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Adyuvancia en cáncer de mama HER2+

Dr E.M. Ciruelos

Servicio Oncología Médica, Unidad Cáncer de mama

Hospital Universitario 12 de Octubre, Madrid

HM CIOCC, Madrid

Overview of eBC outcomes

according to risk

Cortazar, P. Presented at FDA Public Workshop, Innovations in Breast Cancer Drug Development – Neoadjuvant Breast Cancer Workshop, March 22, 2013

EFS, event-free survival.

5-year EFS (%)

Stage II Stage III

Grade II Grade III Grade II Grade III

HR-positive

HER2-negative83 71 63 51

HR-positive

HER2-positive81 69 50 48

HR-negative

HER2-positive61 66 58 46

Triple-negative 66 72 38 37

Four pivotal trials (>12,000 patients) established 18

cycles (1 year) of adjuvant trastuzumab as the SoC for

HER2-positive eBC

1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672; 2. Gianni L, et al. Lancet Oncol 2011; 12:236-244;

3. Slamon D, et al. N Engl J Med 2011; 365:1273−1283; 4. Perez EA, et al. J Clin Oncol 2011; 29:3366−3373.

IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation;SoC, standard of care.

DocetaxelDocetaxel +

carboplatin

Doxorubicin +

cyclophosphamideTrastuzumab Paclitaxel

Chemotherapy

+/- radiotherapy

HERA (ex-USA)1,2

IHC/FISH

N = 5102

Observation

1 year

2 years

NCCTG N9831 (USA)4

IHC/FISH

N = 1944 1 year

1 year

BCIRG 006 (global)3

FISH

N = 32221 year

1 year

NSABP B-31 (USA)4

IHC/FISH

N = 2101

1 year

Favours chemo alone0

These adjuvant trials demonstrated

consistent DFS and OS benefit with 1 year

of trastuzumab vs. observation

1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672; 2. Smith I, et al. Lancet 2007; 369:29–36; 3. Gianni L, et al. Lancet Oncol 2011; 12:236–244; 4.

Goldhirsch A, et al. Lancet 2013; 382:1021–1028; 5. Cameron D, et al. Lancet 2017; 389:1195–1205; 6. Slamon D, et al. SABCS 2015 (Abstract S5-04); 7. Perez EA, et al. J

Clin Oncol 2011; 29:3366–3373;8. Perez EA, et al. J Clin Oncol 2014; 32:3744–3752; 9. Perez EA, et al. J Clin Oncol 2011;

29:4491–4497.

* Selected from a list of approved regimens consisting of ≥4 cycles.AC, doxorubicin plus cyclophosphamide; CT, chemotherapy;DFS, disease-free survival; FU, follow-up; H, trastuzumab; OS, overall survival;Pac, paclitaxel; RT, radiotherapy; T, docetaxel; TCH, docetaxel, carboplatin.

Study

FU

(yrs) N DFS HR

HERA1–5 1 3387 0.54

CT* ± RT→H

(1 year) vs.

CT* ± RT

2 3401 0.64

4 3401 0.76

8 3401 0.76

11 3399 0.76

BCIRG 0066

AC→TH vs.

AC→T

TCH vs. AC→T

10.3 3222

0.72

0.77

Joint analysis7,8

(NCCTG N9831/

NSABP B-31)

2 3351 0.48

4 4045 0.52

AC→PacH

vs. AC→Pac8.4 4046 0.60

NCCTG N98319

AC→Pac→H vs.

AC→Pac

6 2184 0.67

Favours trastuzumab

OS HR

0.66

0.85

0.76

0.74

0.63

0.76

0.61

0.63

0.88

Favours trastuzumabFavours chemo alone

SE

QU

EN

TIA

L

CH

EM

O→

H

CO

NC

OM

ITA

NT

CH

EM

O +

H

SE

QU

EN

TIA

L

CH

EM

O→

H

Long-term relapse rates indicate a need for further

improvements

Slamon D, et al. SABCS 2015 (Abstract S5-04).MFU, median follow-up

BCIRG 006: DFS final analysis (10.3 years’ mFU)

0,4

0,5

0,6

0,7

0,8

0,9

1

0 12 24 36 48 60 72 84 96 108 120 132

DFS

(%

)

Time (years)

100

90

80

70

60

50

40

AC-T AC-TH TCH

74.6%

73.0%

67.9%

0 1 2 3 4 5 6 7 8 9 10 11

NOAH: Trastuzumab increased both pCR and EFS, but

many patients still experience relapse

Gianni L, et al. Lancet 2010; 375:377–384; Gianni L, et al. Lancet Oncol 2014; 15:640–647.

