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Current status of adjuvant HER2 targeting therapy Valentina Guarneri, MD, PhD Istituto Oncologico Veneto IRCCS University of Padova. Outline. Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer

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Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer

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Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Current status of adjuvant HER2 targeting therapyValentina Guarneri, MD, PhDIstituto Oncologico Veneto IRCCSUniversity of Padova


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Outline

  • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer

  • Improving on cardiac toxicity: different regimens and different treatment durations

  • Improving on treatment efficacy: dual blockade and new anti-HER2 agents

  • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Outline

  • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer

  • Improving on cardiac toxicity: different regimens and different treatment durations

  • Improving on treatment efficacy: dual blockade and new anti-HER2 agents

  • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Meta-analysis of adjuvant trastuzumab trials: Disease-free Survival

MojaL, et al. The CochraneLibrary 2012, Issue4


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Meta-analysis of adjuvant trastuzumab trials: Overall Survival

MojaL, et al. The CochraneLibrary 2012, Issue4


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

DFS : ∆ 11.9% at 6y

∆ 11.5% at 10y

OS : ∆ 5.5% at 6y

∆ 8.8% at 10y


Are all trastuzumab adjuvant trials the same

Sequentialadministration

Concurrentadministration

Trastuzumab up to 1 yr

BCIRG 006

DC x 6+ H

AC x 4

D x 4+ H

Joint analysis of

NSABP B31 & N9831

AC x 4

T x 4 + H

N9831

Sequential arm

wT x 12

AC x 4

HERA

Adjuvant CT (Any)

RT

FIN-HER

D/N+H x 9 wks

FECx 3

FEC/ED x 6

RT

PACS 04

Are all trastuzumab adjuvant trials the same?

Randomization

Trastuzumab start

T= paclitaxel; D= docetaxel


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Overall Survival stratified by concurrent or sequential administration

MojaL, et al. The CochraneLibrary 2012, Issue4


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Outline

  • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer

  • Improving on cardiac toxicity: different regimens and different treatment durations

  • Improving on treatment efficacy: dual blockade and new anti-HER2 agents

  • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

High competing mortality risk score

Low competing mortality risk score

Cancer ahead pub 2010


Congestive heart failure chf all studies

Congestive heart failure (CHF): all studies.

Moja L, et al. The Cochrane Library 2012, Issue 4


Lvef decline all studies

LVEF decline-all studies.


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

BCIRG 006: Adjuvant Breast Cancer

Node Positive and High Risk Node Negative

4x AC60/600 mg/m2

4x Docetaxel

100 mg/m2

ACT

HER2+

(central FISH)

N+ or

High risk N-

N=3,222 pts

ACTH

1 Year Trastuzumab

6 x Docetaxel 75 mg/m2

+Carboplatin AUC 6

TCH

1 Year Trastuzumab


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Slamon D, NEJM 2011.


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Slamon D, NEJM 2011.


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Slamon et al. SABCS 2006. Abstract 52.

Slamon D, NEJM 2011.


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

CHF by trastuzumab duration

Moja L, et al. The Cochrane Library 2012, Issue 4


Dfs by trastuzumab duration

DFS by trastuzumab duration

Log (Hazard ratio)HR weight HR (IV,random, 95%CI)

Moja L, et al. The Cochrane Library 2012


Overall survival stratified by duration of trastuzumab treatment

Overall survival stratified by duration of trastuzumab treatment

Moja L, et al. The Cochrane Library 2012, Issue 4


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

SABCS, 2012


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

SABCS, 2012


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

PHARE* Trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancerXavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar.

