NOVEDADES EN LA TERAPIA HER2 · 2017-01-20 · NOVEDADES EN LA TERAPIA HER2 Javier Cortes, Ramon y...

NOVEDADES EN LA TERAPIA HER2

Javier Cortes,

Ramon y Cajal University Hospital, Madrid, Spain

Vall d´Hebron Institute of Oncology (VHIO),

Barcelona, Spain

http://www.google.es/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCIaMz-GTjcYCFYnVFAodG6MAbQ&url=http://www.lamarea.com/2014/07/30/despedazando-el-hospital-ramon-y-cajal-de-madrid/&ei=6GJ8VYb4DImrU5vGgugG&bvm=bv.95515949,d.d24&psig=AFQjCNHbSBjgl462KYIA2TBJUprkG5rtsg&ust=1434301531337413

News SABCS 2016 1. Is everolimus active in aromatase inhibitor resistant breast cancer?

2. Come listen to the latest phase III clinical trials on the extended use of aromatase inhibitors, DATA, NSABP B42

and BOOG 2006-05) and Dr…. discussing these pivotal clinical trials

3. The latest results on the role of the immune system in all breast cancer subtypes will be presented at SABCS

this year

4. Randomized PARP inhibitor clinical trial, somatic BRCA1/2 mutations in breast cancer and other abstracts will be

presented that will change the landscape of treating breast cancer

5. The PERTAIN trial will be presented evaluating for the first time the role of trastuzumab, pertuzumab and an

aromatase inhibitor combination in the metastatic seeting. The NSABP B52 will evaluate the role of combination

of antiHER2 and endocrine therapy in the neoadjuvant setting.

6. Can PAM50 predict pathologic complete response? Find out the first results of the PAMELA clinical trial at

SABCS this year

7. How does radiotherapy impact the cosmetic outcomes of reconstruction? A prospective multicenter clinical trial will provide the answer

8. A novel BRD4 inhibitor can circumvent endocrine resistance

9. BELLE-3: the results of the first phase III randomized clinical trial with a PI3K inhibitor in metastatic breast

cancer will be presented at SABCS.

10.What is the impact of low fat diet and exercise on breast cancer outcomes? SABCS will have the answer.

11.Can a bisphosphonate, ibandronate, improve outcomes in early stage breast cancer? The TEAM IIB trial will

provide the answer.

HER2-POSITIVE PRIMARY BREAST

CANCER

0 1 2 3 4 5

P=0.016

% E

vent

-Fre

e

60

40

20

0

100

80

Years from Randomization

HR=0.64 (95% CI: 0.44-0.93)

Neoadjuvant NOAH

Event-Free Survival

L. Gianni et al, ASCO Annual Meeting 2013. Roche data on file.

HR=0.76 (95% CI: 0.67-0.86)

% E

vent

-Fre

e

60

40

20

0 0 2 4 6 8 10

P<0.0001

100

80


Adjuvant HERA

Disease-Free Survival

Without T With T Without T With T

Trastuzumab Improves Outcomes in HER2+ EBC

HR=0.76 (95% CI: 0.67-0.86)

% E

vent

-Fre

e

60

40

20

0 0 2 4 6 8 10

P<0.0001

0 1 2 3 4 5

P=0.016

Without T With T

100

80 41.9%

28.8%

% E

vent

-Fre

e

60

40

20

0

100

80


HR=0.64 (95% CI: 0.44-0.93)

Without T With T


Neoadjuvant NOAH

Event-Free Survival

L. Gianni et al, ASCO Annual Meeting 2013

Adjuvant HERA

Disease-Free Survival

Unmet Medical Need Remains in HER2+ EBC

Roche data on file.