Time (years)

42%

HR 0.64 (95% CI = 0.44–0.93); p = 0.016

Without HWith H

0 1 2 3 4 5

60

40

20

0

100

80

EF

S (

%)

0

20

40

With

H

Without

H

With

H

Without

H

pC

R (

%)

bpCR tpCR

43%

22%

38%

19%

p = 0.0007

p = 0.001

Increased pCR rates with trastuzumab added to chemotherapy resulted in improved EFS, but 42% of patients had relapsed at 5 years

HERA: Longer duration of trastuzumab did

not improve outcomes

Goldhirsch A, et al. Lancet 2013; 382:1021–1028.CI, confidence interval; obs, observation.

62.5%

68.5%

69.3%

64.7%

70.7%

71.2%

70.0%

75.9%

76.4%

1 2 3 4 5 6 7 8 9 100

100

90

80

70

60

0

10

20

30

40

50

Years from randomisation

Dis

ea

se-f

ree

su

rviv

al

(%)

N EventsHR

(vs obs.)95% CI p value

Observatio

n1697 608

1 year 1702 505 0.76 (0.68–0.86) <0.0001

83.4%

81.3%

75.2%

Trastuzumab 1 year Trastuzumab 2 yearsObservation only

No. at risk

Observation only 1697 1201 1095 946 831

Trastuzumab 1

year1702 1319 1213 1099 996

2 years 1700 518 0.77 (0.69–0.87) <0.0001

Trastuzumab 2

years1700 1361 1222 1087 965

ALTTO study: Adjuvant lapatinib and trastuzumab

Piccart-Gebhart M, et al. Adjuvant Lapatinib and Trastuzumab for Early HumanEpidermal Growth Factor Receptor 2–Positive Breast Cancer: Results From the Randomized Phase III

Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol 2016; 34:1034–1042.p ≤ 0.025 required for statistical significance.

ExteNET: Neratinib in the extended ‘post-adjuvant’ setting

DCIS, ductal carcinoma in situ.

• Primary endpoint: IDFS at 2 years

• Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS metastases, overall survival, safety

• Other analyses: Biomarkers, health outcome assessment (FACT-B, EQ-5D)

• Stratified by: Nodes 0, 1–3 vs. 4+, ER/PR status, concurrent vs. sequential trastuzumab

Surgery

Standard adjuvant

therapyR IDFS

Surgery

RStudy adjuvant

therapyDFS/IDFS

Study post-

adjuvant therapy

ExteNET1 1

Adjuvant

studies2,3

Neratinib x 1 year

240 mg/day

Adjuvant trastuzumab

+ chemotherapy

1. Chan A, et al. Lancet Oncol 2016; 17:367–377;2. Goldhirsch A, et al. Lancet 2013; 382:1021–1028;

3. von Minckwitz G, et al. SABCS 2011 (Abstract OT1-02-04).

ExteNET: 2-year IDFS (ITT population) with extended

‘post-adjuvant’ neratinib

Chan A, et al. Neratinib after trastuzumab-based adjuvant therapy in patients withHER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled,

phase 3 trial. Lancet Oncol 2016; 17:367–377.ITT, intention-to-treat.

APHINITY is a Phase III adjuvant study investigating

PERJETA–Herceptin + chemotherapy

DFS, disease-free survival; DRFI, distant relapse-free interval; HR, hormone receptor;

HRQoL, health-related quality of life; IDFS, invasive disease-free survival; OS, overall survival;

RFI, relapse-free interval. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131;

www.clinicaltrials.gov/ct2/show/NCT01358877.

• Primary endpoint: IDFS

• Secondary endpoints: IDFS with second non-breast primary cancers included, DFS, OS, RFI, DRFI, safety and

HRQoL

• Stratification factors: Chemotherapy regimen, HR status, nodal status, geographic region, Protocol version (A

vs. B)

Chemotherapy* + Herceptin

+ Placebo

Chemotherapy* + Herceptin

+ PERJETA

Randomisation and treatmentwithin 8 weeks

of surgery

Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)

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

Central

confirmation

of HER2 status

(N = 4805)

F

O

L

L

O

W

-

U

P

10

Y

E

A

R

S

R

S

U

R

G

E

R

Y

* Standard anthracycline or non-anthracycline (TCH) regimens were allowed: 3–4 x FEC (or FAC) → 3–4 x TH

4 x AC (or EC) → 4 x TH

6 x TCH

Primary endpoint of APHINITY, IDFS, was event-driven and

measured from the IDFS HR and p-value at the time of the

analysis1

Assumptions about the primary endpoint were based on the following:

• Placebo arm IDFS rate was based on BCIRG 006 data2

• 379 events and 4800 patients required for 80% power and alpha of 5%

HR, hazard ratio; IDFS, invasive disease-free survival.

