Current status of adjuvant HER2 targeting therapy Valentina Guarneri, MD, PhD Istituto Oncologico Veneto IRCCS University of Padova.

Current status of adjuvant HER2 targeting therapy

Valentina Guarneri, MD, PhDIstituto Oncologico Veneto IRCCS

University of Padova

• 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

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

Outline

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

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

Meta-analysis of adjuvant trastuzumab trials: Overall Survival

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

OS : ∆ 5.5% at 6y ∆ 8.8% at 10y

DFS : ∆ 11.9% at 6y ∆ 11.5% at 10y

Are all trastuzumab adjuvant trials the same?

BCIRG 006 DC x 6+ H

AC x 4 D x 4+ H

Trastuzumab up to 1 yr

FIN-HER D/N+H x 9 wks FECx 3

HERA Adjuvant CT (Any) RT

N9831Sequential arm

wT x 12AC x 4

Joint analysis ofNSABP B31 & N9831

AC x 4 T x 4 + H

PACS 04 FEC/ED x 6 RT

Randomization Trastuzumab start T= paclitaxel; D= docetaxel

Concurrent administration

Sequential administration

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

Overall Survival stratified by concurrent or sequential administration

• 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

Outline

Low competing mortality risk score High competing mortality risk score

Cancer ahead pub 2010

Congestive heart failure (CHF): all studies.

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

LVEF decline-all studies.

BCIRG 006: Adjuvant Breast CancerNode Positive and High Risk Node Negative

4x AC60/600 mg/m2

4x Docetaxel100 mg/m2

HER2+(central FISH)

N+ or High risk N-

N=3,222 pts

6 x Docetaxel 75 mg/m2 +Carboplatin AUC 6

1 Year Trastuzumab

1 Year Trastuzumab

ACT

ACTH

TCH

Slamon D, NEJM 2011.

Slamon D, NEJM 2011.

Slamon et al. SABCS 2006. Abstract 52.Slamon D, NEJM 2011.

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

CHF by trastuzumab duration

Moja L, et al. The Cochrane Library 2012

DFS by trastuzumab durationLog (Hazard ratio) HR weight HR (IV,random, 95%CI)

Overall survival stratified by duration of trastuzumab treatment

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

SABCS, 2012

SABCS, 2012

www.esmo2012.org

PHARE* Trial results comparing 6 to 12 months of trastuzumab in

adjuvant early breast cancer 

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.

Protocol of Herceptin®

Adjuvant withReduced Exposure

*lighthouse in French

www.esmo2012.org

Study design

trastuzumab 6 months

trastuzumab up to 12 months

stop trastuzumab

Clinical examLVEF

3

Mammography

6 9 12 15 18 21 24 30 mos

…

0

R

R: Randomization after informed consent

Up to 60 mos…

Stratification1. ER pos / neg2. Chemo: conco/

seq

www.esmo2012.org

Statistical Methods

• Non inferiority randomized trial– 2% variation in terms of absolute difference of recurrence– The 95% CI HR margins should not cross the 1.15 boundary– 1040 DFS events required for 80% power at 5% level 

or4 years of accrual and at least 2 years of follow-up

– HR were estimated from the stratified Cox model

• Accrual target: 3400 patients

www.esmo2012.org

Equivalent

Superior

Non Inferior

Inferior

A

B

C

D

E

.85 1 1.15 1.3 1.45 1.6HR

Primary endpoint scenarii

www.esmo2012.org

Patient Characteristics12 months

n=16906 monthsn=1690

Age, median (range) 54 (21 – 86) 55 (23 – 85)

Tumor :  0 – 2 cm2 – 5 cm>5 cm

54.7%38.5%6.8%

52.4%39.8%7.8%

Nodes: negative1 – 3 nodes4 nodes

55.4%30.0%14.6%

54.7%30.2%15.1%

Positive Estrogen receptor 57.6% 58.8%

Inflammatory disease 3.5% 3.4%

SBR: IIIIII

3.1%41.0%55.6%

3.3%40.9%55.8%

www.esmo2012.org

Treatment Characteristics12 months

n=16906 monthsn=1690

Type of Chemotherapy : No AnthracyclinesAnthracyclines no 

TaxanesAnthracyclines and 

Taxanes

10.2%15.9%73.9%

11.8%15.5%72.7%

Concomitant ChemotherapySequential Chemotherapy

57.8%42.2%

57.7%42.3%

Radiotherapy 87.7% 88.2%

Hormonotherapy 50.6% 50.2%

Trastuzumab duration, mean (sd) 11.8 (6.3) 6.3 (1.46)

www.esmo2012.org

Cardiac toxicity

12 months(n=1690)

