April 26, 2019Global Breast Cancer Conference 2019

Symposium 5

Optimizing Anti-HER2 Therapies for HER2 Positive Breast Cancer

Optimal Sequence of Anti-HER2 Therapy

in the Metastatic Setting

Toshimi Takano, M.D.Department of Medical Oncology,

Toranomon HospitalBreast Cancer Committee,

West Japan Oncology Group (WJOG)

Conflict of Interest disclosure

Toshimi Takano

• Honoraria:

Daiichi-Sankyo, Kyowa Hakko Kirin, Eisai, Pfizer,

and Eli Lilly

• Research funding:

Daiichi-Sankyo, Kyowa Hakko Kirin, Eisai, Ono,

MSD, Merck Serono, Taiho, Novartis, Chugai

Clinical Trial Groups in Japan

WJOG9917B (NEWBEAT)

Results will be reported at SABCS 2019

Nivolumab Evaluation With BEvacizumab And paclitaxel

IIT using investigational drugs

MBC 1st lineHER2 negative

N = 51

Nivolumab Paclitaxel

Bevacizumab

Including Luminal MBCSingle-arm phase II trialPrimary endpoint: ORR

PI: Ozaki Y

・ HR+ HER2- MBC・ No CTx for MBC・ 0 or 1 ET for MBC

N = 53

Phase II trial for Luminal MBC

WJOG11418B (NEWFLAME)

Nivolumab Evaluation With endocrine therapy (Fulvestrant or Letrozole) and AbeMaciclib

Primary endpoint: ORRSecondary endpoint: PFS, OS, Safety

PI: Masuda J

Letrozole cohort

Fulvestrant cohort

6

Anti-HER2 Therapy

Current Situation

ET-resistant

Treatment Strategy for MBC

ET #1

ET #2

ET #3

Tra+Per+CT #1

Lapa+CT #2

Tra+CT #3

T-DM1

Non-life-threatening Life-threatening

HR+ HER2+ TNBC HER2+ HER2-HR+/HER2+

Tra+Per+ ETCT #1

CT #2

CT #3

CT #4

ET: endocrine therapy, CT: chemotherapy Takano T: Original

Non-life-threatening Life-threatening

ET-resistant

Clinical Questions

ET #1

ET #2

ET #3

Tra+Per+CT #1

Lapa+CT #2

Tra+CT #3

T-DM1

HR+ HER2+ TNBC HER2+ HER2-HR+/HER2+

Tra+Per+ ETCT #1

CT #2

CT #3

CT #4

ET: endocrine therapy, CT: chemotherapy Takano T: Original

1st-generationAnti-HER2 drugs

Trastuzumab

（Ｈ: Herceptin）

Lapatinib

（Ｌ: Tykerb）

Mode of action HER2 MAb HER2-TKI

Administrationdiv

q3w or q1w

po

Every day

Approval June 2001 April 2009

ToxicityInfusion reaction

Cardiac toxicity

Rash

Diarrhea

Brain mets Less effective ? Effective ?

Anti-HER2 drugs are needed all the time.

Phase III trials evaluating anti-HER2 drugs in HER2+ MBC

Endocrine therapy

Ana ＜Ana+Ｈ

1st line chemotherapy

PTX＜PTX+Ｈ

2nd line chemotherapy (beyond PD)

X＜X+Ｈ

3rd line chemotherapy (beyond PD)

L＜L+Ｈ

Almost all trials were positive.

X＜X+L

Let ＜Let +L

PTX＜PTX+L

1st line H: H0648g

Slamon DJ: N Engl J Med 344:783, 2001

PTX(or AC)± HMST 25.1 vs 20.3m

P=0.046

Ｈ beyond PD

Cape+H>Cape (GBG-26)

mPFS: 8.2 vs 5.6mP=0.034

von Minckwitz G: J Clin Oncol 27:1999, 2009

PTX＜PTX+HH0648g

Trastuzumab

Trastuzumab to the end?