1. von Minckwitz G, et al. N Engl J Med 2017;

377:122–131;

2. Slamon D, et al. N Engl J Med 2011;

365:1273−1283.

Expected 3-year IDFS rate

PERJETA–Herceptin vs. placebo–Herceptin

HR = 0.7589.2% vs. 91.8%

(∆ = 2.6%)

APHINITY: Primary endpoint (IDFS)

von Minckwitz G, et al. Adjuvant Pertuzumab and Trastuzumabin Early HER2-Positive Breast Cancer. N Engl J Med 2017; 377:122–131.

APHINITY: Safety

von Minckwitz G, et al. Adjuvant Pertuzumab and Trastuzumabin Early HER2-Positive Breast Cancer. N Engl J Med 2017; 377:122–131.NYHA, New York Heart Association; LVEF, left ventricular ejection fraction.

How does APHINITY control arm compare with other

trials?

Proportion of trial

populationHERA1,2

(N = 3387)

BCIRG 0063

(N = 3222)

Joint

analysis4,5

(N = 4046)

BETH6

(N = 3509)

ALTTO7

(N = 8381)

APHINITY8

(N = 4804)

Node-positive 57% 71% 93% 52% 52% 63%

HR-negative 48% 46% 45% 41% 43% 36%

Tumour size

>2 cm48% 59% 59% 53% 50% 61%

3-year DFS/IDFS

(H + chemo)81.3%

87%

88%88% 92% 91%* 93.2%

* ALTTO reported 4-yr DFS result of 86%;3-yr data are estimated from survival curve.

1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672; 2. Jackisch C, et al. SABCS 2015 (Abstract PD5-01);

3. Slamon D, et al. N Engl J Med 2011; 365:1273–1283; 4. Perez EA, et al. J Clin Oncol 2014; 32:3744–3752;

5. Perez EA, et al. J Clin Oncol 2011; 29:3366−3373; 6. Slamon D, et al. SABCS 2013 (Abstract S1-03);

7. Piccart-Gebhart M, et al. J Clin Oncol 2016; 34:1034–1042; 8. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.

Baseline physical function scores were maintained throughout

treatment, except for a decline at the end of taxane treatment

* Indicates time points where there was a clinically meaningful change in absolute score.

1. Baselga J, et al. ASCO 2018 (Abstract 521);

2. Aaronson NK, et al. J Natl Cancer Inst 1993; 85:365–376.

Mean EORTC QLQ-C30 physical functioning by treatment regimen, ITT population1

Physical function scale of the

EORTC QLQ-C301,2 (5 items)

Do you have any trouble doing strenuous activities like

carrying a heavy shopping bag or suitcase?

Do you have any

trouble taking

a long walk?

Do you have

any trouble

taking a short

walk outside

of the house?

Do you need to stay in

bed or a chair during

the day?

Do you need help

with eating,

dressing,

washing or using

the toilet? Visit

Ab

solu

te s

core

Baseline End of

taxane

Week 25 End of

treatment

FU

Month 18

FU

Month 24

FU

Month 36

100

80

60

40

20

0

Treatment

PERJETA + Herceptin + chemo

Placebo + Herceptin + chemo

**

Biological factors

Tumour biology and prognosis in trastuzumab-treated

HER2-positive eBC patients is determined by a number of

different risk factors

1. Martei YM & Matro JM. Breast Cancer (Dove Med Press) 2015; 7:337–343; 2. Sparano JA, et al. N Engl J Med 2015; 373:2005–2014; 3. Drukker CA, et al. Int J Cancer 2013; 133:929–936;

4. Zhang S, et al. BMC Cancer 2017; 17:335; 5. Inwald EC, et al. Breast Cancer Res Treat 2013; 139:539–552.

Risk assessmentRisk assessment

Tumour size1–3 Lymph node

involvement1–3

Lymph node

involvement1–3

Tumour grade1–3Tumour grade1–3

HR status1–3HR status1–3

HER2 status1,2HER2 status1,2

Ki67 status5Ki67 status5 Tumour genomics1–3Tumour genomics1–3

Patient age1,3Patient age1,3

Clinical presentation

Lymphovascular

invasion4

Lymphovascular

invasion4

HOW IMPORTANT IS NODAL STATUS AS A RISK FACTOR

WHEN DECIDING ON TREATMENT FOR A PATIENT WITH

HER2-POSITIVE EBC?

