In the know: HER2+

Sara M. Tolaney, MD, MPH

Dana-Farber Cancer Institute

All Breast Cancers

Triple negative

15%

ER+ 65%-75%

HER2+ 15%-20%

2

Clinical Breast Cancer Subtypes

Milestones in HER2+ Breast Cancer

Trastuzumab for ABC

Trastuzumab for EBC

Lapatinib for ABC

Pertuzumab for ABC

T-DM1 for ABC

Pertuzumab for preop therapy

Pertuzumab for EBC

Neratinib for EBC

1998 2005 2007 2012 2013 2017

First-Generation Adjuvant Trastuzumab Trials

This presentation is the intellectual property of the author/presenter. Contact them at stolaney@partners.org for permission to reprint and/or distribute

What standard therapy?

• Both ACTH and TCH are effective, and TCH

should be considered in patients with risk

factors for cardiac toxicity

OBSERVATION n=1698

Women with locally determined HER2-positive invasive early breast cancer

Surgery + (neo)adjuvant CT ± RT

Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%

Randomization

1 year Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule

n=1703

2 years Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule

n=1701

After ASCO 2005, option of switch to Trastuzumab

HERA TRIAL DESIGN Accrual 2001 – 2005 (n=5102)

CT, chemotherapy; RT, radiotherapy

M Piccart SABCS 2012

Overa

ll S

urv

ival

(%)

Years from randomization No. at risk

Trastuzumab 2 years 1553 1553 1525 1485 1438 1382 1317 1193 708 208

Trastuzumab 1 year 1552 1552 1513 1461 1413 1364 1329 1218 732 225

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9

OS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MFU

97.4%

96.5% 91.4%

92.6% 86.4%

87.6%

Trastuzumab 1 year

Trastuzumab 2 years

Pts Events HR (2 vs 1) 95% CI p-value

2 years 1553 196 1.05 (0.86-1.28) 0.63

1 year 1552 186

Optimal Duration of Trastuzumab

PHARE Study Non-inferiority study; pre-specified HR 1.15

HR = 1.28 (p = 0.29) 2 yr DFS: Tras 12 mos = 93.8% Tras 6 mos = 91.1%

6 months inferior to 12 months of trastuzumab

n = 3,380

FINHER study Subset with HER2+ disease

HR = 0.42 (p = 0.01) 3 yr RFS: Tras 9 weeks = 89% No Tras = 78%

Benefit for only 9 weeks of trastuzumab

Persephone Study Design

Presented By Helena Earl at 2018 ASCO Annual Meeting

Disease-free survival

Presented By Helena Earl at 2018 ASCO Annual Meeting

Duration of anti-HER2 therapy?

• 12 months of trastuzumab remains the

standard, though consideration of

shorter duration in patients who

experience toxicity on therapy is

reasonable

Can we do better?

• Adding targeted agents

– Pertuzumab

– Neratinib

HER2 receptor

Trastuzumab

Pertuzumab

Dimerisation domain of HER2

• Inhibitor of HER dimerization: binds HER2 and prevents formation of homo- or heterodimers

• Suppresses activation of several intracellular signaling cascades driving cancer cell growth

Another “add on” strategy: pertuzumab?

NEOSPHERE1 TRYPHAENA2 TRYPHAENA2

Treatment

Pertuzumab,

Trastuzumab,

Docetaxel

THP x 4

FEC x 3 post-op)

Docetaxel/Carbo/Trast

uzumab/Pertuzumab

TCHP x 6

FEC x 3 THP x 3

N 107 77 75

ypT0/is ypN0 (%) 39.3 63.6 54.6

Neoadjuvant Pertuzumab/Trastuzumab (3 regimens FDA approved 9/2013)

1. Gianni L, et al. Lancet Oncol. 2012;13:25-32. 2. Schneeweiss A, et al. Ann Oncol. 2013;24:2278-2284.

APHINITY: Randomized Adjuvant Phase 3 Trial

A=doxorubicin, E=epirubicin, C=cyclophosphamide, T=taxane (paclitaxel or docetaxel), F=5-fluorouracil, H=trastuzumab, P=pertuzumab

