Evolution of HER2+ breast cancer

Prof. Dr. med. Sibylle Loibl

Chair of the German Breast Group

Centre for Haematology and Oncology, Bethanien, Frankfurt/Germany

Increase in pCR in HER2+

Long CHT + duale anti-

HER2 therapy

Long CHT +Trastuzumab similar to short CHT+duale anti-

HER2

Short CHT +Trastuzumab

CHT allone

20%

48%

74%

38%

15%

25%

45%

65%

Loibl S et al. Curr Opin Obstet Gynecol. 2015 ;27:85-91.

Cortazar P, et al.

Lancet 2014

Increase in pCR by trastuzumab correlates with better prognosis (NOAH – trial)

Gianni L, et al. NOAH study Lancet Oncol

2014 and Lancet 2010

HER2-positive (Techno – Phase II)

87%

Untch M et al., J Clin Oncol 2011

Figure 2

Source: The Lancet Oncology 2014; 15:640-647 (DOI:10.1016/S1470-2045(14)70080-4)

Terms and Conditions

Gianni L, et al. NOAH study Lancet Oncol

2014

10 year update NOAH study

Figure 3

Source: The Lancet Oncology 2014; 15:640-647 (DOI:10.1016/S1470-2045(14)70080-4)

Terms and Conditions

Gianni L, et al. NOAH study Lancet Oncol

2014

10 year update NOAH

NeoSphere: Study Design

S

U

R

G

E

R

Y

Study dosing: q3w x 4

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)

TH (n=107) Docetaxel (75100 mg/m2) Trastuzumab (86 mg/kg)

3xFEC +Trastuzumab for 1 year every 3 weeks

3xFEC +Trastuzumab for 1 year every 3 weeks

3xFEC +Trastuzumab for 1 year every 3 weeks

4xDoc - 3xFEC +Trastuzumab for 1 year every 3 wks

Primary Endpoint: pCR =ypT0/is

FDA-requested Endpoint: pCR =ypT0/is ypN0

Gianni L, et al. Lancet Oncol 2012

29.0

45.8

16.8 24.0 21.5

39.3

11.2 17.7

0

10

20

30

40

50

60

Arm AHT (n = 107)

Arm BPHT (n = 107)

Arm CPH (n = 107)

Arm DPT (n = 96)

NeoSphere: pCR Rates

p = 0.0141

p = 0.0198

p = 0.003

ypT0/is (primary endpoint)

ypT0/is ypN0

pC

R, %

Gianni L, et al. Lancet Oncol 2012

PFS by pCR

Gianni L, et al. Lancet Oncol 2016; 6:791–800.

PFS was substantially better in patients achieving a pCR

NeoSphere: At 5-year analysis, 14% of patients had relapsed or died

Overall population

No tpCR (n = 323)

tpCR (n = 94)

5-year PFS, % (95% CI) 76 (71–81) 85 (76–91)

Stratified HR = 0.54 (95% CI: 0.29, 1.00)

0

10

30

50

70

80

90

100

20

40

60

0 12 24 36 48 60 Time (months)

PFS

(%

)

D+T+P

D+T

T+P; D+P

NeoSphere: PFS

Gianni L et al. Lancet Oncol 2016; 17:791-800

OTHER STUDIES INVESTIGATING THE DUAL BLOCKADE WITH TRASTUZUMAB AND PERTUZUMAB

Neoadjuvant Therapy mit Trastuzumab and Pertuzumab in HER2+ primary b.c.

39.3

63.6

56

66.2

0

10

20

30

40

50

60

70

Neosphere DTP Tryphaena DcbTP Kristin DCbTP G7 P/nab-P TP-ECTP

ypT0/is ypN0

ypT0/is ypN0

0

20

40

60

80

TCH+P T-DM1+P

pC

R (

%)a

Difference: -11.3

95% CI: -20.5, -2.0

Stratified 2-sided P−value: 0.0155b

Kristin Study: pCR (ypT0/is, ypN0)

Presented by: Dr Sara Hurvitz

123/221 99/223

apCR rate and 95% CI are shown. Patients with missing or unevaluable pCR status were considered nonresponders: TCH+P, 7 (3.2%); T-DM1+P, 18 (8.1%). Treatment

discontinuation in the neoadjuvant phase for progressive disease: TCH+P, 0% of patients; T-DM1+P, 7% of patients. bCochran-Mantel-Haenszel Chi-square.