TCH vs. AC-T

BCIRG 006: 5-year DFS and OS according to

nodal status

Slamon D, et al. N Engl J Med 2011; 365:1273–1283.

TCH vs. AC-TSubgroup

Node–

Node+

HR–

HR+

Size <2 cm

Size >2 cm

10 2

AC-TH

HR

AC-THbetter

AC-Tbetter

10 2

HR

TCHbetter

AC-Tbetter

DFS

TCHbetter

AC-Tbetter

AC-THbetter

AC-Tbetter

Subgroup

10 2 10 2

HR HR

Node–

Node+

HR–

HR+

Size <2 cm

Size >2 cm

OS

AC-THTCH TCH

HERA: DFS according to nodal status

Untch M, et al. Ann Oncol 2008; 19:1090–1096.

Population/treatment N DFS events, n

(%)

3-year DFS, % (95% CI) Δ in 3-year DFS, %

(95% CI)

HR

(95% CI)

Overall population

1-year trastuzumab

Observation

170

3

169

8

218 (12.8)

321 (18.9)

80.6 (77.7, 83.4)

74.3 (72.0, 80.8)

6.3

(2.2, 10.4)

0.64

(0.54, 0.76)

Nodal status

Node negative

1-year trastuzumab

Observation

544

555

34 (6.3)

58 (10.5)

90.8 (87.1, 94.4)

84.9 (80.4, 89.5)5.8

(0.0, 11.7)

0.59

(0.39, 0.91)

Node negative (1.1–

2.0 cm)

1-year trastuzumab

Observation

252

258

12 (4.8)

23 (8.9)

91.3 (85.3, 97.2)

86.7 (80.5, 92.9)

4.6

(–4.0, 13.2)

0.53

(0.26, 1.07)

1-3 positive nodes

1-year trastuzumab

Observation

486

490

50 (10.3)

80 (16.3)

84.7 (80.4, 88.9)

75.9 (70.6, 81.1)

8.8

(2.0, 15.6)

0.61

(0.43, 0.87)

≥4 positive nodes

1-year trastuzumab

Observation

479

474

95 (19.8)

132 (27.8)

67.8 (60.6, 75.0)

62.2 (55.9, 68.6)

5.6

(–0.4, 15.1)

0.64

(0.49. 0.83)


APHINITY: IDFS forest plot by subgroups

APHINITY: Treatment effect in subgroup with

node-positive disease


HOW IMPORTANT IS TUMOUR SIZE AS A RISK FACTOR

WHEN DECIDING ON TREATMENT FOR A PATIENT WITH

HER2-POSITIVE EBC?

HERA: Trastuzumab treatment of patients with tumours

≤2 cm*

Smith I, et al. Lancet 2007; 369:29–36.

*Eligibility criteria included node-positive disease, or node-negative disease if the pathological tumour size was >1 cm

Subgroup (number of

patients)

Pathological tumour size

Number of events

trastuzumab vs.

observationHR (95% CI)

Any (neoadjuvant chemo) (372) 39 vs. 50 0.66 (0.43, 1.00)

0‒2 cm* (1351) 61 vs. 95 0.65 (0.47, 0.90)

>2‒5 cm (1482) 97 vs. 150 0.55 (0.43, 0.71)

>5 cm (171) 20 vs. 25 1.14 (0.63, 2.06)

All patients (3401)218 vs.

321

0.64 (0.54,

0.76)

0.0 0.5 1.0 1.5

HR for DFS1 yr trastuzumab vs. observation

Patients with small tumours derive similar benefit

from

1 year of trastuzumab treatment to that of the

overall population

Patients with small tumours derive similar benefit

from

1 year of trastuzumab treatment to that of the

overall population

NCCTG N9831/NSABP B-31: Trastuzumab increases OS and DFS

regardless of tumour size

Perez EA, et al. J Clin Oncol 2014; 32:3744–3752.

