HER2 pos. Disease

Supportive care

Hans WildiersUniversity Hospitals Leuven

• HER2 pos. Disease– Adjuvant Trastuzumab:

• HERA (2y vs 1y)• Phare (6 mo vs 1y)• NSABP B-31 and NCCTG N9831 (1y vs nil)

– Metastatic Pertuzumab: Cleopatra – HER2 Translational

• Supportive care– MDS/AML after breast cancer– Neurocognitive impact of adjuvant chemotherapy– Bone

OBSERVATIONn=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 Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule

n=1703

2 years Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule

n=1701

After ASCO 2005, option of switch to Trastuzumab

HERA TRIAL UPDATE at 8 y FUP Accrual 2001 – 2005 (n=5102)

CT, chemotherapy; RT, radiotherapy

S5-2

Final analysis planned for 725 disease-free survival (DFS) events to obtain 80% power to detect a true hazard ratio of 0.80.

HER2 adjuvant

Dis

ease

-fre

e su

rviv

al (

%)

Years from randomization

89.1%

86.7%81.0%

81.6%75.8%

76.0%

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

100

80

60

40

20

00 1 2 3 4 5 6 7 8 9

No. at risk

Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194

Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205

Trastuzumab 1 year

Trastuzumab 2 years

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

2 years 1553 367 0.99 (0.85-1.14) 0.86

1 year 1552 367

S5-2HER2 adjuvant

Hormone receptor negative2.8% received endocrine therapy

Hormone receptor positive92.6% received endocrine therapy

Years from randomization

Dis

ea

se

-fre

e s

urv

iva

l (%

)

Trastuzumab 2 years

Trastuzumab 1 year

DFS BY HORMONE RECEPTOR STATUS AT 8 YRS MFU

No. at risk

Trastuzumab 2 years 798 798 747 710 673 642 597 544 321 97

Trastuzumab 1 year 790 790 736 691 663 634 617 559 337 106

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9

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

2 years 798 185 1.05 (0.85-1.29) 0.67

1 year 790 175

90.3%

89.6%

83.1%

82.9%

76.1%

77.2%

Years from randomization

Dis

ea

se

-fre

e s

urv

iva

l (%

)

Trastuzumab 2 years

Trastuzumab 1 year

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9

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

2 years 755 182 0.93 (0.76-1.14) 0.51

1 year 762 192

No. at risk

Trastuzumab 2 years 755 755 695 651 619 581 556 507 312 97

Trastuzumab 1 year 762 762 677 628 602 580 563 512 312 99

87.8%

83.8%

80.1%

78.9%

75.4%

74.7%

S5-2HER2 adjuvant

Ove

rall

Su

rviv

al (

%)

Years from randomizationNo. 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

00 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

S5-2HER2 adjuvant

Observation Trastuzumab Trastuzumab

Only 1 Year 2 Years

N=1744 N=1682 N=1673

≥ 1 grade 3 or 4 AE 8.2% 16.3% 20.4%

Secondary Cardiac1 0.9% 4.1% 7.2%

Primary Cardiac2 0.1% 0.8% 1.0%

Fatal adverse event 0.4% 1.1% 1.2%

ADVERSE EVENTS(SAFETY ANALYSIS POPULATION)

1 LVEF < 50% and ≥ 10% below baseline confirmed by repeat assessment, excluding patients with a primary cardiac endpoint.

2NYHA class III or IV, confirmed by a cardiologist, and LVEF < 50% and ≥ 10% below baseline, OR cardiac death.

S5-2HER2 adjuvant

Median follow-up(% follow-up time

after selective crossover)

No. of DFS events1 year trastuzumab

vs observation

127 vs 220P<0.0001

218 vs 321P<0.0001

369 vs 458P<0.0001

DFS benefit

Favours 1 year trastuzumab Favours observation0 1 2

HR (95% CI)

1 YEAR TRASTUZUMAB VS. OBSERVATION: DFS ITT ANALYSES

Extended from Gianni et al. Lancet Oncol. 2011.

2005(0%)

2006(4.3%)

2008(33.8%)

1 yr MFU

4 yrs MFU

2 yrs MFU

0.54

0.64

0.76

471 vs 570P<0.0001

2012(48.6%)

8 yrs MFU

0.76

S5-2HER2 adjuvant

Favours 1 year trastuzumab Favours observation0 1 2

HR (95% CI)

OS benefit

1 YEAR TRASTUZUMAB VS. OBSERVATION:OS ITT ANALYSES

Extended from Gianni et al. Lancet Oncol. 2011.