56% 44%

pCR Rates in subgroups of GeparSepto

Loibl S, et al. Annals Oncol 2016

HER2+ HER2-

APHINITY: Randomization Stratification Factors by Treatment

Pertuzumab

n=2400 Placebo n=2404*

Nodal status, n (%)

0 positive nodes and T ≤1 cm*

0 positive nodes and T >1 cm*

1–3 positive nodes

≥ 4 positive nodes

90 (3.8)

807 (33.6)

907 (37.8)

596 (24.8)

84 (3.5)

818 (34.0)

900 (37.4)

602 (25.0)

Adjuvant chemotherapy regimen (randomised), n (%)

Anthracycline-containing regimen

Non-anthracycline-containing regimen

1865 (77.7)

535 (22.3)

1877 (78.1)

527 (21.9)

Hormone receptor status (central), n (%)

Negative (ER- and PgR-negative)

Positive (ER- and/or PgR-positive)

864 (36.0)

1536 (64.0)

858 (35.7)

1546 (64.3)

Geographical region, n (%)

USA

Canada/Western Europe/Australia – New Zealand/South Africa

Eastern Europe

Asia Pacific

Latin America

296 (12.3)

1294 (53.9)

200 (8.3)

550 (22.9)

60 (2.5)

294 (12.2)

1289 (53.6)

200 (8.3)

557 (23.2)

64 (2.7)

Protocol Version, n (%)

Protocol A

Protocol Amendment B

1828 (76.2)

572 (23.8)

1827 (76.0)

577 (24.0)

* One patient was excluded from the ITT population due to her falsification of personal information

APHINITY:Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival

Number needed to treat: at 3 years 112 at 4 years 59

expected: 89.2%

APHINITY: Node-positive Subgroup

Number needed to treat: at 3 years 56 at 4 years 32

APHINITY: Hormone Receptor-negative Subgroup

Number needed to treat: at 3 years 63 at 4 years 44

* 1st interim analysis at 26% of the target events for the final overall survival analysis

3-year Pertuzumab

n=2400 Placebo n=2404 Hazard ratio (95% CI) p value

IDFS (primary endpoint), % 94.1 93.2 0.81 (0.66, 1.00) 0.045

Secondary efficacy endpoints, %

IDFS incl. second primary non-BC events (STEEP definition)

93.5 92.5 0.82 (0.68, 0.99) 0.043

Disease-free interval 93.4 92.3 0.81 (0.67, 0.98) 0.033

Recurrence-free interval 95.2 94.3 0.79 (0.63, 0.99) 0.043

Distant recurrence-free interval 95.7 95.1 0.82 (0.64, 1.04) 0.101

Overall survival (first interim analysis)*

97.7 97.7 0.89 (0.66, 1.21) 0.467

APHINITY: Secondary Efficacy Endpoints

APHINITY: Cardiac Endpoints

N (%) Pertuzumab n=2364

% Treatment difference (95% CI)

Placebo n=2405

Primary cardiac endpoint 17 (0.7) 0.4 (0.0, 0.8) 8 (0.3)

• Heart failure NYHA III/IV + LVEF drop* • Cardiac death**

15 (0.6) 2 (0.08)

6 (0.2) 2 (0.08)

• Recovered according to LVEF 7 4

Secondary cardiac endpoint Asymptomatic or mildly symptomatic LVEF drop*

64 (2.7) -0.1 (-1.0, 0.9) 67 (2.8)

*LVEF drop = ejection fraction drop ≥10% from baseline AND to below 50%; **Identified by the Cardiac Advisory Board for the trial according to a prospective definition

von Minckwitz G, et al. New Engl J Med 2017

Pertuzumab n=2364

Placebo n=2405

Neutropenia 385 (16.3%) 377 (15.7%)