6 months(n=1690)

P

Cardiac events* 5.7% 1.9% <0.0001

LVEF** < 50%  6.3% 4.7% 0.04LVEF** < 50% and  > 10% 4.8% 3.6% 0.071LVEF** > 50% and  > 15% 7.4% 7.0% NS

*   Investigator reported events (composite with clinical and LFEV finding)** Based on more than > 25,000 assessments

www.esmo2012.org

DFS Events12 mos(n=1690)

6 mos(n=1690)

DFS Events (n=395) 10.4% 13.0%

Local RecurrenceRegional RecurrenceDistant Recurrence

Controlateral Breast Cancer2nd Primary Malignancy

Death

1.1%0.6%6.4%

0.4%1.5%

0.4%

1.4%0.5%8.3%

0.7%1.5%

0.5%

42.5mos. median Follow-up

www.esmo2012.org

0.00

0.25

0.50

0.75

1.00P

roba

bilit

y

1690 1586 1353 939 526 23H 6m1690 1613 1390 980 544 18H-12m

At risk

0 12 24 36 48 60Months

H-12m H-6m

Disease Free Survival

* Cox model stratified by ER status and concomitant chemotherapy 

95.5 91.2 87.8 84.9

97.0 93.8 90.7 87.8

Events HR 95%CIp-value

H 12m 176H 6m 219 1.28 (1.05 – 1.56) 0.29

www.esmo2012.org

0.00

0.25

0.50

0.75

1.00Pr

obab

ility

1690 1645 1438 1016 566 25H 6m1690 1662 1463 1042 583 19H-12m

At risk

0 12 24 36 48 60Months

H-12m H-6m

Overall Survival

* Cox model stratified by ER status and concomitant chemotherapy 

42.5mos. median FU

99.3 97.2 95.2 93.1

99.9 98.7 96.9 95.0

Events HR 95%CI p-valueH 12m 66H 6m 93 1.47 (1.07 – 2.02)

www.esmo2012.org

Equivalent

Superior

Non Inferior

Inferior

A

B

C

D

E

.85 1 1.15 1.3 1.45 1.6HR

Primary endpoint scenarii

PHARE trial

Trastuzumab duration effects in patient subgroups in the

PHARE* trial

Protocol of Herceptin®

Adjuvant withReduced Exposure

*lighthouse in French

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

Subgroup Results

0.00

0.25

0.50

0.75

1.00

DFS

 Pro

bability

314 282 244 188 113 8T-6m312 288 254 210 130 5T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mER neg - Sequential

HR = 1.57 : 95%CI: (1.08 - 2.28)

0.00

0.25

0.50

0.75

1.00

DFS

 Pro

bability

1376 1304 1109 751 413 15T-6m1378 1325 1136 770 414 13T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mOther groups

HR = 1.18 : 95%CI: (0.93 -1.49)

ER- status & Sequential modality

Other groups

Short-HER: study design

R

RT/HT

RT/HT

Trastuzumab 4 mg/kg loading dose 2 mg/kg weekly

3 mos 6 mos 9 mos 12 mos 18 mos

: LVEF measurement

PI: PF Conte

Sample size 1250 pts

FEC (600/60/600)AC60/600 orEC90/600

Trastuzumab 8 mg/kg loading dose 6 mg/kg q 3 wks

Docetaxel 100

EUDRACT-2007-004326-25, NCT00629278

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

• 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

Outline

TEACH Trial

Placebo qd × 1 yr

Lapatinib 1500 mg qd × 1 yr

Stratification• Time from diagnosis ≤4 vs >4 yrs

• Lymph node +ve vs -ve

• ER+ and/or PgR+ vs ER–/PgR–

4 yr

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

N=3147Aug 2006-May 2008

33 countries

RANDOMIZE

DiagnosisDisease-free survival (DFS):local, regional, distant recurrence,contralateral BRCA,other 2nd primary cancers,death from any cause

Goss, SABCS 2011

0.0

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

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

Lapatinib

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

Median Follow up: 4 years

Number of patients at risk

Lapatinib 1500 mg 1571 1431 1349 1293 1233 1168 1001 661 299

Placebo 1576 1487 1412 1343 1295 1247 1048 706 327

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

Goss, SABCS 2011

TEACH: Forest Plot of DFS for Subgroups in ITT Population

L=lapatinib; P=placebo.

