targeting her family receptors in breast cancer prof. sabino de placido dip. di endocrinologia ed...

Targeting HER family receptors in breast cancer

Prof. Sabino De PlacidoDip. di Endocrinologia ed Oncologia Molecolare e Clinica

Università Federico II --- Napoli, Italia

Targeting HER2: Key points

HER2 gene amplification and/or overexpression occurs in about 20% of breast cancers and is associated with more-aggressive disease and, until the advent of HER2-targeted agents, a worse outcome

The monoclonal antibody, trastuzumab (which targets HER2), and the small molecule tyrosine kinase inhibitor, lapatinib (which targets HER1 and HER2), have considerable efficacy in HER2-positive breast cancer

Adjuvant SettingWhat we know

Trastuzumab has changed the natural history of early HER2+ BC

Incidence of MBC without Herceptin

Adjuvant Trastuzumab predicted to prevent recurrence in almost 28,000 patients over a 10-year period in the 5 major EU countries

Weisgerber-Kriegl et al, ASCO 2008

Patients,n

27,737

20,000

18,000

16,000

14,000

12,000

10,000

8000

6000

4000

2000

0

2000 2005 2010 2015

Herceptin introduced

No. of patients prevented from developing metastases

Year

More than 14.000 patients were recruited in 4 international clinical trials

Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006

NCCTG N9831 (USA)

HERA (ex-USA) BCIRG 006 (global)

NSABP B-31 (USA)

IHC / FISH (n=5,090)

Observation

1 year

2 years


1 year

1 year

FISH(n=3,222)

1 year

1 year


1 year

DocetaxelDocetaxel + carboplatin

Doxorubicin + cyclophosphamide TrastuzumabStandard CTx Paclitaxel

IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy

Neoadjuvant setting

What we know

Adjuvant setting

What we do not know

Small, node negative tumors are under represented in clinical trials

• Overall 7,164 pts. with pT1pN0 tumors – median follow-up 4.5 - 12.4 yrs.)

– 600 pts. with HER-2 + tumors

• % HER-2 + disease – ranging between 7 and 10%

• Absolute risks of distant relapse HER2+– 5 yrs. ± 10-15% – 10 yrs. 22-28%

• Increased risk of disease relapse if HER-2 +– hazard ratios ranging between 2.4 and 8.99

Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Results

Reviewed by Oakman C et al, Educational book – ESMO meeting, Milan – October 2010

• Caveats - heterogeneity in adjuvant therapies

- HRs status not always centrally revised- in 3 out of 7 studies pT1c tumors were eligible- only 2 out of 7 studies evaluate outcome by combination of

HER-2 and HRs status

• “Take-home” messages- there is a substantial degree of concordance in considering HER-2 + patients with pT1pN0 tumors at increased risk of relapse compared to the HER-2 negative population (2 to 9 fold increase)

Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Caveats and Conclusions

Reviewed by Oakman C et al, Educational book – ESMO meeting, Milan – October 2010

Key question

Is proportional benefit from adjuvant systemic therapies

dependent on disease stage ?

Potential options for adjuvant treatment of endocrine-resistant pT1b pN0 tumors

• Docetaxel-Cyclophosphamide (TC) x 4 + Trastuzumab*

(lack of phase III data)

• Docetaxel-Carboplatin-Trastuzumab (TCH) x 6

(BCIRG 006 data)

HER-2 +

* concomitant trastuzumab > sequential trastuzumab

Trastuzumab

Trastuzumab

Treatment decision: a multi-factorial process

Patient :

Co-morbidities

Age

Patient :

Expectations

Preferences

Tumor* :