  • Protocol of

  • Herceptin®

  • Adjuvant with

  • Reduced

  • Exposure

  • *lighthouse in French


Study design

Study design

trastuzumab up to 12 months

trastuzumab 6 months

R

Stratification

1. ER pos / neg

2. Chemo: conco/ seq

stop trastuzumab

Clinical exam

LVEF

0

3

6

9

12

15

18

21

24

30 mos

Mammography

Up to 60 mos…

R: Randomizationafterinformed consent


Statistical methods

Statistical Methods

  • Non inferiorityrandomized trial

  • 2% variation in terms of absolutedifference of recurrence

  • The 95% CI HR marginsshould not cross the 1.15 boundary

  • 1040 DFS events required for 80% power at 5% level

    or

    4 years of accrual and at least 2 years of follow-up

  • HR were estimated from the stratified Cox model

  • Accrualtarget: 3400 patients


Primary endpoint scenarii

Primary endpoint scenarii

A

Equivalent

B

Superior

C

D

Non Inferior

E

Inferior

.85

1

1.15

1.3

1.45

1.6

HR


Patient characteristics

Patient Characteristics


Treatment characteristics

Treatment Characteristics


Cardiac toxicity

Cardiac toxicity

* Investigatorreportedevents (composite withclinical and LFEV finding)

** Based on more than > 25,000 assessments


Dfs events

DFS Events

42.5mos. median Follow-up


Disease free survival

Disease Free Survival

97.0 93.8 90.7 87.8

95.5 91.2 87.8 84.9

EventsHR95%CIp-value

H 12m 176

H 6m 2191.28 (1.05 – 1.56) 0.29

* Cox model stratified by ER status and concomitant chemotherapy


Overall survival

42.5mos. median FU

Overall Survival

99.9 98.7 96.9 95.0

99.3 97.2 95.2 93.1

EventsHR95%CIp-value

H 12m 66

H 6m 931.47(1.07 – 2.02)

* Cox model stratified by ER status and concomitant chemotherapy


Primary endpoint scenarii1

Primary endpoint scenarii

A

Equivalent

B

Superior

PHARE trial

C

D

Non Inferior

E

Inferior

.85

1

1.15

1.3

1.45

1.6

HR


Trastuzumab duration effects in patient subgroups in the phare trial

Trastuzumab duration effects in patient subgroups in the PHARE*trial

  • Protocol of

  • Herceptin®

  • Adjuvant with

  • Reduced

  • Exposure

Xavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar.

SABCS 2012

  • *lighthouse in French


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Subgroup Results

ER- status &

Sequentialmodality

Other groups


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

R

9 mos

3 mos

6 mos

12 mos

Trastuzumab 8 mg/kg

loading dose  6 mg/kg q 3 wks

AC60/600 or

EC90/600

Docetaxel 100

FEC (600/60/600)

Trastuzumab 4 mg/kg

loading dose 2 mg/kg weekly

:LVEF measurement

Short-HER: study design

PI: PF Conte

RT/HT

Sample size 1250 pts

RT/HT

18 mos

EUDRACT-2007-004326-25, NCT00629278


Enrollment as of may 2013

Enrollment as of May, 2013

  • 1176 patients

    • Arm A (Long) 586 patients

    • Arm B (Short) 590 patients


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Outline

  • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer

  • Improving on cardiac toxicity: different regimens and different treatment durations

  • Improving on treatment efficacy: new anti-HER2 agents and multiple dual blockade

  • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups


Teach trial

TEACH Trial

  • Eligibility

  • HER2+ Local IHC3+ or FISH +ve

  • Resected Stage I-IIIc primary BRCA

  • No prior trastuzumab

  • Neo-/adjuvant chemotherapy (CMF, anthracycline, or taxane)

  • Appropriate endocrine therapy

  • Stratification

  • Time from diagnosis ≤4 vs >4 yrs

  • Lymph node +ve vs -ve

  • ER+ and/or PgR+ vs ER–/PgR–

R

A

N

D

O

M

I

Z

E

Lapatinib

1500 mg qd × 1 yr

N=3147

Aug 2006-May 2008

33 countries

Placebo

qd × 1 yr

4 yr

Diagnosis

  • Disease-free survival (DFS):local, regional, distant recurrence,contralateralBRCA,other 2nd primary cancers,death from any cause