NeoSphere – Study Design NeoSphere

S

U

R

G

E

R

Y

Study dosing: q3w x 4

TH (n=107) docetaxel (75100 mg/m2) trastuzumab (86 mg/kg)

THP (n=107) docetaxel (75100 mg/m2) trastuzumab (86 mg/kg) pertuzumab (840420 mg)

HP (n=107) trastuzumab (86 mg/kg) pertuzumab (840420 mg)

TP (n=96) docetaxel (75100 mg/m2) pertuzumab (840420 mg)

FEC q3w x 3

FEC q3w x 3

Docetaxel q3w x 3 FEC q3w x 3

FEC q3w x 3

Trastuzumab q3w cycles 5 - 17




Identical chemotherapy backbone and identical adjuvant trastuzumab

= any improvement in long-term outcomes can be attributed solely to the neoadjuvant therapy

FEC; 5-fluorouracil, epirubicin and cyclophosphamide Gianni L. et al. Lancet Oncol 2012

Pathological Complete Response in

Breast (ypT0/is) NeoSphere

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

pC

R, %

9

5%

CI

p=0.003

29.0

45.8

16.8

24.0

N=107 N=107 N=107 N=96

Gianni L. et al. Lancet Oncol 2012

• Part of the German Phase II/III ADAPT umbrella study, designed to:

– Identify early molecular or imagining markers predictive of response

– Determine whether patients with eBC can be spared traditional chemotherapies

• WSG-ADAPT HER2+/HR– study design:

WSG-ADAPT HER2+/HR–: 12 weeks of neoadjuvant trastuzumab +

pertuzumab ± weekly paclitaxel in HER2-positive/HR-negative eBC

U Nitz, et al. Poster presentation and discussion, Abstract 518

Week 3: Ki67, cellularity

PH

PH + pac

R

2.5:1

S

U

R

G

E

R

Y

HER2-positive

hormone receptor-

negative eBC

(N = 134)

12 weeks of neoadjuvant therapy

Initial prognostic biopsy:

baseline Ki67, HR and

HER2 status

Primary objective:

• Non-inferiority of tpCR (ypT0/is ypN0): PH responders vs all

PH + pac patients

Secondary objectives:

• Evaluation of dynamic testing

• EFS

• OS

• Safety

WSG-ADAPT HER2+/HR–: Efficacy


34,4

90,5

24,4

78,6

0

10

20

30

40

50

60

70

80

90

100

PH (n = 92)

PH + pac (n = 42)

pC

R/t

pC

R r

ate

, %

tpCR (ypT0/is, ypN0) pCR (ypT0, ypN0)

8,3

44,7

4,2

31,6

0

10

20

30

40

50

60

70

80

90

100

PH: no early response

PH: early response

pC

R/t

pC

R r

ate

, %

tpCR (ypT0/is, ypN0) pCR (ypT0, ypN0)

pCR/tpCR pCR/tpCR: responders vs. non-responders (PH group)

WSG-ADAPT HER2+/HR–: Safety


AE, adverse event; SAE, serious adverse event

• Most AEs were grade 1 or 2

• Rates of grade 3–4 AEs were similar between arms

• There were five SAEs per arm

AE, n (%) PH (n = 62) PH + pac (n = 40) p-value

Anaemia 0 11 (26.8) < 0.001

Cardiac disorders 1 (1.1) 3 (7.3) 0.09

Ear/labyrinth disorders 1 (1.1) 3 (7.3) 0.09

Eye disorders 1 (1.1) 4 (9.8) 0.03

Gastrointestinal disorders

Diarrhoea

Vomiting

33 (36.7)

26 (28.9)

2 (2.2)

25 (61.0)

19 (46.3)

1 (2.4)

0.01

0.07

1.0

Fatigue 15 (16.7) 15 (36.6) 0.01

Infections/infestations 10 (11.1) 13 (31.7) 0.01

Decreased appetite 0 4 (9.8) 0.01

Nervous system disorders 14 (15.6) 23 (56.1) < 0.01

Skin disorders 16 (17.8) 26 (63.4) < 0.001

Respiratory disorders 8 (8.9) 16 (39.0) < 0.001

• Studies such as NeoSphere and TRYPHAENA have demonstrated high pCR rates with

pertuzumab- and trastuzumab-containing regimens (PHT, FEC-PHT and TCHP)