Size

Vascular invasion

Ki-67

Treatment decision

Adjuvant setting

What we do not know

Duration of Trastuzumab

Adjuvant trials with different duration of trastuzumab administration

• HERA (PI M. Piccart): sample size ~34001

– 12 vs 24 months of H following adjuvant CT

• Phare (PI X. Pivot): sample size ~34002


• Persephone (UK-NCRI): sample size ~40003


• Hellenic Oncology Group (Greece): sample size 4784

– 6 vs 12 months of H with ddDoc after FEC

• SOLD (PI H. Joensuu): sample size ~30006

– HD 3-wkly x3 ->FE75C x3 vs – HD 3-wkly x3 ->FE75C x3 -> H 3-wkly x14

• ShortHER (PI PF. Conte): sample size ~12505

– D 3-wkly x3 + H weekly x 9 -> FE60C x3 vs– AC or EC x 4 -> HD or HP 3-wkly x4 -> H 3-wkly x14

Metastatic Disease

Overall Survival by Trastuzumab Treatment Groups

1.01.0

0.00.0

Ove

rall

Su

rviv

al P

rob

abil

ity

Ove

rall

Su

rviv

al P

rob

abil

ity

Months from DiagnosiMonths from Diagnosi

0.60.6

0.40.4

00 6060

0.20.2

0.80.8

1212 2424 48483636

Negative Negative No TrastuzumabNo TrastuzumabTrastuzumabTrastuzumab

HER2+ / Herceptin

HER2+ /

No Herceptin

HER2-

What we Know

The first line

HERNATA Study

HERNATA study : results

Time to Progression Overall Survival

Andersson JCO 2010

Time to Treatment Failure

HERNATA study: results

Andersson JCO 2010

HERNATA study : safety profile

Andersson JCO 2010

The second line

What we Know

Tyverb plus capecitabine: significantly longer TTP in difficult to treat population (EGF100151, independent assessment)

Cu

mu

lati

ve p

rog

ress

ion

-fre

e (%

)

Tyverb + capecitabineCapecitabine

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

p=0.00013

18.6 wks

(4.3 mos)

27.1 wks

(6.2 mos)

1. Cameron et al. Breast Cancer Res Treat 2008;[Epub ahead of print].Figure Adapted from Cameron D, Casey M, Press M et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat, 2008 Epub ahead of print, with kind permission of Springer Science and Business Media.

Beyond the second line

What we Know

Lapatinib in combination with trastuzumab significantly prolonged PFS compared with

lapatinib alone (EGF104900)

Lapatinib Lapatinib + trastuzumab

n=145 n=146

Progressed or died, n 128 127

Median, wks 8.1 12.0

HR (95% CI) 0.73 (0.57, 0.93)

p value 0.008

Subjects at risk:148

148

Lapatinib

Lapatinib + trastuzumab

53

73

21

42

13

27

5

8

0

2

6-month PFS

Cu

mu

lati

ve p

rog

ress

ion

-fre

e (%

)

13%

28%

0

20

40

60

80

100

0 10 20 30 40 50 60Time from randomisation (weeks)

Updated overall survival in ITT (EGF104900)

L n=145

L+T n=146

Died, n (%) 113 (78) 105 (72)

Median, months 9.5 14

Hazard ratio (95% CI) 0.74 (0.57, 0.97)

Log-rank p value .026

6 month OS

80%

70%

12 month OS

56%

41%

Cu

mu

lati

ve %

ali

ve w

ith

ou

t p

rog

ress

ion

Patients at risk148148

LL+T

121102

8865

6447

4328

2513

0

20

40

60

80

100

0 5 10 15 20 25

Time from randomization (months)

30 35

1

L+TL

Lapatinib effect on ErbB2 accumulation at cell membrane: novel mechanism for enhanced

effects of combined anti-ErbB2 therapy

Lapatinib has been shown to enhance antitumour effect of trastuzumab in vitro and in clinical studies

This study explored the mechanism for this effect by investigating impact of lapatinib and trastuzumab on receptor expression and signalling

Treatment:lapatinib,

trastuzumab, or both

ErbB2-positive BC cells (SKBR3 and MCF7-HER2)

In vitro assays:Receptor expression,

phosphorylation, signalling, tumour growth

Mouse xenograft

Scaltriti et al., J Clin Oncol ASCO Annual Meeting Proceedings 2008; 26(Suppl.): Abstract 3594 and poster