X＜X+HGBG-26

L＜L+HEGF104900

XLX

P=0.00013

4.36.2Median TTP, mo

201198No. of pts

0.57 (0.43, 0.77)HR (95% CI)

Cameron D: Breast Cancer Res Treat 112:533, 2008

（％）100

0

60

（week）9010 20 30 40 50

80

40

20

060 70 80

70

90

50

30

10

Switch to Lapatinib is also effective.

EGF100151: TTP

Clinical Question

Early switch to Lapatinib

vs.

Trastuzumab beyOnd PD

ELTOP study

WJOG6110B/ELTOP

Takano T: The Breast 40:67-75, 2018

Previously

treated with

Tmab and

Taxane

HER2(+)MBC

2ndor3rd line

N=170

R

HX “Trastuzumab beyond PD”

Trastuzumab+Capecitabine

LX “Early Switch to Lapatinib”

Lapatinib+Capecitabine

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

ELTOP: PFS

Median PFS (months)

LX 7.1

HX 6.1

Hazard ratio 0.81 (90% CI, 0.55 to 1.21)

Log-rank P = .39

Pro

gre

ssio

n-F

ree S

urv

ival (%

)

Time (months)Number at risk

LX HX

43 38 25 14 8 7 7 3 2 1 1 1 0 0 0 043 31 22 10 6 4 3 3 3 3 3 2 2 2 2 0

Takano T: The Breast 40:67-75, 2018

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54

Overa

ll S

urv

ival (%

)

Time (months)Number at risk

LX HX

43 42 42 33 26 18 8 5 1 043 40 34 27 18 11 7 5 1 0

ELTOP: OS

Median OS (months)

LX Not reached

HX 31.0

Hazard ratio 0.58 (95% CI, 0.26 to 1.31)

Log-rank P =.18

Takano T: The Breast 40:67-75, 2018

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Time (months)

Pro

gre

ssio

n-F

ree S

urv

iva

l (%

)

5 3 3 0 0 0 0 0 0 0 0 0 0 0 0 0

14 11 6 4 1 0 0 0 0 0 0 0 0 0 0 03 3 1 1 0 0 0 0 0 0 0 0 0 0 0 0

Number at risk

LX, wild type

HX, wild type

LX, mutant

HX, mutant

13 13 9 5 5 5 5 2 2 1 1 1 0 0 0 0

median PFS (months)

LX, PIK3CA wild type 8.2

HX, PIK3CA wild type 4.9

LX, PIK3CA mutant 4.1

HX, PIK3CA mutant 6.1

Hazard ratio (PIK3CA wild type) 0.38 (95% CI, 0.16 to 0.93)

Hazard ratio (PIK3CA mutant) 0.60 (95% CI, 0.11 to 3.13)

PFS by PIK3CA mutations

Takano T: The Breast 40:67-75, 2018

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48

5 4 4 2 1 0 0 0 0

14 12 9 6 4 2 1 0 03 3 3 1 0 0 0 0 0

13 13 13 12 11 6 2 1 0Number at risk

LX, wild type

HX, wild type

LX, mutant

HX, mutant

Time (months)

Ove

rall

Su

rviv

al (%

) median OS (months)

LX, PIK3CA wild type Not reached

HX, PIK3CA wild type 18.7

LX, PIK3CA mutant 15.4

HX, PIK3CA mutant 15.7

Hazard ratio (PIK3CA wild type) 0.088 (95% CI, 0.011 to 0.73)

Hazard ratio (PIK3CA mutant) 1.20 (95% CI, 0.20 to 7.32)