– However, there are currently no data for the combination of PH with dose-dense AC, an

anthracycline regimen commonly used in the US

• This was a single-centre retrospective analysis of 80 patients with Stage II–III HER2-positive breast

cancer treated with a neoadjuvant pertuzumab-containing regimen or AC-TH (2011–2015)

• pCR rates were highest with AC-PHT and TCHP (but not statistically significant vs. AC-TH), but toxicity

was also higher than with the other regimens

– One symptomatic LVEF decrease was reported in a patient receiving AC-PHT

Neoadjuvant pertuzumab-containing regimens vs. AC-TH for

HER2-positive localised breast cancer

L Spring, et al. Poster presentation, Abstract 586

AC-PHT

(n = 31)

TCHP

(n = 15)

PHT

(n = 17)

AC-TH

(n = 17)

pCR, % 64.5 60.0 41.8 41.2

Planned cycles completed, % 71 73 94 65

• T-DM1 has demonstrated significant improvements in survival compared with lapatinib and

capecitabine in HER2-positive second-line mBC, and pertuzumab has proven efficacy in both

eBC and mBC

– The combination of the two agents offers a potential for a traditional chemotherapy-free treatment regimen

• KRISTINE is a randomised, multicentre, open-label Phase III study of neoadjuvant T-DM1 plus

pertuzumab vs. TCHP in HER2-positive eBC

– Primary endpoint: pCR rate (ypT0/is, ypN0)

KRISTINE: pCR rates after neoadjuvant T-DM1 + P vs. TCHP in

patients with HER2-positive eBC

SA Hurvitz, et al. Oral presentation, Abstract 500

HER2-positive,

operable, locally advanced or

inflammatory

eBC (>2 cm)

N = 444

Docetaxel

+ carboplatin

+ pertuzumab

+ trastuzumab

T-DM1 + pertuzumab

Su

rge

ry

Pertuzumab +

trastuzumab

T-DM1

+ pertuzumab

Fo

llow

-up

6 cycles of neoadjuvant therapy

KRISTINE: Efficacy and HRQoL results


* Time to a ≥10-point decrease from baseline

ITT population TCHP

(n = 221)

KP

(n = 223) p-value

pCR rate

Overall, % (95% CI) 55.7 (48.8–62.3) 44.4 (37.8–51.2) 0.0155

ER+, % 43.8 35.1

ER–, % 73.2 54.2

BCS rate, % 52.6 41.7 0.0228

HRQoL

Median time to deterioration

in HRQoL, months* 3.0 4.6

Median time to deterioration

in physical function, months* 2.8 4.9

KRISTINE: Safety and conclusions


• KRISTINE did not meet its primary endpoint of superior pCR with KP vs. TCHP; the safety profile of the KP

arm was better than the TCHP arm, with fewer SAEs and grade ≥3 AEs

Safety population TCHP

(n = 219)

KP

(n = 223)

SAE, % 28.8 4.9

Grade ≥3 AE, % 64.4 13.0

Selected grade ≥3 AEs, %

Neutropenia 25.1 0.4

Diarrhoea 15.1 0.9

Febrile neutropenia 15.1 0

Anaemia 9.6 0.9

Neutrophil count decreased 9.1 0

Platelet count decreased 5.0 1.3

Fatigue 3.2 1.3

LVEF <50% and ≥10% points decrease from BL 0.5 0.4

• Lapatinib is indicated for use in second-line HER2-positive mBC, but it is not currently

approved for use in eBC

• NSABP B-41 is a Phase III open-label, randomised trial

– Primary endpoint: pCR

• pCR results were previously reported: 52.5% with Hpac, 53.2% with Lpac, 62.0% with HLpac

5-year outcomes of NSABP protocol B-41: Lapatinib as part of

a neoadjuvant treatment regimen in HER2-positive eBC

A Robidoux, et al. Oral presentation, Abstract 501

HER2-positive

eBC

N = 529

AC lapatinib + paclitaxel

AC trastuzumab + paclitaxel

Su

rge

ry

Trastuzumab to

complete 1 year HER2-

targeted therapy AC lapatinib +

trastuzumab + paclitaxel

NSABP B-41 5-year outcomes: Results

A Robidoux, et al. Oral presentation, Abstract 501

• In a subgroup analysis of RFI, the combination of the two HER2-targeted agents was favoured in most groups

compared with the trastuzumab regimen and trastuzumab was favoured over lapatinib across the same subgroups