Scaltriti et al., Oncogene 2009; www.nature.com/onco

HER2+ and HR+

What we Know

HER2 and hormone receptor-positive BCClinical trials to assess therapy

Cortes Nat Rev Clin Oncol 2010

HER2 and hormone receptor-positive BC Clinical trials to assess therapy

Cortes Nat Rev Clin Oncol 2010

100

80

60

40

20

0

Ove

rall

resp

on

se r

ates

(%

)

TAnDEMEGF30008

Combination with Aromatase inhibitors

Combination with chemotherapy

H0648g M77001

Trastuzumab+

anastrozole

Lapatinib+

letrozole

Trastuzumab+

paclitaxel

Trastuzumab+

docetaxel

Drug regimen

Figure 1: Overall response rates in HER2-positive and hormone receptor-positive metastatic breast cancer. Anti-HER2 therapy was combined either with chemotherapy or aromatase inhibitors in four pivotal trials. The combination with chemotherapy showed higher overall response rates. 8.10-12

The Future

What else we Know

Trastuzumab + Pertuzumab

Copyrights for this presentation are held by the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011

35

Pertuzumab and trastuzumab have complementary mechanisms of action

ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain

HER2

Dimerizationdomain

Pertuzumab

HER1/3/4

Trastuzumab

Subdomain IV

Trastuzumab:

• Inhibits ligand-independent HER2 signaling

• Activates ADCC

• Prevents HER2 ECD shedding

Pertuzumab:

• Inhibits ligand-dependent HER2 dimerization and signaling

• Activates ADCC



36

MBC, metastatic breast cancer; PD, progressive disease

Patients withHER2-positive MBCcentrally confirmed

(N = 808)

Placebo + trastuzumabn=406

• Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)

• Study dosing q3w:− Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance− Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated

1:1

n=402

Docetaxel*≥6 cycles recommended

PD

Pertuzumab + trastuzumab

Docetaxel*≥6 cycles recommended

PD

* <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion

CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st-line setting



37

Primary endpoint: Independently assessed PFSn = 433 PFS events

D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

n at risk

402 345 267 139 83 32 10 0 0Ptz + T + D

406 311 209 93 42 17 7 0 0Pla + T + D

Time (months)

Ptz + T + D: median 18.5 months

Pla + T + D: median 12.4 months

HR = 0.6295% CI 0.51‒0.75

p<0.0001

∆ = 6.1 months

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Stratified by prior treatment status and region



38

Overall survival: Predefined interim analysisMedian follow-up: 19.3 months, n = 165 OS events

D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 40 45

0

10

20

30

40

50

60

70

80

90

100

n at risk

Pertuzumab + T + D 402 387 367 251 161 87 31 4 0 0

406 383 347 228 143 67 24 2 0 0Placebo + T + D

Time (months)

Ptz + T + D: 69 events

Pla + T + D: 96 events

HR = 0.64*95% CI 0.47‒0.88

p = 0.0053*

* The interim OS analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p ≤0.0012)

Ove

rall

surv

ival

(%

)



39

Cardiac tolerability

LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction

Placebo

+ trastuzumab + docetaxel(n = 397)

Pertuzumab+ trastuzumab + docetaxel

(n = 407)

Investigator-assessedsymptomatic LVSD*

1.8% 1.0%

Independently adjudicatedsymptomatic LVSD* 1.0% 1.0%

Fall in LVEF to <50% and by ≥10 percentage points from baseline

6.6% 3.8%

* LVSD was defined as NYHA class III/IV



40

Adverse events (all grades)≥25% incidence or ≥5% difference between arms

Adverse event, n (%)

Placebo+ trastuzumab + docetaxel

(n = 397)

Pertuzumab+ trastuzumab + docetaxel

(n = 407)

Diarrhea 184 (46.3) 272 (66.8)

Alopecia 240 (60.5) 248 (60.9)