Median follow-up(% follow-up time

after selective crossover)

No. of deaths1 year trastuzumab

vs observation

29 vs 37P=0.26

59 vs 90P=0.0115

182 vs 213P=0.1087

2005(0%)

2006(4.1%)

2008(30.9%)

0.76

0.66

0.85

1 yr MFU

4 yrs MFU

2 yrs MFU

278 vs 350P=0.0005

2012(45.5%)

0.768 yrs MFU

S5-2HER2 adjuvant

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

adjuvant early breast cancer

Protocol of Herceptin®

Adjuvant withReduced Exposure

*lighthouse in French

Xavier Pivot, Gilles Romieu, Marc Debled, 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.

S5-3HER2 adjuvant

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

S5-3HER2 adjuvant

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

S5-3HER2 adjuvant

Treatment Characteristics

12 monthsn=1690

6 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 (2.03) 6.3 (1.46)

S5-3HER2 adjuvant

DFS Events

12 mos(n=1690)

6 mos(n=1690)

DFS Events (n=394) 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

S5-3HER2 adjuvant

0.00

0.25

0.50

0.75

1.00D

FS P

roba

bilit

y

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

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6m

HR (95% CI): 1.28 (1.05 - 1.56)

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%CI p-valueT 12m 176T 6m 219 1.28 (1.05 – 1.56) 0.29

S5-3HER2 adjuvant

Equivalent

Superior

Non Inferior

Inferior

A

B

C

D

E

.85 1 1.15 1.3 1.45 1.6

HR

Primary endpoint scenarios

PHARE trial

X Pivot et al, ESMO 2012, LBA5_PR

S5-3HER2 adjuvant

SubanalysisHR (95% CI)

ER and Chemotherapy modalities

1.57 (1.08 - 2.28)

1.25 (0.81 - 1.91)

1.10 (0.73 - 1.65)

1.23 (0.83 - 1.82)

1.28 (1.05 - 1.56)

ER - Sequential (676)

ER + Sequential (850)

ER - Concomitant (786)

ER + Concomitant (1118)

All patients (3380)

0 1.15 2 Favors 6 months Favors 12 months

S5-3HER2 adjuvant

Trastuzumab plus Adjuvant Chemotherapy for HER2-positive Breast Cancer:

Final Planned Joint Analysis of Overall Survival from NSABP B-31 and NCCTG N9831

San Antonio Breast Cancer Symposium – December 4-8, 2012 Abstract #S5-5

S5-5

Median follow-up: 8.4 years

Definitive survival analysis at 710 OS events

HER2 adjuvant

N9831/B-31 Disease-Free Survival

A P

AC P+H

N EventsAC→P 2018 680AC→P+H 2028 473

HRadj=0.60 (95% CI: 0.53-0.68) P<0.0001

62.2%

73.7%

64.9%

76.8%81.4%

San Antonio Breast Cancer Symposium, December 4-8, 2012S5-5HER2 adjuvant

B-31/N9831 Overall Survival

AC P87.0%

89.8%

79.4%84.3%

N EventsAC→P 2018 418AC→P+H 2028 286

90.3%

∆=2.9% ∆=5.5% ∆=7.6% ∆=8.8%

San Antonio Breast Cancer Symposium, December 4-8, 2012S5-5HER2 adjuvant

1. Baselga J, et al. SABCS 2011 (Abstract S5-5);2. Baselga J, et al. N Engl J Med 2012; 366: 109–119.

CLEOPATRA: update

* < 6 cycles allowed for unacceptable toxicity or PD; > 6 cycles allowed at investigator discretionHER2, human epidermal growth factor receptor 2; PD, progressive disease

Patients withHER2-positive MBCCentrally confirmed

(N = 808)

Placebo + trastuzumabn = 406

• Primary endpoint: Independently-assessed progression-free survival (PFS)

• Collection of tumor tissue (archival in >90%) and serum samples was mandatory

• 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

P5-18-26HER2 metastatic

CLEOPATRA: overall survival

22Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138D, docetaxel; 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

0Ptz + T + D

0Pla + T + D

Time (months)

Ove

rall

surv

ival

(%

)

45 50 55

0

0

9

4

33

22

84

67

143

128

230

198

317

285

342

324

371

350

387

383

402

406

89%

94%

1 year

2 years

69%

81% 3 years

66%

50%

Ptz + T + D: 113 events; median not reachedPla + T + D: 154 events; median 37.6 months

