–6; oral presentation); www.clinicaltrials.gov/ct2/show/NCT00976989.

TRYPHAENA: A Phase II study of pertuzumab and trastuzumab in the neoadjuvant setting

pCR 45-52% in 3 arms Very few cardiac events: - Symptomatic LVSD (grade ≥3) 0-3% - LVEF decline ≥10% points and below 50% 4-5%

S U R G E R Y

Central confirmation

of HER2 status

Randomisation within 7 weeks

of surgery

Start treatment

within 1 week

F O L L O W

U P

10

Y E A R S

R A N D O M I Z A T I O N

Chemotherapy plus trastuzumab and pertuzumab

Chemotherapy plus trastuzumab and placebo

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

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

Phase 3 APHINITY trial (BO25126): Adjuvant trial

NCT01358877

T-DM1 in MBC: Phase III study EMILIA: T-DM1 compared with lapatinib+capecitabine

Blackwell et al. J Clin Oncol 2012

• Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease

• Primary end points: PFS by independent review, OS, and safety

• Key secondary end points: PFS by investigator, ORR, DOR, time to symptom progression

1:1

HER2+ (central) LABC or MBC (N=980)

• Prior taxane and trastuzumab • Progression on metastatic

treatment or within 6 months of adjuvant therapy

PD

T-DM1

Lapatinib + Capecitabine

PD

EMILIA: Progression-Free Survival by Independent Review

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Cap + Lap T-DM1

No. at risk by independent review:

Median (months)

No. of events

Cap + Lap 6.4 304 T-DM1 9.6 265 Stratified HR=0.650 (95% CI, 0.55, 0.77)

P<0.0001

0.0

0.2

0.4

0.6

0.8

1.0

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

Prop

ortio

n pr

ogre

ssio

n-fr

ee

Time (months)

Unstratified HR=0.66 (P<0.0001).

PFS

EMILIA: Significant Overall Survival benefit

496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + Lap T-DM1

No. at risk: Time (months)

78.4% 64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n su

rviv

ing

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

Median (months) No. of events Cap + Lap 25.1 182 T-DM1 30.9 149 Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006

Efficacy stopping boundary P=0.0037 or HR=0.727

OS

ESMO, 2012

EMILIA: safety data

Blackwell et al. J Clin Oncol 2012 ALT = alanine aminotransferase;

AST= aspartate aminotransferase

T-DM1 (n = 490) Lapatinib/capecitabine (n = 488)

Adverse event All Grades, % Grade 3–4, % All Grades, % Grade 3–4, % Diarrhea 23.3 1.6 79.7 20.7

Hand-foot syndrome 1.2 0 58.0 16.4 Vomiting 19.0 0.8 29.3 4.5 Neutropenia 5.9 2.0 8.6 4.3 Hypokalemia 8.6 2.2 8.6 4.1 Fatigue 35.1 2.4 27.9 3.5 Nausea 39.2 0.8 44.7 2.5 Mucosal inflammation 6.7 0.2 19.1 2.3 Thrombocytopenia 28.0 12.9 2.5 0.2

Increased AST 22.4 4.3 9.4 0.8

Increased ALT 16.9 2.9 8.8 1.4

Anemia 10.4 2.7 8.0 1.6

Safety endpoints favoured T-DM1

Phase 2 ZEPHIR trial (MO27955) – Prospective Imaging study

HER2+ MBC (n=60)

Early FDG-PET/CT

T-DM1 3.6 mg/kg Q3w x 2

T-DM1 3.6 mg/kg x 1

T-DM1 3.6 mg/kg Q3w

until progression or severe toxicity

FDG-PET/CT + 89Zr-trastuzumab PET/CT +

Biopsy + Brain MRI

Late FDG-PET/CT

RECIST 1.1 + MRI

Primary endpoint: - To show that pre-treatment 89Zr-trastuzumab PET/CT is able to select lesions not responding from treatment with T-DM1 Secondary endpoint: - To show that early FDG PET/CT is able to select lesions not responding from treatment with T-DM1 Patient Eligibility: - HER2-positive locally recurrent or metastatic disease scheduled for a first or any subsequent metastatic treatment line - The patient must have at least 2 visceral or nodal “target” metastatic lesions - A biopsy of a metastatic site is required if not done previously - Primary tumour blocks available for confirmatory central laboratory HER2 testing NCT01565200

ip, intraperitoneal; iv, intravenous; SEM, standard error of the mean Adapted from Fields C, et al. AACR 2010 (Abstract 5607; poster presentation).

Combining T-DM1 with pertuzumab results in enhanced anti-tumour activity

0 40 50 10 20 30 0

300

900

1200

600

T-DM1 Pertuzumab

KPL-4 breast cancer xenograft model

Vehicle control

T-DM1 (1 mg/kg iv) + pertuzumab (15 mg/kg ip)

Pertuzumab (15 mg/kg ip) T-DM1 (1 mg/kg iv)

Time (days)

Mea

n tu

mou

r vol

ume

(mm

3 ) ±

SEM

MARIANNE: T-DM1 + Pertuzumab in first line HER2+ MBC

• Primary endpoints: • PFS, safety

www.clinicaltrials.gov. NCT01120184

HER2-positive MBC No prior chemotherapy

(n = 1092)

Trastuzumab + taxane

T-DM1 + placebo

T-DM1 + pertuzumab

MARIANNE: T-DM1 in combination with pertuzumab in the treatment of first-line HER2-positive MBC

Secondary endpoints: ORR, OS, CBR, TTF, DoR

TTF = time to treatment failure; DoR = duration of response

Timelines SABCS 2011 CLEOPATRA

results

March 4th 2013 EU label for

Pertuzumab in 1L HER2+ MBC

2012 2013 2014

ASCO/ESMO 2012 EMILIA results

*Q4 2013 EU label

T-DM1 in 2L+ HER2+ MBC

June 8th 2012 FDA approval for Pertuzumab in 1L

HER2+ MBC

Feb 22th 2013 FDA approval T-DM1 in 2L+ HER2+ MBC

*Estimated timeline