OS

Factor N HR 95% CI

0.1–2.0 1598 0.51 0.38, 0.69

2.1–5.0 2096 0.68 0.56, 0.82

>5.0 345 0.58 0.39, 0.88

DFS

Factor N HR 95% CI

0.1–2.0 1598 0.55 0.44, 0.68

2.1–5.0 2096 0.65 0.56, 0.76

>5.0 345 0.47 0.33, 0.67

HR with 95% CI

0.5 1 1.5 20.0

Favours AC→PacHFavours AC→Pac

Tumour size

(cm)

Tumour size

(cm)

APT (Tolaney) trial: Adjuvant paclitaxel and trastuzumab for

low-risk HER2-positive breast cancer

Tolaney SM, et al. N Engl J Med 2015; 372:134-141.

* Loading dose of 4 mg/kg IV trastuzumab on Day 1;† Radiation and hormonal therapy was initiated after completion of paclitaxel;‡ Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks; qxw, every x weeks.ER, oestrogen receptor

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

H

Pac

Paclitaxel (80 mg/m2) + trastuzumab

(2 mg/kg) x 12 weeks (q1w)*†

N = 406

• HER2-positive

• ER+ or ER–

• Node-negative

tumour ≤3 cm

Primary

endpoint:

Invasive DFS

HH H H H H H H H H H H H

Q3w doses of trastuzumab (6 mg/kg) x 13‡

Total 18 cycles of trastuzumab

NOTE: This is a single-arm, single-centre study, so is unable to provide definitive data on treatment benefit

APT (Tolaney) trial: 7-year follow-up

Tolaney SM, et al. ASCO 2017 (Abstract 511).

von Minckwitz G, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med 2017; 377:122–131.

APHINITY: IDFS forest plot by subgroups

HOW IMPORTANT IS HORMONE RECEPTOR STATUS

AS A RISK FACTOR WHEN DECIDING ON TREATMENT

FOR A PATIENT WITH HER2-POSITIVE EBC?

HERA: Benefit of trastuzumab related to HR status and

rates of DFS events between the two cohorts

Jackisch C, et al. SABCS 2015 (Poster PD5-01).BC, breast cancer.

HR-positive HR-negative

Number at risk

Observation 855 648 598 513 443

Trastuzumab 1

year859 691 634 570 524

Pro

ba

bil

ity

Time from randomisation (years)

0 1 2 3 4 5 6 7 8 9 10

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.45

0.40

Pro

ba

bil

ity

Time from randomisation (years)

0 1 2 3 4 5 6 7 8 9 10

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.45

0.40

Number at risk

Observation 842 553 497 433 388

Trastuzumab 1

year843 628 579 529 472

Trastuzumab 1 year: BC events

HERA results are aligned with joint analysis of NCCTG

N9831 and NSABP B-31

Romond EH, et al. SABCS 2012 (Abstract S5-5).

B-31/N9831: Cumulative incidence of distant recurrence (metastasis) as a first event

HR-positive HR-negative

Cu

mu

lati

ve

in

cid

en

ce (

%)

Time (years)

0

5

10

15

20

25

0 1 2 3 4 5 6 7 8 9 10

Cu

mu

lati

ve

In

cid

en

ce (

%)

Time (years)

0 1 2 3 4 5 6 7 8 9 10

AC→P

AC→P+H

22.3%

12.7%

∆= 9.6%

AC→P

AC→P+H

21.5%

11.9%

∆= 9.6%

N Events

AC→P 1105 216

AC→P+

H

1110 124

N Events

AC→P 911 175

AC→P+

H

917 1030

5

10

15

20

25

ExteNET: Treatment effect in ITT according to hormone

receptor status

Hormone receptor-positive Hormone receptor-negative

Chan A, et al. Neratinib after trastuzumab-based adjuvant therapy in patients withHER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled,

phase 3 trial. Lancet Oncol 2016; 17:367–377 (supplementary information).

APHINITY: IDFS in subgroup with HR-

negative disease

von Minckwitz G, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-PositiveBreast Cancer. N Engl J Med 2017; 377:122–131 (supplementary information).

APT: Small node-negative, HER2-positive tumours treated with

1 year of adjuvant trastuzumab are more likely to recur if HR-

negative

Tolaney SM, et al. ASCO 2017 (Abstract 511; poster presentation).

HR-positive

HR-negative

HOW IMPORTANT IS THE OUTCOME OF NEOADJUVANT

TREATMENT WHEN DECIDING ON ADJUVANT TREATMENT

FOR A PATIENT WITH HER2-POSITIVE EBC?