Febrile Neutropenia 287 (12.1%) 266 (11.1%)

Anaemia 163 ( 6.9%) 113 ( 4.7%)

Diarrhoea 232 (9.8%) 90 ( 3.7%) - with chemotherapy and targeted therapy 232 ( 9.8%) 90 ( 3.7%)

- with targeted therapy (post-chemotherapy)

12 ( 0.5%) 4 ( 0.2%)

- with AC->T (N=1834; 1894) 137 ( 7.5%) 59 ( 3.1%)

- with TCH (N= 528; 510) 95 (18.0%) 31 ( 6.1%)

APHINITY: Common Grade ≥ 3 Adverse Events

von Minckwitz G, et al. New Engl J Med 2017

A. Schneeweiss et al. Ann Oncol 2013;24:2278-2284

TRYPHAENA - Mean change in LVEF from baseline during the treatment period

APHINITY: Health-related Quality of Life

Plot of Mean EORTC QLQ-C30 global health status by treatment regimen, ITT population

OTHER ADJUVANT STUDIES INVESTIGATING SINGLE OR DUAL HER2+ THERAPY IN BREAST CANCER

ALTTO update DFS

Moreno-Aspitia M et al. on behalf of the ALTTO investigators

HERA 11 Year Update

3 Types of patients:

1.Patients who needed more to be cured

2.Patients who had just enough

3.Patients who did not need trastuzumab to be cured

Cameron D, Lancet Oncol 2017

BCIRG 006: Node positive subgroup

1. Slamon D, et al. SABCS 2015 (Abstract S5-04; oral presentation); 2. Slamon D, et al. N Engl J Med 2011; 365:1273–1283.

0.4

0.5

0.6

0.7

0.8

0.9

1.0

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

Pro

po

rtio

n d

ise

ase

-fre

e

Time (months)

80%2

78%2

71%2

69.6%

68.4%

62.2% ACT

AC-HT

TCH

Relapse rate still 30% Within 10 years

Relapse rate 20% in 5 years

Tolaney et al, et al. New Engl J M 2015

HER2+

ER+ or ER-

Node Negative

< 3 cm

Enroll

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12

T T T T T T T T T T T T T

FOLLOWED BY 13 EVERY 3 WEEK DOSES

OF TRASTUZUMAB (6 mg/kg)*

N=406

*Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks ** Radiation and hormonal therapy was initiated after completion of paclitaxel

APT Trial Design

Patient Characteristics

N %

Age

<50

50-70

≥70

132

233

41

33

57

10

Size of Primary Tumor

T1a ≤0.5 cm

T1b >0.5-≤1.0

T1c >1.0-≤2.0

T2 >2.0-≤3.0

77

124

169

36

19

31

42

9

Histologic Grade

I Well differentiated

II Moderately differentiated

III Poorly differentiated

44

131

228

11

32

56

HR Status (ER and/or PR)

Positive

Negative

272

134

67

33

50% 91%

Tolaney et al, et al. New Engl J M 2015

Paclitaxel + Trastuzumab for small tumours

Tolaney S et al. New Engl J Med. 2015

3-year rate of 98.7% (95% confidence interval [CI], 97.6 to 99.8).

Invasive Disease-Free Survival

Tolaney et al, et al. New Engl J M 2015 and ASCO 2017

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

ExteNET: study design

Chan et al. Lancet Oncol 2016 Clinicaltrials.gov identifier: NCT00878709

• HER2+ breast cancer

– IHC 3+ or ISH amplified (locally determined)

– Prior adjuvant trastuzumab + chemotherapy

– Lymph node +/–, or residual invasive disease after neoadjuvant therapy

• Stratified by: nodal status, hormone receptor status, concurrent vs sequential trastuzumab

Ran

do

miz

atio

n (1

:1)

Neratinib x 1 year

240 mg/day

Placebo x 1 year

2-y

ear

fo

llow

-up

for

iDFS

5-y

ear

fo

llow

-up

for

iDFS

Ove

rall

surv

ival

Part A Part B Part C

N=2840

Primary endpoint: invasive disease-free survival (iDFS)

Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS recurrences, OS, safety

Other analyses: biomarkers, health outcome assessments (FACT-B, EQ-5D)

Endocrine adjuvant therapy given to patients with HR-positive tumors according to local practice

34

EXTENET 5-year analysis: iDFS

35

Neratinib

Placebo

50

60

70

Two-sided P = 0.008

HR (95% CI) = 0.73 (0.57–0.92)

80

90

0 6 12 18 24 30 36 42 48 54 60

No. at risk

Neratinib

Placebo

1420

1420

1316

1354

1272

1298

1225

1248

1106

1142

978

1029

965

1011

949

991

938

978

920

958

885

927

Months after randomization

Inva

sive

dis

ease

-fre

e s

urv

ival

(%

)

100

95.5%

∆ 2.4%

97.9%

91.7%

∆ 2.6%

94.3%

90.2%

∆ 2.0%

92.2%

89.1%

∆ 2.1%

91.2%

87.7%

∆ 2.5%

90.2%

0

Intention-to-treat population. Cut-off date: March 1, 2017

Treatment

EXTENET iDFS by hormone receptor status

36

Neratinib

Placebo

50

60

70

80

90

0 6 12 18 24 30 36 42 48 54 60

No. at risk

Neratinib

Placebo

816

815

757

779

731

750

705

719

642

647

571

581

565

567

558

556

554

551

544

542

523

525

Months after randomization

HR-positive subgroup In

vasi

ve d

isea

se-f

ree

su

rviv

al (

%)

100

96.1%

98.1%

91.7%

95.4%

89.8%

93.6%

88.5%

92.6%

86.8%

91.2%

0

50

60

70

Two-sided P = 0.762

HR (95% CI) = 0.95 (0.66–1.35)

80

90

0 6 12 18 24 30 36 42 48 54 60

No. at risk

Neratinib

Placebo

604

605

559

575

541

548

520

529

464

495

407

448

400

444

391

435

384

427

376

416

362

402

Months after randomization

HR-negative subgroup

100

94.7%

97.5%

91.8%

92.8%

90.4%

90.8%

89.3%

89.9%

88.8%

88.9%

0

Inva

sive

dis

ease

-fre

e s

urv

ival

(%

)

Neratinib

Placebo

Two-sided P = 0.002

HR (95% CI) = 0.60 (0.43–0.83)

Intention-to-treat population. Cut-off date: March 1, 2017

GUIDELINES

Recommendation of anti-HER2 therapy in high risk HER2+ breast cancer

1. Curigliano G, et al. Ann Oncol 2017; 28:1700–1712; 2. NCCN Breast Cancer Guidelines. Version 4, 2017 – February 7, 2018.

St. Gallen Expert Consensus1 NCCN Breast Cancer Guidelines2

Adjuvant systemic treatment recommendations:

Dual blockade with pertuzumab and trastuzumab improves outcome among patients who are at high risk of relapse due to lymph node involvement or hormone receptor negativity†

Adjuvant systemic treatment recommendations: If HER2-positive, node-positive, HR-positive or HR-negative receive adjuvant chemotherapy with trastuzumab ± pertuzumab (plus endocrine therapy if HR-positive)

© AGO e. V. in der DGGG e.V.

sowie

in der DKG e.V.

Guidelines Breast

Version 2018.1

www.ago-online.de

Subtype-specific Strategies for Systemic Treatment

AGO If chemotherapy is indicated due to tumor biology consider

systemic treatment before surgery (neoadjuvant) ++

HR+/HER2- and „low risk” Endocrine therapy without chemotherapy ++

HR+/HER2- and „high risk” Conventionally dosed AT-based chemotherapy ++ Dose dense chemotherapy ++ Followed by endocrine therapy ++

HER2+ Trastuzumab (plus Pertuzumab neoadjuvant at high risk) ++

Sequential A/T-based regimen with concurrent T + H ++ Anthracycline-free, platinum-containing regimen + Anthracycline-free, taxane-containing regimen +

Triple-negativ (TNBC) Conventionally dosed AT-based chemotherapy ++ Dose dense chemotherapy ++ Neoadjuvant platinum-containing chemotherapy +

© AGO e. V. in der DGGG e.V.

sowie

in der DKG e.V.