OS by PIK3CA mutations

Takano T: The Breast 40:67-75, 2018

2nd or more-generation anti-HER2 drugs

Pertuzumab

T-DM1

Neratinib or other HER2-TKIs

DS-8201a or other HER2-ADCs

Combinations with other agents

CDK4/6-I

Immune checkpoint inhibitors

1st line Pertuzumab

CLEOPATRA：HER2+ MBC 1st line

Trastuzumab + Pertuzumab + Docetaxel

Baselga J: N Engl J Med 366:109, 2012

OS was also improvedSwain SM: N Engl J Med 372:724-34, 2015

MST40.8m → 56.5m

MST of CT alone arm in H0648g was 20.3m

CLEOPATRA1

n=808

EGF30008 6

n=219

TAnDEM 7

n=208

M770014

n=188

H0648g 5

n=469

HERNATA2

n=284

BCIRG0073

n=263

56.5

40.8

38.8

35.7

37.4

37.1

31.2

22.7

25.1

20.3

33.3

32.3

28.5

23.9

HER+DTX+PER

HER+DTX

HER+VNR

HER+DTX

HER+DTX+CBDCA

HER+DTX

HER+DTX

DTX

HER+CT

CT

LAP+FEM

FEM

HER+ANA

ANA

0 10 20 30 40 50 60

ER and/or

PgR positive

P<0.001

P=0.046

P=0.0325

P=0.98

P=0.99

P=0.113

P=0.325

1) Baselga J, et al. N Engl J Med 2012; 366: 109-119

2) Andersson M, et al. J Clin Oncol 2011; 29: 264-71

3) Valero V, et al. J Clin Oncol 2011; 29: 149-156

4) Marty M, et al. J Clin Oncol 2005; 23: 4265-74

5) Slamon DJ, et al. N Engl J Med 2001; 344: 783-92

6) Johnston S, et al. J Clin Oncol 2009; 27:5538-46

7) Kaufman B, et al. J Clin Oncol 2009; 27:5529-37

HER2+ MBC： MST (1st line)

T-DM1: 2nd line

EMILIA

Verma S: N Engl J Med 367:1783, 2012

T-DM1: 1st line

• Stratification factors: World region, Prior neo-/adjuvant therapy (if Yes: prior

trastuzumab/lapatinib), Visceral disease

• Primary end point: PFS by independent review facility (IRF), non-inferiority and superiority

assessed

• Key secondary end points: OS, PFS by investigator, ORR, Safety, Patient-reported outcomes

MARIANNE

• HER2-positive (central) LABC or MBC

• No prior chemotherapy for LABC/MBC

• >6 months from prior neo-/adjuvant vincaalkaloid or taxane chemotherapy

N = 1095

Trastuzumab + docetaxelOR

Trastuzumab + paclitaxel

T-DM1 + placebo

T-DM1 + pertuzumab

Ellis PA, J Clin Oncol, 2015 ASCO Annual Meeting abstr 507

MARIANNE: PFS T-DM1(+Pmab) was not superior to Tmab+Taxane

Ellis PA, J Clin Oncol, 2015 ASCO Annual Meeting abstr 507

Standard Tx for HER2+ MBC

1st line

Trastuzumab+Pertuzumab+Taxane

2nd line

T-DM1

3rd or later line

Lapatinib+Capecitabine

Trastuzumab beyond PD+CT

Others

30

Anti-HER2 Therapy

Clinical Questions

1st line T-DM1?

T-DM1=Tmab+Taxane<Tmab+Pmab+Taxane

In selected patients, can T-DM1 be an option?

Elderly patients?

Patients with predictive biomarkers (e.g. PIK3CA mutations)?

HER2+ MBC

Elderly Pts65-79yo

R

Tmab+Pmab+DTX

T-DM1

<JCOG1607 (HERB TEA Study)>

Pertuzumab Beyond PD?

“Trastuzumab beyond PD” is supported by several trials.

Significance of “Pertuzumab beyond PD” is unknown.

HER2+ MBC

R

Tmab+Pmab+

Taxane

T-DM1

T-DM1+Pmab

<Proposed Trial>

PD

JBCRG-M05 (PRECIOUS)

“Rechallenge of Pertuzumab”

3rd/4th line

R

Tmab + CT

(N=218)

CT: Taxane, Vinorelbine, Eribulin, Capecitabine, or Gemcitabine

Primary endpoint: PFS

Previously treated with Pmab

HER2+ MBC Tmab + Pmab+ CT

Phase III

Best partner for Tmab + Pmab?