N=3800 planned (4800 enrolled)

trastuzumab + pertuzumab* x 1 year

S

U

R

G

E

R

Y

Central confirmation

of HER2 status

ACT or TCH

trastuzumab + placebo* x 1 year

ACT or TCH

*antibody therapy starts with taxane

Population: Node + or high risk node negative

Von Minckwitz et al. ASCO 2017 Abs LBA500

APHINITY: Disease-Free Survival

4yr iDFS: HR = 0.81 (p = 0.045)

Absolute benefit = 1.7%

Δ % (H/P vs. H)

Absolute Δ

N0 96.7 v 96.2% 0.5%

N1 89.9 v 86.7% 3.2%

ER/PR+ 93 v 91.6% 1.4%

ER/PR- 91 v 88.7% 2.3%

iDFS subset analysis

*No difference in iDFS by type of chemotherapy

von Mickwitz G et al, ASCO 2017

Who should get adjuvant pertuzumab?

• Should be reserved for high-risk patients:

– Node-positive

– Hormone-receptor negative

Can we do better?

• Adding targeted agents

– Pertuzumab

– Neratinib

Neratinib

• Low-molecular-weight, irreversible, pan-HER inhibitor (ErbB1,2,4)

Neratinib

Burstein et al JCO. 2010. 28:1301

ExteNET Study Design

• Primary endpoint: invasive disease-free survival (iDFS)a

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

• Stratification: nodes 0, 1-3 vs 4+, ER/PR status, concurrent vs sequential trastuzumab

• Study blinded: Until primary analysis; OS remains blinded

Neratinib × 1 yr 240 mg/day

n=1420

Placebo × 1 yr n=1420

Randomize 1:1

N=2840 Primary analysis

iDFSa

Extended follow-up:

5-yr for iDFS &

overall survival

Prior adjuvant trastuzumab

2 years

a All iDFS events up to the cutoff date of 2 years + 28 days for each patient were included in the primary analysis.

0 12 24 36 48 60

Months after randomization

Neratinib

Placebo

HR (95% CI): 0.95 (0.66-1.35) Two-sided P=0.762

604 559 541 520 464 407 400 391 384 376 362

605 575 548 529 495 448 444 435 427 416 402

97.5%

94.7% 92.8%

91.8% 90.8%

90.4% 89.9%

89.3% 88.8%

88.9%

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60

Dis

ea

se

-fre

e s

urv

iva

l

Months after randomization

Neratinib

Placebo

HR (95% CI): 0.60 (0.43-0.83) Two-sided P=0.002

At risk

Neratinib 816 757 731 705 642 571 565 558 554 544 523

Placebo 815 779 750 719 647 581 567 556 551 542 525

iDFS by Hormone Receptor Status 5-Year Analysis

98.1%

96.1% 95.4%

91.7% 4.4% Δ

93.6%

89.8%

92.6%

88.5%

91.2%

86.8%

Hormone receptor positive Hormone receptor negative

(Descriptive P value)

Antidiarrheal Prophylaxis Reduces the Incidence and Severity of Diarrhea

ExteNET and Study 6201 (CONTROL)

22%

24% 23%

31%

5%

23%

32%

40%

None

Grade 1

Grade 2

Grade 3

25%

28% 27%

20%

ExteNET n=1408

Loperamide n=137

Loperamide + budesonide n=64

46%

26%

20%

8%

Colestipol + loperamide n=39

Can we do better?

• Adding targeted agents

– Pertuzumab

– Neratinib

• Improvement in DFS within hormone-

receptor positive patients, but associated

with increased toxicity

• Unclear if benefit would persist after

pertuzumab

Can we deescalate therapy?

• Small HER2+ tumors

APT Trial: Study Design

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)*

Planned N=400

*Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks

** Radiation and hormonal therapy was initiated after completion of paclitaxel

Tolaney SM et al, ASCO 2017

APT: Recurrence Free Interval

Time (Months)