RFI OS

N Events HR (vs T) P value (vs T)

AC→WP+T 177 23 1 NA

AC→WP+L 171 31 1.27 (0.74, 2.2) 0.14

AC→WP+T+L 171 16 0.66 (0.34, 1.25) 0.33

N Events HR (vs T) P value (vs T)

AC→WP+T 179 10 1 NA

AC→WP+L 171 17 1.52 (0.69, 3.35) 0.11

AC→WP+T+L 172 7 0.63 (0.24, 1.67) 0.55

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n o

f re

cu

rre

nce

-fre

e

0 1.0 2.0 3.0 4.0 5.0

Time (years)

Overall log-rank test: P=0.049

90% 86.9%

80.7%

1.0

0.8

0.6

0.4

0.2

0

Ove

rall

su

rviv

al

0 1.0 2.0 3.0 4.0 5.0

Time (years)

Overall log-rank test: P=0.07

95.7% 94.5%

89.4%

Trastuzumab 6 mg/kg every 3

weeks

Lapatinib 1000 mg/day

+ Letrozole or Tamoxifen if HR+

HER2+ Breast

Cancer

stage I-IIIA

N=150 S

U

R

G

E

R

Y

18 weeks

Baseline PAM50

Week 2 PAM50

Week 6 Ultrasound

PAMELA trial schema Prat A, et al. SABCS 2016

Trastuzumab 6 mg/kg every 3 weeks

Lapatinib 750 mg/day

Paclitaxel 80 mg/m2 weekly x 12

PD

*

*, defined as any increase in tumor size.

Adjuvant systemic

treatment was at

the discretion of

the treating

physician

PAMELA trial objectives

• Primary objective:

o To evaluate the ability of the HER2-E subtype to predict

pathological complete response (pCR) in the breast (ypT0-is) in

all patients (ITT population) at the time of surgery.

• Secondary objectives included:

o pCR in the breast and axilla (ypT0-isN0).

o Association of subtype at baseline with pCR beyond HR status.

o Changes in subtype calling at baseline vs. week 2.

o Association of subtypes identified at week 2 with pCR.

o Safety.

Intrinsic subtype at baseline vs. pCR in the breast

0%

20%

40%

60%

80%

100%

pCR breast pCR breast/axilla

Baseline samples (N=151)

10.0%

∆=30.6%

pC

R r

ate

40.6%

∆=24.7%

34.7%

10.0%

pCR


0%

20%

40%

60%

80%

100%

pCR breast pCR breast/axilla

Baseline samples (N=151)

10.0%

∆=30.6%

pC

R r

ate

40.6%

∆=24.7%

34.7%

10.0%

pCR

0%

20%

40%

60%

80%

100%

HER2-E(n=101)

LumA(n=22)

LumB(n=16)

Basal-like(n=9)

Normal-like(n=3)

12.5%

40.6%

0%

11.1%

pCR breast

66.7%


Signatures NBreast

pCR rateOR

Lower

95%

Upper

95%p-value OR

Lower

95%

Upper

95%p-value

HR status

HR+ 77 18.2% 1 - - - 1 - - -

HR-negative 74 43.2% 3.4 1.64 7.2 0.001 2.3 1.05 5.05 0.038

Intrinsic subtype

nonHER2-E 50 10.0% 1 - - - 1 - - -

HER2-E 101 40.6% 6.2 2.25 16.81 <0.001 4.5 1.6 12.94 0.005

Univariate Bivariate


Signatures NBreast

pCR rateOR

Lower

95%

Upper

95%p-value OR

Lower

95%

Upper

95%p-value

HR status

HR+ 77 18.2% 1 - - - 1 - - -

HR-negative 74 43.2% 3.4 1.64 7.2 0.001 2.3 1.05 5.05 0.038

Intrinsic subtype

nonHER2-E 50 10.0% 1 - - - 1 - - -

HER2-E 101 40.6% 6.2 2.25 16.81 <0.001 4.5 1.6 12.94 0.005

Univariate Bivariate

• No other clinical-pathological variable was found associated with pCR.