Neutropenia 197 (49.6) 215 (52.8)

Nausea 165 (41.6) 172 (42.3)

Fatigue 146 (36.8) 153 (37.6)

Rash 96 (24.2) 137 (33.7)

Decreased appetite 105 (26.4) 119 (29.2)

Mucosal inflammation 79 (19.9) 113 (27.8)

Asthenia 120 (30.2) 106 (26.0)

Peripheral edema 119 (30.0) 94 (23.1)

Constipation 99 (24.9) 61 (15.0)

Febrile neutropenia 30 (7.6) 56 (13.8)

Dry skin 17 (4.3) 43 (10.6)



41

Summary and conclusions

• CLEOPATRA met its primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in PFS (HR = 0.62) in patients with HER2-positive MBC

– Median PFS increased by 6.1 months from 12.4 to 18.5 months– The PFS improvement was consistent across subgroups and

supported by the secondary endpoints of ORR and OS (immature)

• The combination of pertuzumab and trastuzumab plus docetaxel increased rates of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin

– These adverse events were primarily grades 1‒2, manageable, and occurred during docetaxel therapy

– There was no increase in cardiac adverse events or LVSD

• This new regimen may be practice-changing in HER2-positivefirst-line MBC

The Future

What else we Know

T-DM1

43

Monoclonal antibody: trastuzumab

Target expression: HER2

Highly potent chemotherapy(maytansine derivative)

Cytotoxic agent: DM1

Systemically stableBreaks down in target cancer cell

LinkerT-DM1

Trastuzumab emtansine (T-DM1): the first-in-class HER2-targeted antibody-drug

conjugate

44

• Randomized, phase II, international, open-label studyb

• Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval

• Primary end points: PFS by investigator assessment, and safety

• Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover

• Key secondary end points: OS, ORR, DOR, CBR, and QOL

Study DesignTDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab +

docetaxel in first-line HER2-positive MBC

1:1

HER2-positive, recurrent locally advanced breast cancer or MBC

(N=137)

Trastuzumab 8 mg/kg loading dose;

6 mg/kg q3w IV

+ Docetaxel 75 or 100 mg/m2 q3w

(n=70)

Crossover toT-DM1

(optional)PDa

T-DM13.6 mg/kg q3w IV

(n=67)PDa

aPatients were treated until PD or unacceptable toxicity.bThis was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred.

45

Time (months)

Progression-Free Survival by InvestigatorRandomized Patients

Pro

por

tion

prog

ress

ion

-fre

e

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8 10 12 14 16 18 20

Number of patients at risk

T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0

Hazard ratio and log-rank P value were from stratified analysis.

Trastuzumab + docetaxel (n=70)T-DM1 (n=67)

MedianPFS, mos

Hazard ratio 95% CI

Log-rank P value

9.214.2 0.594

0.364– 0.968

0.0353

46

Duration of objective response (months)

Duration of Response by InvestigatorPatients with Measurable Disease at Baseline with an Objective Response

Pro

por

tion

prog

ress

ion

-fre

e

Number of patients at risk

T+D 40 40 38 32 19 8 2 1 1 0T-DM1 43 41 38 33 27 19 12 6 3 0Kaplan-Meier estimates are shown. aNR, not reached; longer follow-up is needed to estimate the duration of response in the T-DM1 arm.

0 2 4 6 8 10 12 14 16 18

1.0

0.8

0.6

0.4

0.2

0.0

MedianDOR, mos 95% CI

9.5NRa

6.6–10.6–

Trastuzumab + docetaxel (n=40)T-DM1 (n=43)

47

Incidence of Nonhematologic Adverse Events: ≥30% (All Grade) and/or ≥5% (Grade ≥3) of Patientsa

Green represents those AEs with ≥20% difference between treatment arms.

aIn either treatment arm.bNo adverse events listed were grade 5.cTwo patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses.dIncludes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel.eNational Cancer Institute Common Terminology Criteria for Adverse Events v.3 only categorizes alopecia as grade 1 or grade 2; there is no grade ≥3 for this AE.