Goss, SABCS 2011

Phase III NeoALLTO study

Phase II CHER-LOB study

Dual anti-HER2 blockade (neoadjuvant studies)

Baselga J et al. Lancet 2012 Guarneri V et al, J Clin Oncol 2012

pCR (breast & axilla)

0

10

20

30

40

50

60

Arm A: CT + TArm B: CT + L Arm C: CT + T + L

Exploratory p=0.0187

Dual Anti-HER2 blockade significantly increases the pCR rate

25% 26.3%

46.7%

ALTTO study design (8000 patients)

Aphynity

R

6-8 cyclesAdj CHT

6-8 cyclesAdj CHT

52 weeks

Trastuzumab i.v. 8 mg/kg LD then 6 mg/kg, q3w Pertuzumab 840 mg i.v. LD then 420 mg, q3w

Placebo i.v., q3w

HER2+ BCN+ or high-risk N0

Expected enrollment: 3806 pts

T, P/Pl concomitant to taxane-based CT

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

• 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

Outline

Author median FU Cohort # Relapses % P value

Amar SSABCS 2007 3 y.

HR+/HER2- 350 1.30.007HER2+ 27 7.4

TN 24 12.5

Zambelli AAIOM 2008

4 y. HER2- 309 30.038

HER2+ 31 13

Ananthakrishnan PSABCS 2008

4 y. HER2-770

3.0ns

HER2+ 9.0

Tovey SMSABCS 2008

5 y. HER2- 309 40.001

HER2+ 58 32

Curigliano GJCO 2009

4.6 y HR+/HER2- 158 1.3

0.09HER2+/HR- 71 7

HER2+/HR+ 79 7.6

TN 71 7

Gonzalez-Angulo AJCO 2009

6.2 y HER2- 867 5.9<0.001

HER2+ 98 21.4

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

Trastuzumab Adjuvant trials: subset analysis

N = node

1–3+ nodes

0 0.5 2.51.0 1.5 2.0

1–3+ nodes

≥4+ nodes

Not assessed

N9831/B-31 N–

4–9+ nodes

>10+ nodes

TCHN–

N+

N+

BCIRG 006 N–ACTH

N– HERA

Favours trastuzumab Favours no trastuzumab HR

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

32 % N0

7% N0

29% N029% N0

Characteristic Adjuvant trastuzumab trials (B31/N9831/HERA/FinHer/BCIRG006/PACS04)

Modena Cancer Registry

Age (median) 49 59

T1N0 % ~ 2 38.8

HER2+ EBC patients Adjuvant trastuzumab trials vs Modena Cancer Registry

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

pCR by Hormone Receptor Status

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

pCR rate*

HR + HR -

Neo-ALLTO Lapatinib (L) +paclitaxel 16.2% 33.8%

Trasuzumab (T) +paclitaxel 22.7% 36.5%

L+T+ paclitaxel 41.6% 61.3%

Cher-LOB L + P-FEC 22.7% 35.7%

T + P-FEC 25% 26.6%

L+T+ P-FEC 35.7% 56.2%

Neo-Sphere Docetaxel-T 20% 36.8%

Docetaxel + T+ Pertuzumab 26% 63.2%

T+pertuzumab 5.9% 29.1%

Docetaxel + pertuzumab 17.4% 30%

Chang, JCO 2013

Neoadjuvant trastuzumab + lapatinib w/o chemotherapy

Summary of HER2+ EBC

• CT+ 1yr trastuzumab is the standard regimen• Studies evaluating optimal trastuzumab duration in terms

of efficacy and safety are critical:• to take into account the sustainability for the NHS• to facilitate the introduction of new antiHER2 treatments

• Neoadjuvant studies are essential to rank treatment activity, prior to move to large adjuvant studies

• A dual HER2 inhibition seems a winner strategy

• New promising agents are entering the adjuvant phase

• The possibility to avoid chemotherapy in case of small T size, N0, HR+, elderly and frail patients is intriguing, but still matter of study