HER2-POSITIVE METASTATIC BREAST

CANCER

Pertuzumab in MBC: 1st Line

Baselga J, et al. NEJM 2012; Swain S, et al. NEJM 2015

HER2+ MBC: Still an unmet need...

100

80

60

40

20

0

0 12 24 36 48 60

Time From Diagnosis, months

Pro

bab

ility

of

Su

rviv

al, %

• PHEREXA is a multi-centre, open-label, randomised Phase III trial of H + capecitabine ± P (PHX) in

patients who progressed during/after H-based first-line treatment for HER2-positive mBC

• Primary endpoint: Independent Review Facility (IRF) PFS

• Key secondary endpoints: OS and safety

PHEREXA (Phase III): Trastuzumab + capecitabine ±

pertuzumab for second-line treatment of HER2-positive mBC

A Urruticoechea, et al. Oral presentation, Abstract 504

Patients with

HER2-positive mBC, who received

prior taxane and progressed after 1L H

N = 452

Trastuzumab + capecitabine (HX)

Pertuzumab + trastuzumab + capecitabine

(PHX)

PHEREXA: Efficacy


* Stratified

0 10 20 30 40 50 60 70 80 0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (months)

Pro

po

rtio

n s

urv

ivin

g

HX

PHX

224 190 130 51 19 6 0 0 0

228 205 162 66 31 12 1 0 0

HX (n = 224)

PHX

(n = 228)

Events, n (%) 115 (51) 98 (43)

mOS, months 28.1 36.1

∆, months 8.0

HR (95% CI)* 0.68 (0.51–0.90)

mFU, months 29.5 29.3

HX

(n = 224)

PHX

(n = 228)

Events, n (%) 158 (71) 168 (74)

mPFS, months 9.0 11.1

∆, months 2.1

HR (95% CI)* 0.82 (0.65–1.02)

Log-rank p-value* 0.07

mFU, months 28.6 25.3

224 142 74 38 26 21 11 5 3 2 1 0 0 0

228 165 99 58 39 23 9 5 4 3 2 1 0 0

0 5 10 15 20 25 30 35 40 45 50 55 60 65 0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (months)

Pro

po

rtio

n p

rog

res

sio

n-f

ree

HX

PHX

• PHEREXA did not meet its primary endpoint of IRF PFS

PFS (IRF) OS

• The PHEREXA study did not meet its primary PFS endpoint, as the addition of pertuzumab to

trastuzumab and capecitabine did not significantly improve PFS compared with trastuzumab and

capecitabine

– There was an absolute improvement seen in OS (of 8 months to 26.1 months); however, this was

not statistically significant because of the hierarchical testing design of the study

• No new safety signals were identified when pertuzumab was used in combination with trastuzumab

and capecitabine

PHEREXA: Conclusions


• HERMYL-1401O trastuzumab was developed as a biosimilar antibody to Herceptin

• HERiTAge is a Phase III study designed to test the bioequivalence of HERMYL-1401O trastuzumab

to the originator product, Herceptin

• Primary endpoint: overall response rate

– Key secondary endpoints: time to progression, overall survival, duration of response

HERiTAge (Phase III): Safety and efficacy of the proposed

trastuzumab biosimilar MYL-1401O vs. Herceptin

HS Rugo, et al. Oral presentation, Abstract LBA503

HER2-positive mBC

(first-line)

N = 600

Herceptin + taxane

HERMYL-1401O trastuzumab + taxane

• ORR results fell within the pre-defined equivalence margin

• PFS at 24 weeks n (%): MYL-1401O – 41 (17.8); Herceptin: 48 (21.1); p = 0.303

• Unstratified HR (95% CI): 0.8 (0.529–1.218); p = 0.302

HERiTAge: Efficacy


71,2 67,1

0

20

40

60

80

100

MYL-1401O Herceptin

OR

R a

t 2

4 w

ee

ks, %

71.2 (65.21, 77.13) 67.1 (60.87, 73.39)