AE

All grade, n (%) Grade ≥3b, n (%)

Trastuzumab + docetaxel (n=66)c

T-DM1 (n=69)c,d

Trastuzumab + docetaxel (n=66)c

T-DM1 (n=69)c,d

Alopecia 44 (66.7) 3 (4.3) e e

Fatigue 30 (45.5) 34 (49.3) 3 (4.5) 3 (4.3)Nausea 29 (43.9) 33 (47.8) 0 2 (2.9)Diarrhea 30 (45.5) 11 (15.9) 2 (3.0) 0Peripheral edema 29 (43.9) 7 (10.1) 3 (4.5) 0Increased AST 4 (6.1) 27 (39.1) 0 6 (8.7)Pyrexia 15 (22.7) 27 (39.1) 1 (1.5) 0Headache 12 (18.2) 25 (36.2) 0 0Back pain 20 (30.3) 18 (26.1) 3 (4.5) 1 (1.4)Increased ALT 4 (6.1) 16 (23.2) 0 6 (8.7)Pneumonia 1 (1.5) 6 (8.7) 0 4 (5.8)

48

Cardiac Safety

• Cardiac function was assessed locally and centrally based on cardiac ECHO/MUGA

• Prior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectively

• Asymptomatic LV dysfunction

• There were no clinically significant cardiac events reported

LVEF assessmentTrastuzumab +

docetaxel T-DM1

Local assessment

Patients assessed 65 67

Patients with post-baseline LVEF ≤40% 2a 0

Central assessment

Patients assessed 60 65

Patients with post-baseline LVEF ≤40% 1b 0

aBoth patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting.

bThis patient did not receive prior treatment with an anthracycline.

49

Summary and Conclusions

•This is the first randomized study to evaluate an antibody-drug conjugate for HER2-positive MBC

•First-line treatment of HER2-positive MBC with T-DM1, compared with trastuzumab + docetaxel was associated with:

– A significant improvement in PFS (14.2 vs 9.2 mos; HR=0.594; P value=0.0353)

– Similar ORR but more durable responses (64.2%, median duration not reached vs. 58.0%, median duration 9.5 months)

– A lower rate of grade ≥3 AEs (46.4% vs 89.4%)

• These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index

– Improved PFS with T-DM1 may result from improved tolerability/duration of treatment/response and intrinsic potency of HER2-targeted DM1

•T-DM1 is being evaluated in phase III randomized clinical trials for HER2-positive MBC

• HER2-positive LABC or MBC (N=980)

• Previously received trastuzumab-based therapy

Lapatinib (1250 mg/day, days 1–21)

+ capecitabine (1000 mg/m2, days 1–14) q3w

T-DM1 (3.6 mg/kg) q3w

TDM4370g (EMILIA) Phase III Study: T-DM1 vs Capecitabine + Lapatinib in HER2-Positive MBC

• Multicenter, randomized, open-label study• Treatment continues until progressive disease/unacceptable toxicity• Primary end points: PFS by IRF, OS, 1-y and 2-y survival rates, Safety• Secondary end points: PFS by INV, ORR, CBR, DoR, QOL, TTF

www.clinicaltrials.gov. NCT00829166.

1:1

51

HER2-positive progressive or recurrent locally advanced BC or

previously untreated MBC(n=1092)

Trastuzumab + taxane(n=364)

T-DM1 + pertuzumab(n=364)

T-DM1 + placebo(n=364)

BC = breast cancer; MBC = metastatic breast cancer; PFS = progression-free survival

MARIANNE:

• Primary efficacy objective:

– PFS assessed by an independent review facility

• Primary safety objective:

– To compare the safety of T-DM1 + pertuzumab or T-DM1 + placebo vs trastuzumab + taxane

targeting her family receptors in breast cancer prof. sabino de placido dip. di endocrinologia ed...

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