HR=0.6695% CI 0.52−0.84

p=0.0008

P5-18-26HER2 metastatic

CLEOPATRA: PFS

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

Time (months)

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

45 50

0

0

0

0

8

8

34

26

67

42

108

72

178

110

218

148

284

223

341

329

402

406

Ptz + T + D: median 18.7 monthsPla + T + D: median 12.4 months

HR=0.6995% CI 0.58−0.81

∆=6.3 months

n at risk

Ptz + T + D

Pla + T + D

P5-18-26HER2 metastatic

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Time (months)

Ptz + T + D <65 Pla + T + D <65Ptz + T + D ≥65 Pla + T + D ≥65

CLEOPATRA PFS according to age

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

24

P5-18-01HER2 metastatic

CLEOPATRA PFS according to age:Exposure to docetaxel treatment

<65 years ≥65 years

Placebo+ trastuzumab

+ docetaxel(n=332)

Pertuzumab+ trastuzumab

+ docetaxel(n=346)

Placebo+ trastuzumab

+ docetaxel(n=65)

Pertuzumab+ trastuzumab

+ docetaxel(n=61)

Median number of cycles administered (range)

8.0 (1−41) 8.0 (1−35) 6.5 (1−26) 6.0 (1−16)

Median dose intensity, mg/m2/week

24.8 24.5 24.8 24.8

Dose escalation to 100 mg/m2,n (%)

53 (16.0) 41 (11.8) 8 (12.3) 7 (11.5)

Dose reduction to <75 mg/m2,n (%)

72 (21.7) 85 (24.6) 17 (26.2) 19 (31.1)

25

P5-18-01HER2 metastatic

CLEOPATRA PFS according to age: Ten most common grade ≥3 adverse events overall

<65 years ≥65 years

n (%)

Placebo+ trastuzumab

+ docetaxel(n=332)

Pertuzumab+ trastuzumab

+ docetaxel(n=346)

Placebo+ trastuzumab

+ docetaxel(n=65)

Pertuzumab+ trastuzumab

+ docetaxel(n=61)

Neutropenia 156 (47.0) 174 (50.3) 26 (40.0) 25 (41.0)Leukopenia 51 (15.4) 44 (12.7) 7 (10.8) 6 (9.8)Febrile neutropenia 26 (7.8) 51 (14.7) 4 (6.2) 5 (8.2)Diarrhea 16 (4.8) 23 (6.6) 4 (6.2) 9 (14.8)Anemia 9 (2.7) 10 (2.9) 5 (7.7) 0 (0.0)Fatigue 9 (2.7) 7 (2.0) 4 (6.2) 2 (3.3)Peripheral neuropathy 6 (1.8) 6 (1.7) 1 (1.5) 5 (8.2)LVSD 8 (2.4) 4 (1.2) 3 (4.6) 1 (1.6)Asthenia 4 (1.2) 10 (2.9) 2 (3.1) 0 (0.0)Granulocytopenia 9 (2.7) 4 (1.2) 0 (0.0) 2 (3.3)

26LVSD, left ventricular systolic dysfunction

P5-18-01HER2 metastatic

The HER2 signalling pathway Selection of biomarkers

ER

Nucleus

c-myc

Raf

MEK 1/2

MAPK

Akt

GSK3 BAD

Cell-cycleprogression

PTEN

mTOR

p27

Cyclin D1, E

FKHR

Grb2 Sos

Cell survival

Ras

Shc SosGrb2

PI3K

Cell proliferation

Y

ER

HER2EGFR HER2 HER3IGF1R

YsHER2

HER ligands

(AREG, EGF, TGFα)

NO RESULTS(except HER2)

HER2 translational S5-7

• Neosphere: associaton between pCR and immune biomarkers S6-7

• Lapatinib decreases Ki67 by 27% in HER2 neg tumors in a ‘window of opportunity’ study (mainly if also high HER3 expression) PD07-07

• New techniques for HER2 determination – Next generation sequencing is highly concordant with FISH

for HER2, and uncovers actionable genomic alterations PD02-07

– MPLA PD02-03,

– RNA scope analysis PD02-04

– AQUA: predicts trastuzumab benefit in BCIRG-005/6

PD02-01

HER2 translational

Activating HER2 mutations in HER2 Gene Amplification Negative Breast Cancers

• HER2 mutations predominantly occur in HER2 gene amplification negative patients.