NeoALTTO: Achieving a pCR with dual blockade of

trastuzumab and lapatinib did not translate into

improvement in long-term outcomes

1. Baselga J, et al. Lancet 2012; 379:633–640;2. de Azambuja E, et al. Lancet Oncol 2014; 15:1137–1146.

pCR was significantly higher in the

trastuzumab, lapatinib + chemotherapy arm1

But, no significant differences in EFS were

seen between arms in follow-up analysis2

NeoSphere: All patients are at risk of disease

recurrence, whether or not they achieve a pCR

Gianni L, et al. Lancet Oncol 2016; 6:791–800 (supplementary information).

PFS, progression-free survival; tpCR, total pathological complete response (in breast and axillary nodes).

Subgroup

PHT

better

HT

better

Events

n (%) HR (95% CI)

5-year PFS rate,

%

PHT HT

OVERALL (n=214) 36 (17)0.69 (0.34–

1.40)86 81

tpCR (n=65) 10 (15) 0.63 (0.17-2.38) 88 81

No tpCR (n=149) 26 (17) 0.74 (0.32-1.70) 84 81

HR-positive (n=100) 14 (14) 0.86 (0.27-2.75) 86 87

HR-negative (n=114) 22 (19) 0.60 (0.24-1.48) 85 75

tpCR/HR-positive (n=17) 2 (12) - (-) 91 80

tpCR/HR-negative (n=48) 8 (17) 0.78 (0.17-3.47) 87 81

No tpCR/HR-positive

(n=83)12 (14) 0.93 (0.26-3.34) 85 88

No tpCR/HR-negative

(n=66)14 (21) 0.51 (0.13-1.97) 83 73

0

.

1

1 1

0

Both tpCR and non-

tpCR patients are at

risk of relapse

• In patients with no tpCR

following PHT, 16% had

relapsed after 5 years vs.

12% of those who did

achieve tpCR

Both tpCR and non-

tpCR patients are at

risk of relapse

• In patients with no tpCR

following PHT, 16% had

relapsed after 5 years vs.

12% of those who did

achieve tpCR

Continuation of trastuzumab in non-pCR patients

Gonzalez-Angulo AM, et al. Br J Cancer 2015; 112:630–635.

In a retrospective analysis,

patients with HER2-positive eBC

who did not achieve a pCR with

neoadjuvant trastuzumab-based

therapy appeared to

benefit from adjuvant

trastuzumab (N = 589)

In a retrospective analysis,

patients with HER2-positive eBC

who did not achieve a pCR with

neoadjuvant trastuzumab-based

therapy appeared to

benefit from adjuvant

trastuzumab (N = 589)

No trastuzumab, no pCR

Yes trastuzumab, no pCRP

rob

ab

ilit

y o

fo

ve

rall

su

rviv

al

Time since diagnosis (years)

0 1 2 3 4 5 6 7 8

0.5

0.6

0.7

0.8

0.9

1

The outcome of neoadjuvant therapy may still influence

subsequent treatment decisions

1. FDA Guidance for Industry. https://www.fda.gov/downloads/drugs/guidances/ucm305501.pdf.

Potential outcomes

following neoadjuvant (TP)

therapy

Potential outcomes

following neoadjuvant (TP)

therapy

pCR: No malignant cells

found on pathological

examination in breast

and axilla1

An alternative treatment might improve

the chances of achieving a positive

long-term outcome?

(to be addressed by ongoing

clinical trials!)

No pCR: Residual

macroscopic or

microscopic disease

present in breast and

axilla1

Need to maintain the same treatment?

Take advantage of tumours sensitive to

neoadjuvant treatment?

(to be addressed by ongoing

clinical trials!)

Indicated for use in combination with trastuzumab and chemotherapy as neoadjuvant treatment of patients with HER2-

positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node-positive) as

part of a complete treatment regimen for early breast cancer and the adjuvant treatment of patients with HER2-positive early

breast cancer at high risk of recurrence. Following surgery, patients should continue to receive PERJETA and trastuzumab to

complete 1 year of treatment (up to 18 cycles)

PERJETA Prescribing Information1

Based on APHINITY, the FDA and CHMP support the use of

adjuvant PERJETA–Herceptin for 18 cycles in high-risk HER2-

positive eBC

1. PERJETA (pertuzumab) Prescribing Information, 2017. Available at:

https://www.gene.com/download/pdf/perjeta_prescribing.pdf (Accessed May 2018);

2. CHMP Meeting Minutes from 23–26 April 2018. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Agenda/2018/04/WC500247822.pdf;

3. PROPOSED PERJETA SmPC 2018.

PERJETA is indicated for use in combination with trastuzumab and chemotherapy in the adjuvant treatment of adult patients

with HER2-positive early breast cancer at high risk of recurrence.