Goss, SABCS 2011


Teach primary endpoint k m plot of dfs in itt population time from randomization

TEACH Primary Endpoint: K-M Plot of DFS inITT Population—Time From Randomization

Lapatinib

HR 0.83 (0.70-1.00); p=0.053a

Placebo

Median Follow up: 4 years

0.0

  • No improvement in OS demonstrated with use of lapatinib:HR: 0.99 (95% CI: 0.74-1.31; P = .966)

Goss, SABCS 2011

ap value based on 2-sided stratified log-rank test


Teach forest plot of dfs for subgroups in itt population

TEACH: Forest Plot of DFS for Subgroups in ITT Population

L=lapatinib; P=placebo.

Goss, SABCS 2011


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Dual anti-HER2 blockade

(neoadjuvant studies)

Phase III NeoALLTO study

Phase II CHER-LOB study


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Dual Anti-HER2 blockade significantly increases the pCR rate

60

Exploratory p=0.0187

50

40

46.7%

30

20

25%

26.3%

10

0

Arm A: CT + T

Arm B: CT + L

Arm C: CT + T + L

pCR (breast & axilla)

Guarneri V et al, J Clin Oncol 2012

Baselga J et al. Lancet 2012


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

ALTTO study design (8000 patients)


Aphynity

Aphynity

R

IBCSG 39-11 / BIG 4-11 (APHINITY)

HER2+ BC

N+ or high-risk N0

6-8 cycles

Adj CHT

6-8 cycles

Adj CHT

52 weeks

Expectedenrollment: 3806 pts

Trastuzumab i.v.8 mg/kg LD then6 mg/kg, q3w

Pertuzumab 840 mg i.v. LD then 420 mg, q3w

T, P/Pl concomitant to taxane-based CT

Placebo i.v., q3w


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Outline

  • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer

  • Improving on cardiac toxicity: different regimens and different treatment durations

  • Improving on treatment efficacy: dual blockade and new anti-HER2 agents

  • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Outcome of HER2+ T1a,b N0 tumors (w/o Trastuzumab)


Trastuzumab adjuvant trials subset analysis

Trastuzumab Adjuvant trials: subset analysis

N–

HERA

32 % N0

1–3+ nodes

≥4+ nodes

Not assessed

7% N0

N9831/B-31

N–

1–3+ nodes

4–9+ nodes

>10+ nodes

BCIRG 006

29% N0

N–

ACTH

N+

29% N0

N–

TCH

N+

0

0.5

1.0

1.5

2.0

2.5

HR

Favours trastuzumab

Favours no trastuzumab

Slamon, et al. SABCS 2006 Perez, et al. ASCO 2007; Smith, et al. Lancet 2007

N = node


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

HER2+ EBC patients

Adjuvanttrastuzumabtrials vs Modena CancerRegistry

Piccart N Engl J Med 2005; Romond N Engl J Med 2005; Joensuu N Engl J Med 2006; Slamon D, SABCS 2006; Spielmann M et al, SABCS 2007; Federico M, RTM 1998-2009


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

pCR by Hormone Receptor Status

Baselga J et al. SABCS 2010; Gianni et al, SABCS 2010, Guarneri et al, ASCO 2011


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Neoadjuvant trastuzumab + lapatinib w/o chemotherapy

Chang, JCO 2013


Trastuzumab plus chemotherapy the gold standard for her2 positive early breast cancer

Summary of HER2+ EBC

  • CT+ 1yr trastuzumab is the standard regimen

  • Studiesevaluatingoptimal trastuzumab duration in termsofefficacy and safety are critical:

    • to take into account the sustainabilityfor the NHS

    • to facilitate the introductionofnew antiHER2 treatments

  • Neoadjuvant studies are essentialtorank treatment activity, priortomovetolargeadjuvantstudies

  • A dualHER2 inhibitionseems a winnerstrategy

  • New promisingagents are entering the adjuvantphase

  • The possibilitytoavoidchemotherapy in case ofsmallTsize, N0, HR+, elderly and frailpatientsisintriguing, butstillmatterofstudy


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