Re

cu

rre

nce

-Fre

e In

terv

al

0 12 24 36 48 60 72 84 96

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72 84 96

0.0

0.2

0.4

0.6

0.8

1.0

All patientsNumber at risk

406 388 385 378 362 347 247 120 34

RFI Events=

•Invasive Local/Regional Recurrence

•Distant Recurrence

•Death from Breast Cancer

Point Est. 95% Conf. Interval No. of

events

3-yr RFI 99.2% 98.4% to >99.9% 3

5-yr RFI 98.1% 96.8% to 99.5% 7

7-yr RFI 97.5% 95.9% to 99.1% 9

Tolaney SM et al, ASCO 2017

APT: Implications

• Paclitaxel and trastuzumab (TH) can be considered a

reasonable and appealing approach for the majority of

patients with stage I HER2+ breast cancer

– Not all patients require adjuvant trastuzumab-based

chemotherapy (particularly T1aN0)

– Standard regimens from the pivotal trials can be

considered for patients with particularly high risk

features

ATEMPT Trial Schema

Stage I

HER2+*

ER+ or ER-

PS 0-1

Adequate organ fx

N=500

Trastuzumab-DM1 q3weeks X17

*HER2-positive defined as IHC 3+ or FISH≥2.0; will be confirmed by central HER2 testing prior to study enrollment

Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy

Adjuvant radiation therapy can be administered concurrently with study treatment.

Paclitaxel + Trastuzumab x12

Trastuzumab q3weeks x13

N=375

N=125

R

3

1

PI: Sara Tolaney, MD, MPH

Summary: Early Stage Disease

• Trastuzumab significantly improves survival in both adjuvant and neoadjuvant setting

• Pertuzumab can be considered in patients with node-positive and hormone-receptor negative disease

• Neratinib can be considered in high risk ER+ patients

• TH is a reasonable standard for stage I disease

Survival with HER2+ Metastatic Disease

CLEOPATRA Study Design

HER2-positive MBC centrally confirmed

(N = 808)

Placebo + trastuzumab

1:1

Docetaxel

≥ 6 cycles

n = 406

n = 402

Pertuzumab + trastuzumab

Docetaxel

≥ 6 cycles

PD

PD

Baselga J, et al. N Engl J Med 2012; 366:109–119.

• Randomization stratified by geographic region and

neo/adjuvant chemotherapy

• Study dosing q3w:

– Pertuzumab/placebo: 840 mg loading → 420 mg maintenance

– Trastuzumab: 8 mg/kg loading → 6 mg/kg maintenance

– Docetaxel: 75 mg/m2 → 100 mg/m2 escalation if tolerated

CLEOPATRA: Final OS Analysis Median follow-up 50 months (range 0–70 months)

ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.

CI, confidence interval; Pla, placebo; Ptz, pertuzumab. 32

OS

(%)

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 70 60

Time (months)

HR 0.68 95% CI = 0.56, 0.84

p = 0.0002

Ptz + T + D

Pla + T + D

1 28 104 226 268 318 371

0 23 91 179 230 289 350

n at risk

Ptz + T + D

Pla + T + D

402

406

40.8 months 56.5

months Δ 15.7

months

Swain et al, ESMO 2014

ORR

80.2%

69.3%

p=0.001

Pertuzumab for Advanced HER2+ Disease

• Standard of care to give chemotherapy with HP for first line therapy

– Taxane (Docetaxel or paclitaxel) or Vinorelbine

• Use of pertuzumab in the 2nd line setting in a patient who never received pertuzumab is reasonable

• No data for use of pertuzumab beyond progression

Trastuzumab Emtansine (T-DM1)

• T-DM1 is a novel antibody drug-

conjugate.

• Trastuzumab linked to DM1, a

microtubule inhibitor

• T-DM1 binds to HER2 with affinity

similar to trastuzumab

LoRusso Pet al, Clinical Cancer Research 2011

T-DM1: Standard 2nd line therapy

1:1

HER2+ (central) LABC or MBC

(N=980)

• Prior taxane and trastuzumab

• Progression on metastatic tx or within 6 mos of adjuvant tx

T-DM1

Capecitabine + Lapatinib

Dieras V et al, Lancet Oncology 2017

EMILIA

Overall Survival

SYD985: [vic-]trastuzumab duocarmazine

• HER2-targeting antibody-drug conjugate (ADC) based on trastuzumab

• Protease cleavable linker with a DNA alkylating toxin duocarmycin

• Toxin incorporated into the linker-drug as an inactive prodrug

• Proteolytic cleavage results in release of the membrane permeable active toxin

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37

Trastuzumab Deruxtecan (DS-8201a)