PERJETA should be administered in combination with trastuzumab for a total of 1 year (up to 18 cycles or until disease

recurrence, or unmanageable toxicity, whichever occurs first) as part of a complete regimen for early breast cancer and

regardless of the timing of surgery

CHMP opinion: PERJETA label extension2,3

Treatment improvement by adding Pertuzumab to

Trastuzumab was classified as Grade B on the ESMO-MCBS

CI, confidence interval;

ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale;

HR, hazard ratio.

1. Cherny NI, et al. Ann Oncol 2015; 26:1547–1573;

2. http://www.esmo.org/content/download/117385/2059134/file/ESMO-MCBS-Version-1-1-

Evaluation-Form-1.pdf (Accessed May 2018);

3. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.

ESMO-MCBS guidelines categorised the APHINITY data

(HR 0.81; 95% CI = 0.66, 1.00)3 as a ‘Group B

intervention’ in the curative setting, which means they

correspond to a substantial improvement

A

B

C

Adjuvant treatment

with curative intent

Grades with

substantial

improvement

Magnitude of Clinical

Benefit Scale guidelines1,2

Introduction of new treatment modalities over

time has improved recurrence outcomes in the

ADJUVANT setting

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet 2012; 379:432–444;2. EBCTCG. Lancet 2015; 386:1341–1352; 3. EBCTCG. Lancet 2005; 365:1687–1717;

4. Jackisch C, et al. SABCS 2015 (Abstract PD5-01); 5. Slamon D, et al. SABCS 2015 (Abstract S5-04);6. Slamon D, et al. N Engl J Med 2011; 365:1273−1283.

AI, aromatase inhibitor; CMF, cyclophosphamide, methotrexate and fluorouracil;HR, hazard ratio; RR, risk ratio.

TamoxifenAromatase

inhibitors

Anti-HER2

therapy4

Trastuzumab vs.

observation

DFS benefit

after

5 years+5.9–9.0%

After 10/11

years

(HR = 0.72–

0.77)

Trastuzumab +

chemo

Anthracycline

+ taxane

combination

Anthracycline

+ taxane

combination

CMFCMF

AnthracyclinesAnthracyclines

Chemotherapy1 CMF vs.

no chemo

Anthracycline

vs. CMF

Taxane +

anthracycline

vs. anthracycline

Improvement in

recurrence rate

after 5 years+9.9% +3.2% +3.6%

After 10 years RR = 0.70 RR = 0.89 RR = 0.84

Endocrine

therapy2,3

Tam 5 years vs. no

tam

AI 5 years

vs. tam 5 years

Improvement in

recurrence rate

after 5 years+11.4% +1.1–3.1%

After 5 years RR = 0.50RR = 0.80–

0.90

Anti-HER2

therapy4

Trastu+Pertu vs.

Trastu

DFS benefit

after

4 years+1.7%

(HR = 0.81)

International guidelines

AGO, Arbeitsgemeinschaft Gynäkologische Onkologie E.V.;

ASCO, American Society of Clinical Oncology;

HR, hormone receptor; NCCN, National Comprehensive Cancer Network.

1. Curigliano G, et al. Ann Oncol 2017; 28:1700–1712;

2. NCCN Breast Cancer Guidelines. Version 4, 2017 – February 7, 2018;

3. Denduluri N, et al. J Clin Oncol 2018; doi: 10.1200/JCO.2018.78.8604 (ePub ahead of print);

4. https://www.ago-online.de/en/guidelines-mamma/march-2018 (Accessed May 2018).

St. Gallen Expert Consensus1

High risk due to lymph node

involvement or HR-negativity

Recommendations in the adjuvant setting:

Dual blockade with PERJETA–Herceptin for HER2-positive patients at

high risk of relapse

ASCO Guidelines3

High-risk, such as

node-positive disease

NCCN Breast Cancer Guidelines2

If node-positive (HR-positive and

HR-negative disease)

AGO Guidelines4

Node-positive or HR-negative disease

• The introductions of trastuzumab and pertuzumab have each substantially

improved outcomes for patients with HER2-positive eBC1–7

Summary

1. Cameron D, et al. Lancet 2017; 389:1195–1205; 2. Slamon D, et al. N Engl J Med 2011; 365:1273−1283;3. Perez EA, et al. J Clin Oncol 2011; 29:3366−3373; 4. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131;

5. Gianni L, et al. Lancet 2010; 375:377–384; 6. Gianni L, et al. Lancet Oncol 2014; 15:640–647; 7. Gianni L, et al. Lancet Oncol 2012; 13:25–32; 8. Schneeweiss A, et al. Ann Oncol 2013; 24:2278–2284;

9. Goldhirsch A, et al. Lancet 2013; 382:1021–1028; 10. Slamon D, et al. SABCS 2015 (Abstract S5-04)11. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.