Tmab + Pmab + Cytotoxic agents

DTX (Phase III CLEOPATRA)

PTX (Phase II)

Vinorelbine (Phase II)

Capecitabine (Phase II)

Eribulin (Phase II)

Tmab + Pmab + Endocrine therapy

AI

Fulvestrant

ET+CDK4/6-I

EMERALD (JBCRG-M06)

HER2+ MBC 1st line, Phase III

HER2+MBC

N=480

Tmab+Pmab+Taxane

R

Tmab+Pmab+Eribulin

HER2+ ER+ MBC: Options

1st line

Trastuzumab+Pertuzumab+Taxane

2nd line

T-DM1

3rd or later line

Lapatinib+Capecitabine

Trastuzumab beyond PD+CT

Others

Tmab+Pmab+Endocrine Tx

Tmab+Pmab+Endocrine Tx(Maintenance Tx)

Anti-HER2 drug+Endocrine Tx

PERTAIN: Tmab+Pmab+AI

Rimawi M: J Clin Oncol 36:2826-2835, 2018

PERTAIN: PFS

Rimawi M: J Clin Oncol 36:2826-2835, 2018

PERTAIN: PFS (No induction CTx)

Rimawi M: J Clin Oncol 36:2826-2835, 2018

Therapy without CTx yielded a median PFS of 21.7m.

PATINA: Tmab+Pmab+ET+Palbo

Maintenance Tx after Tmab+Pmab+CT

Predictive biomarkers?

Biomarkers will guide the selection of anti-HER2 therapy in the future, but not yet.

Many candidates have been suggested.

HER2, HER2-ECD, p95HER2, HER2 mut

HER2/HER3 heterodimers

FcγR polymorphisms

Ligands (e.g. TGFα, Heregulin)

Immunology (e.g. TILs, PD-L1)

PI3K/Akt pathway (e.g. PIK3CA mut, PTEN)

CLEOPATRA

Baselga J: SABCS 2012 #S5-1

CLEOPATRA

Baselga J: SABCS 2012 #S5-1

PIK3CA mut is not a predictor of pertuzumab efficacy.

PIK3CALap ＋ Cap T-DM1

N mPFS N mPFS HR 95% CI

Mutated

Wild-type

39

87

4.3

6.4

40

93

10.9

9.8

0.45

0.740.25–0.82

0.50–1.10

Lap＋Cap（PIK3CA mutated）

Lap＋Cap（PIK3CA wild-type）

T-DM1（PIK3CA mutated）T-DM1（PIK3CA wild-type）

Time (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 280.0

0.2

0.4

0.6

0.8

1.0

EMILIA: PFS by PIK3CA mutations

Baselga J, et al. AACR 2013

EMILIA

PIK3CA mut may be a predictor of T-DM1 efficacy.

New Antibody-Drug Conjugate

trastuzumab deruxtecan

Standard Tx will be changed?

1st line

Trastuzumab+Pertuzumab+Taxane

2nd line

T-DM1

3rd or later line

Lapatinib+Capecitabine

Trastuzumab beyond PD+CT

Others

DS-8201a?

DS-8201a?

DS-8201a is also effective in HER2-low BC

HER2-positive Breast Cancer HER2-low Breast Cancer

Modi S: SABCS2017 PD3-07

This drug will change the concept of HER2 positivity.

Summary

Tmab+Pmab+Taxane as 1st line and T-DM1

as 2nd line are current standard strategy.

Tmab+Pmab+ET is also an important

option.

We need predictive biomarkers to select

individualized therapy.

Many clinical questions remain to be

solved.

Let’s solve them in inter-group

collaboration!

Toshimi Takano

Thank you !