• The majority of HER2 mutations are activating events that cause oncogenic transformation, thus they are highly likely to be driver events in these breast cancers.

• Neratinib is a highly potent, irreversible pan-ErbB tyrosine kinase inhibitor for all of the HER2 mutations (clinical trial has been launched)

HER2 translational S5-6

MDS/AML after BC diagnosis• Previous reports:

– NSABP trials: 0,27% after AC at 8y if RT after lumpectomy or CSF use.

– An “environmental” cancer

AML/MDS S3-5

AML/MDS S3-5

Characteristics of Leukemia cohort

AML/MDS S3-5

Cumulative incidence of Leukemia

Chemo vs no chemo: HR 2,5 p0,007

AML/MDS S3-5

Conclusions

• Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of ~ 0.5%

• Almost half of the events occurred beyond year 5 • Radiation alone appears to be a risk factor, but may

not add much to patients already treated with chemotherapy

• Leukemia risk was not limited to MDS/AML, and cases of high risk lymphoid leukemia were observed

• This study highlights the challenges of studying infrequent but important clinical events

AML/MDS S3-5

Neurocognitive Impact in Adjuvant Chemotherapy for Breast Cancer Linked to

Fatigue: A Prospective Functional MRI Study

• Prospective non-randomized comparative trial

chemobrain

S6-3

n=28

n=37

n=32

• Frontal Brain Activation by group and time

chemobrain

S6-3

• Neurocognitive alterations in working memory processes and greater fatigue were evident before any adjuvant chemotherapy.

• Pre-adjuvant treatment brain alterations during working memory task predict severity of fatigue post-treatment.

• Greater fatigue across all groups was related to reduced cognitive function over time.

chemobrain S6-3Results and conclusion

Vitamin D, But Not Bone Turnover Markers, Predict Relapse In Women With Early Breast

Cancer: An AZURE Translational Study.

Bone S6-4

And 25HO VitD

Prognostic effectS6-4

only for 25HO VitD

Bone

Predictive effectS6-4

* CTX, PINP : ZOL benefit NOT predicted by higher bone turnover

* 25HO Vit D

Bone

• Population: 157 pts, 92% continued ZOLonly 37% received per label (q3-4w)

• SRE: - SRE rate 0,13 per person year during 18 month study (vs 0,13 in 18 months

before inclusion)- 83% SRE free at 18 months- persistent ZOL therapy per label ≈ lower SRE rate

(HR 0,26 p 0,009)

• Safety: - renal deterioration in 6 pts- No symptomatic hypoCa (but only 16% taking

supplements!)- Acute phase reactions 9,5%- ONJ in 7 pts (4,5%)

LOTUS trial: Prospective study of treatment pattern, effectiveness, and safety of Zoledronic acid (ZOL) beyond 2y:

subgroup analysis of pts with metastatic breast cancer.

S3-13-01Bone

• Neoadj FEC-paclitaxel +/- ZOL. PD07-05

– randomized trial (n= 182)– pCR 14,9 vs 7,9% (p 0,16)

– in postmenopauzal 18,4 vs 5,4% (p 0,15)

• iv ZOL vs po ibandronat PD09-07

– randomized trial (n=1405)– MBC with bone metastases– SRE rate per year lower for ZOL (0,44 vs 0,54, p 0,02)

BisphosphonatesBone

Conclusions HER2• HER2 adjuvant:

– HERA and NSABP B-31/NCCTG N9831 results at 8 yrs FUP show sustained and statistically significant DFS and OS benefit for 1 year trastuzumab versus observation in ITT analyses despite selective crossover. No benefit for extension to 2 years in HERA.

– PHARE failed to show that 6 months of trastuzumab is non inferior to 12 months. Subgroup analysis suggested that

• Sequential modality for ER negative tumors impacted the overall results.

• Results in other groups seemed compatible with non-inferiority hypothesis

– 1 year of trastuzumab remains the standard of care as adjuvant therapy for patients with HER2-positive early breast cancer.

• HER2 metastatic: – Addition of pertuzumab to trastuzumab and docetaxel improves OS

and PFS significantly in HER2-positive first-line without important toxicity aspects.

Conclusions supportive care

• Adjuvant chemotherapy is associated with a cumulative 10-year incidence of leukemia of ~ 0.5%

• Neurocognitive alterations in working memory processes and greater fatigue are present before any adjuvant chemotherapy.

• Low baseline VitD is associated with increased risk of bone and distant recurrence