• The current standard of care regimens in HER2-positive eBC are:

– Neoadjuvant setting: trastuzumab and pertuzumab plus

chemotherapy7,8

– Adjuvant setting: trastuzumab plus chemotherapy9 x 1 year

* Consider < 1 year duration if cardiac risk

Summary






• The current standard of care regimens in HER2-positive eBC are:

– Neoadjuvant setting: trastuzumab and pertuzumab plus

chemotherapy7,8

– Adjuvant setting: trastuzumab plus chemotherapy9 x 1 year

* Consider < 1 year duration if cardiac risk

• There remains a need to do more for patients with HER2-positive eBC,

particularly for those with higher-risk disease10

– In the adjuvant setting, the APHINITY trial was positive, showing better

outcomes in patients with higher-risk disease11

– Neratinib is an option as late adjuvant treatment for HER2+ ER+ (high

risk) in whom pertuzumab has not been used (?)

Summary




• Risk factors are important in both predicting the prognosis of patients and

in making treatment decisions1

– For lower-risk patients, e.g. those with node-negative small tumours

(<2 cm), treatment with a de-escalated APT regimen may be sufficient2

– Patients indicated for neoadjuvant treatment (pertuzumab +

trastuzumab + Chemo) are higher-risk in clinical practice (usually

tumours >2 cm and/or node-positive disease)3

– Higher-risk patients, such as those with node-positive or hormone

receptor-negative disease, appear to gain the most benefit from dual

HER2 blockade (pertuzumab + trastuzumab) in eBC4 (neo- and adjuvant)

1. Cortazar P, et al. Lancet 2014; 384:164–172; 2. Tolaney SM, et al. ASCO 2017 (Abstract 511);3. Smith I, et al. Lancet 2007; 369:29–36; 4. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.

Summary (II)

• Risk factors are important in both predicting the prognosis of patients and

in making treatment decisions1

– For lower-risk patients, e.g. those with node-negative small tumours

(<2 cm), treatment with a de-escalated APT regimen may be sufficient2

– Patients indicated for neoadjuvant treatment (pertuzumab +

trastuzumab + Chemo) are higher-risk in clinical practice (usually

tumours >2 cm and/or node-positive disease)3

– Higher-risk patients, such as those with node-positive or hormone

receptor-negative disease, appear to gain the most benefit from dual

HER2 blockade (pertuzumab + trastuzumab) in eBC4 (neo- and adjuvant)

• Knowledge from the neoadjuvant setting should enable us to design new

adjuvant trials that will help in personalising treatment regimens according

to risk stratification

1. Cortazar P, et al. Lancet 2014; 384:164–172; 2. Tolaney SM, et al. ASCO 2017 (Abstract 511);3. Smith I, et al. Lancet 2007; 369:29–36; 4. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.

Summary (II)

KATHERINE (BO27938) Non-pCR study of T-DM1 vs. trastuzumab in adjuvant HER2-positive

eBC

Geyer CE, et al. SABCS 2013 (Abstract P3-04-02).T-DM1 is not approved for use in eBC in Europe.PROs, patient-reported outcomes.

Primary endpoint

• IDFS

Secondary endpoints

• IDFS (including second non-breast cancers), DFS, OS, DRFI, cardiac safety, safety, PROs

Key inclusion criteria

• Clinical stage T1–4/N0–3/M0 at presentation (patients with T1a/bN0 tumours will not be eligible)

• Completion of pre-operative systemic treatment (≥6 cycles of chemotherapy; total duration of ≥16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane-based therapy)

• No more than 12 weeks between the date of surgery and the date of randomisation

• LVEF ≥50% at screening and not decreasing by more than 15% from pre-chemotherapy LVEF

S

U

R

G

E

R

Y

Residual invasive tumour

(breast/node)

T-DM13.6 mg/kg IV q3w

Trastuzumab6 mg/kg IV q3wHER2-positive

eBC, pre-operative

chemotherapy + trastuzumab

(N = 1484) 14 cyclesR

1:1

https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590005.htm

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125409s113s118lbl.pdf

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