N=230 N=228

HERiTAge: Safety, immunogenicity and PK summary


MYL-1401O

n = 247

Herceptin

n = 246

≥1 SAEs, n (%) 94 (38.1) 89 (36.2)

Neutropenia, n (%) 68 (27.5) 62 (25.2)

Febrile neutropenia, n (%) 11 (4.5) 10 (4.1)

Leukopenia, n (%) 4 (1.6) 12 (4.9)

Pneumonia, n (%) 4 (1.6) 5 (2.0)

Treatment-related deaths, n (%) 4 (1.6) 4 (1.6)

64 63 63,5 63 63 63

0

10

20

30

40

50

60

70

80

Baseline Cycle 5 Cycle 9

%

% LVEF (Median)

MYL-1401O Herceptin

246 212 209 148 244 140

• Immunogenicity was low, similar between the two products and

consistent with published Herceptin data

• Similar overall ADA rate

• MYL-1401O: 2.4%; Herceptin: 2.8%

• PK was similar for both products

MYL-1401O had equivalent efficacy and safety

to trastuzumab and has low immunogenicity

Clinical Quality Attribute Evaluation

(>100 analytical attributes – eg amino

acid sequence glycosylation etc)

Non-clinical and pre-clinical studies

(eg PK, PD toxicology binding antibody, immunogenicity)

Clinical equivalence study

(PK, immunogenicity and primary clinical

endpoint)

Biosimilarity – what does it take?

Clinical Quality Attribute Evaluation

(>100 analytical attributes – eg amino

acid sequence glycosylation etc)

Non-clinical and pre-clinical studies

(eg PK, PD toxicology binding antibody, immunogenicity)

Clinical equivalence study

(PK, immunogenicity and primary clinical

endpoint)

Is MYL-1401O a biosimilar?

(?) (Yes) (Yes)

• Analysis of registry data suggests that patients with HER2-positive mBC have a worse

prognosis if they have CNS metastases (CNS+) than if they do not

• ONT-380-004 is a Phase Ib study of T-DM1 plus escalating doses of ONT-380 in

HER2-positive mBC, including patients with previously treated (stable or progressive)

or untreated CNS lesions

– Data presented are for all patients treated at the recommended Phase II dose of ONT-380

CNS-penetrant TKI (ONT-380) + T-DM1 in HER2-positive mBC,

including patients with brain metastases

VF Borges, et al. Poster presentation and discussion, Abstract 513

* Including patients with previously treated CNS lesions (stable or progressive) or untreated

asymptomatic CNS lesions

HER2-positive mBC, prior trastuzumab and

a taxane*

Recommended Phase II dose

ONT-380 (300 mg BID) & T-DM1

(3.6 mg/kg IV q3w)

n = 50

Dose escalation and

cohort expansion

ONT-380 + T-DM1 in HER2-positive mBC: Results &

conclusions

VF Borges, et al. Poster presentation and discussion, Abstract 513

* In patients with measurable disease

• Clinical benefit was similar whether patients had CNS metastases or not and regardless of the number of

prior HER2-containing regimens they had received for their disease

• The safety profile was similar for patients both with and without CNS metastases, and was in line with

previously reported safety findings

• Encouraging efficacy and tolerability suggest further investigation of this combination is warranted

Overall

N = 50

With CNS mets

n = 30

Without CNS mets

n = 20

ORR, % 47* NR NR

RR in CNS, % NR 36* N/A

Median PFS, mo

(95% CI)

8.2

(5.1–10.2)

6.7

(5.1–9.2)

8.2

(3.1–N/A)

San Antonio Breast Cancer Symposium, December 6–10, 2016

This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute 55

Primary analysis of PERTAIN: A randomized, two-arm, open-label, multicenter phase II trial

assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an

aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer

Mothaffar Rimawi,1 Jean-Marc Ferrero,2 Juan de la Haba-Rodriguez,3

Valerie Easton,4 Christine Schuhmacher,4 Eleonora Restuccia,4 and Grazia Arpino5

1Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX; 2Département d'Oncologie Médicale, Centre Antoine Lacassagne, Nice, France;