Guidelines Breast

Version 2018.1

www.ago-online.de

Adjuvant Treatment with Trastuzumab +/- Pertuzumab

Oxford LoE GR AGO

Trastuzumab 1a A ++ Trastuzumab + Pertuzumab

N+ and / or HR- 1b B + • N- and HR+ 1b B +/-

Trastuzumab in node-negative disease (if

chemotherapy is indicated) 10 mm 1a A ++ > 5–10 mm 2b B + ≤ 5 mm 2b B +/-

© AGO e. V. in der DGGG e.V.

sowie

in der DKG e.V.

Guidelines Breast

Version 2018.1

www.ago-online.de

Adjuvant Systemic Therapy after Neoadjuvant Systemic Therapy

Oxford LoE GR AGO

Endocrine treatment in endocrine responsive disease 1a A ++

Complete trastuzumab treatment for 1 year in HER2-positive disease

2b B ++

Complete pertuzumab treatment for 1 year in HER2-positive disease

1b B +/-

if N+ or HR- 2b B +

If insufficient response in case of non-pCR (invasive residual tumor in the breast and / or axillary nodes) after adequate NACT (antracyclines, taxanes, 18 weeks)

Capecitabine adjuvant in TNBC 2b B + Capecitabine adjuvant in HR+/Her-2- BC 2b B +/- Experimental therapies in controlled trials 5 D +

Options for HER2+ Primary Breast Cancer

12 -18 weeks Paclitaxel plus Trastuzumab -1 year of Trastuzumab

EC x4 q3/2w weeks - 12 weeks Paclitaxel plus Trastuzumab-1 year anti-HER2 therapy

18 weeks Paclitaxel plus Trastuzumab plus Pertuzumab – 1 year of Trastuzumab/Pertuzumab

EC x4 q3/2w weeks - 12 weeks Paclitaxel plus Trastuzumab/Pertuzumab -1 year anti-HER2 therapy

EC x4 q3/2w weeks - 12 weeks Paclitaxel plus Trastuzumab -1year Trastuzumab -1 year Neratinib

EC x4 q3/2w weeks - 12 weeks Paclitaxel plus Trastuzumab/Pertuzumab: no pCR – T-DM1

Standard for the majority

increasing risk

Proposed Treatment Algorithm

Low risk Intermdiate risk High risk Super high

Surgery PT or PTPer EC-PT-T EC-Taxane plus Trastuzumab+Pertuzumab

NACT none EC-Taxane plus Trastuzumab+Pertuzumab or EC-Taxane plus Trastuzumab

EC-Taxane plus Trastuzumab +Pertuzumab

EC-Taxane plus Trastuzumab+Pertuzumab

After surgery Trastuzumab for up to one year

Trastuzumab +Pertuzumab for up to one year

1. Trastuzumab +Pertuzumab for up to one year irrespective of pCR

2.Trastuzumab ± Pertuzumab for up to one year – Neratinib for another year for HR+ and no pCR?

Summary - HER2+ breast cancer

Early Breast Cancer All patients with HER2+ primary breast cancer recieve trastuzumab for 1 year – either adjuvant or part of the

neoadjuvant therapy

– Low risk: Paclitaxel plus Trastuzumab

– Intermediate risks: EC-Paclitaxel weekly plus Trastuzumab

– High risk tumours: EC-Paclitaxel plus Trastuzumab and Pertuzumab

The majority of women with high risk HER2+ breast cancer scheduled for neoadjuvant therapy recieve the dual blockade with pertuzumab in addition to EC-Paclitaxel for up to six cycles preoperatively

– Treatment effect could be maximised with pCR rate in HR- of >70%

Patients achieving a pCR have a significantly better outcome than pts without

– Non-pCR patients might need a better anti-HER2 treatment – KATHERINE trial

Higher pCR rate in:

– HR-pts

– PIK3CA wild-type

Greetings from Frankfurt