Her2-Directed ADCs Agent Payload Drug to

Antibody Ratio

Phase of Development

ORR in HER2+

ORR in HER2 low

Trastuzumab-DM1 (T-DM1) 1

DM1 (antitubulin)

3.5 FDA Approved 43.6% ------

Trastuzumab Duruxtecan (DS-8201A)2

Exatecan derivative (topoisomerase I)

8 II/III (NCT03248492)

61.4% 31.6%

SYD9853 Duocarmacine derivative (alkylator)

2.8 III (NCT03262935) 33% 31%

XMT-15224 Monomethyl Auristatin F (antitubulin)

12 I (NCT02952729) unknown unknown

ARX788 Amberstatin 269 (AS269) (antitubulin)

1.9 I (NCT03255070) unknown unknown

DHES0815A Pyrrolo[2,1-c][1,4]benzodiazepine monoamide (PBD-MA) (alkylator)

2 I (NCT03451162) unknown unknown

MEDI-4276 Tubulysin (antitubulin)

3.6 I (NCT02576548) unknown unknown

1Verma S et al, NEJM 2012, 2Modi S et al, SABCS 2017 3Saura C et al, ASCO 2018,4Yurkovetskiy A et al, AACR 2017

Novel Approaches

• Cdk 4/6 Inhibitors

• HER2 TKIs

• Immunotherapy

• HR+/HER2+ MBC

• No prior treatment in the advanced setting beyond induction treatment

• No evidence of disease progression after induction treatment

Anti-HER2 Therapy + Endocrine Therapy

Palbociclib + Anti-HER2 Therapy +

Endocrine Therapy

N=496

Abemaciclib 150 mg

Q12hr PO +

fulvestrant +

trastuzumab

Trastuzumab +

physican’s choice

single agent

chemotherapy

N = 225

R

A

N

D

O

M

I

Z

E

1:1:1

Abemaciclib 150 mg

Q12hr PO +

trastuzumab

monarcHER

PI: Otto Metzger

Can the addition of cdk 4/6 inhibition to anti-HER2 therapy improve outcomes for ER+ HER2+

disease?

Tucatinib – Potent & Selective HER2

Inhibitor Additive with multiple SOC agents in preclinical models

Demonstrated clinical activity in HER2+ patients

Superior safety profile in patients

Improved convenience of an oral drug vs. IV mAbs

Compound

Cellular Selectivity Data

HER2

IC50 (nM)

EGFR

IC50 (nM)

p95 HER2

IC50 (nM)

HER2 IC50 (nM)

50% Human Serum

Tucatinib 8 4000 7 67

Neratinib 7 8 NT 39

Lapatinib 49 31 NT 810

HN

HN

O

N

N

N

NN

N

O

Tucatinib

HER2Climb: Does tucatinib add to trastuzumab/capecitabine?

Loi et al, SABCS 2017

Loi et al, SABCS 2017

Current Approach for Metastatic HER2+ Breast Cancer

1st Line 2nd Line 3rd Line -10th Line+

THP ( ET if ER+) T-DM1 Capecitabine + lapatinib

Chemotherapy + Trastuzumab

Endocrine therapy (ET) + HL or HP

THP + PD-L1

THP ET+ palbociclib

DS8201A Capecitabine + Trastuzumab + Tucatinib

DS8201A

SYD985

Capecitabine + Neratinib

Capecitabine + Pyrotininb

Abemaciclib + Trastuzumab (+Fulvestrant)

Margetuximab + Chemotherapy

Potential Future Therapy Options

Summary • The addition of pertuzumab to trastuzumab and capecitabine in the 2nd

line does not result in a statistically significant improvement in PFS or OS, but there is a trend to benefit in OS

– Consideration of addition of pertuzumab to chemotherapy and trastuzumab in a pertuzumab-naïve patient beyond the first line is reasonable

• T-DM1 remains a standard in the 2nd line setting, but several new ADCs are in development

– Phase 3 studies ongoing with SYD985 and DS8201a

• Several new tyrosine kinase inhibitors in development being explored with capecitabine, including tucatinib which is more specific for HER2

• Work ongoing exploring immunotherapy and cdk 4/6 inhibitors