3Oncology Department, Maimonides Institute of Biomedical Research, Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; 4F. Hoffmann-La Roche Ltd, Basel, Switzerland;

5Department of Clinical Medicine and Surgery, Università degli Studi di Napoli Federico II, Naples, Italy

S3-04



PERTAIN Study Design (Phase II Trial)

Postmenopausal patients

with HER2-positive and

hormone receptor-

positive LA/MBC, not

previously treated with

systemic non-hormonal

anticancer therapy in the

advanced setting

(N = 258)*

Stratification factors:

• Chemotherapy (yes/no)

• Time since adjuvant hormone therapy

(<12 months/≥12 months/no prior therapy)

Pertuzumab + Trastuzumab

Trastuzumab

* 165 events to detect significant improvement in PFS from 7 months to 10.8 months (i.e. HR 0.645) with 80% power and a 2-sided log-rank test at an alpha level of 0.05. † Choice of chemotherapy must be specified before randomization; administered per product labelling. LA, locally advanced; R, randomization.

+

Aromatase Inhibitor

Docetaxel or Paclitaxel Aromatase Inhibitor (18–24 weeks)†

OR

+

Aromatase Inhibitor

Docetaxel or Paclitaxel Aromatase Inhibitor (18–24 weeks)†

OR

R

Choice of

chemotherapy

must be

specified

before

randomization



Study Endpoints

CBR, clinical benefit rate; DoR, duration of response; ORR, overall response rate; QoL, quality of life.

Primary endpoint

• PFS

• Event-driven analysis

• 165 events needed; 166 events observed; median follow-up 31 months

Secondary endpoints

• OS

• Final analysis after a minimum follow-up of 60 months for all patients

• ORR

• CBR

• DoR

• Time to response

• Safety and tolerability

• QoL



Primary Progression-Free Survival Analysis (Stratified, ITT Population)

Analysis based upon Kaplan–Meier approach including stratification factors from IXRS. HR from a stratified Cox proportional hazards model including stratification factors from IXRS.

Median time of follow-up: 31 months. CI, confidence interval; HR, hazard ratio.

Pertuzumab + Trastuzumab + AI

(n = 129)

Trastuzumab + AI

(n = 129)

Events, n (%) 74 (57.4) 92 (71.3)

Median, months 18.89 15.80

(95% CI) (14.09, 27.66) (11.04, 18.56)

∆, months 3.09

HR (95% CI) 0.65 (0.48, 0.89)

p-value 0.0070

129 123 121 116 114 107 102 91 89 84 81 77 74 71 69 65 62 58 57 56 55 53 48 46 43 39 37 36 33 28 28 26 21 16 13 13 12 10 7 5 4 3 1 1 0

129 122 116 108 104 93 90 81 80 75 73 67 64 61 60 56 54 47 47 39 39 36 33 32 29 26 26 23 18 15 14 12 10 9 8 6 5 3 2 2 1 1 1 1 0 N at risk

Months

Event-

free P

robabili

ty (

%)

44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

100

90

80

70

60

50

40

30

20

10

0

Median


Trastuzumab + AI



Progression-Free Survival by Stratification Subgroups

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

* HR for pertuzumab arm vs. control arm (control arm, reference category) from an unstratified Cox model.

ITT population 258 166 0.66 (0.48, 0.89)

Chosen to receive induction chemotherapy

Yes 148 94 0.75 (0.50, 1.13)

No 110 72 0.55 (0.34, 0.88)

Time since adjuvant hormone therapy

<12 months 48 37 0.79 (0.42, 1.52)

≥12 months 84 45 0.50 (0.27, 0.91)

No prior hormone therapy

126 84 0.71 (0.46, 1.09)

Subgroup n Events HR* (95% CI) Pertuzumab

arm better Control arm better



Progression-Free Survival by Baseline Subgroups

* HR for pertuzumab arm vs. control arm (control arm, reference category) from an unstratified Cox model. † Includes treatment in the neoadjuvant, adjuvant, and other settings.

ITT population 258 166 0.66 (0.48, 0.89)

Prior (neo)adjuvant treatment with trastuzumab Yes 59 40 0.68 (0.37, 1.27)

No 199 126 0.64 (0.45, 0.92)

Prior (neo) adjuvant chemotherapy Yes 115 71 0.64 (0.40, 1.02)

No 143 95 0.67 (0.44, 1.02)

Prior hormone therapy†

Yes 110 70 0.64 (0.40, 1.02)

No 148 96 0.67 (0.44, 1.00)

Age category <65 years 172 108 0.66 (0.45, 0.97)

≥65 years 86 58 0.66 (0.39, 1.12)

Disease type at screening

Visceral 182 118 0.67 (0.47, 0.97)

Non-visceral 76 48 0.65 (0.36, 1.16)

Subgroup n Events HR* (95% CI)

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

Pertuzumab arm better

Control arm better



Overall Response Rate (ITT Population with Measurable Disease at Baseline)

Based on best overall response according to RECIST Version 1.1. NE: Patients who did not have any evaluable post-baseline assessments.

95% CIs were computed using the Clopper–Pearson approach. 95% difference in ORR between treatment arms with associated 95% CIs calculated using the Hauck–Anderson approach.

CR, complete response; NE, not evaluable; PR, partial response; SD, stable disease.

63,3

55,7

7,3

0,9

56,0 54,7

26,6 27,4

5,5

12,3

4,6 4,7

0

10

20

30

40

50

60

70

Pertuzumab + Trastuzumab + AI (n = 109)

Trastuzumab + AI (n = 106)

Pa

tie

nts

, %

Δ ORR = 7.6% (95% CI –6.0, 21.3)

Chi-squared p = 0.2537

ORR CR PR SD PD NE ORR CR PR SD PD NE



Most Common Adverse Events (Incidence ≥20%; Safety Population)


(n = 127)

Trastuzumab + AI

(n = 124)

Diarrhea 70 (55.1) 45 (36.3)

Alopecia 36 (28.3) 40 (32.3)

Nausea 41 (32.3) 32 (25.8)

Asthenia 39 (30.7) 31 (25.0)

Arthralgia 37 (29.1) 29 (23.4)

Edema peripheral 31 (24.4) 22 (17.7)

Vomiting 29 (22.8) 22 (17.7)

Anemia 26 (20.5) 18 (14.5)

Data are number of patients, n (%).



Worst LVEF While on Treatment (Safety Population)

Data are number of patients, n (%).

Local assessment by ECHO or MUGA; change from baseline was only calculated where the type of scan was the same as at baseline.

* Seven patients had an LVEF of exactly 45%.

† Eight patients discontinued before post-baseline LVEF assessment was due, two patients discontinued and left the study before LVEF was completed,

one patient discontinued and a post-baseline assessment was not done (site error).

LVEF Pertuzumab + Trastuzumab + AI

(n = 127)

Trastuzumab + AI

(n = 124)

>45% 110 (86.6) 112 (90.3)

40–45% and ≥10% fall

from baseline* 6 (4.7) 4 (3.2)

<40% 5 (3.9) 3 (2.4)

No LVEF measurement

on treatment† 6 (4.7) 5 (4.0)



Conclusions

• PERTAIN met its primary PFS objective:

Pertuzumab + Trastuzumab + AI was superior to Trastuzumab +

AI in postmenopausal women with HER2-positive/hormone

receptor-positive LA/MBC

• Secondary efficacy endpoints (ORR and DoR) supported the primary

PFS analysis

• Subgroup analyses were generally consistent with the primary analysis

• Pertuzumab + Trastuzumab + AI was well tolerated and no new safety signals

were identified

Conclusions

HER2+ MBC: Still an unmet need...

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NOVEDADES EN LA TERAPIA HER2 · 2017-01-20 · NOVEDADES EN LA TERAPIA HER2 Javier Cortes, Ramon y...

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