esmo summit middle east 2018€¦ · mucositis/stomatitis 20 (1.7) 43 (3.7) .003 arthralgia/myalgia...

ESMO SUMMIT MIDDLE EAST 2018Current standards and practice changing studies in Early

Breast Cancer in 2017

Shaimaa Lasheen MD, MSc

Clinical Oncology department

Faculty of Medicine-Cairo University

6-7 April 2018, Dubai, UAE

CONFLICT OF INTEREST DISCLOSURE

No conflict of interest

CURRENT STANDARDS AND PRACTICE CHANGING

STUDIES IN EBC IN 2017

EBC

Her2+ BC

CTH + T

HR+ Her2-

ET +/- CTH

TNBC

CTH

•Established role of GEP in de-escalating cth

ESTABLISHED ROLE OF GEP IN DE-ESCALATING CTH

IN HR+ HER2- EBC

The majority of ER+/HER2- are “Good Tumors” Adjuvant endocrinal treatment alone is highly effective in patients

with N- /Luminal EBC

15

85

Recurrence

Disease free

IF 100 WOMEN WITH ER+, N- DISEASE ARE TREATED WITH 5 YEARS OF TAMOXIFEN

ALONE, ~ 15% WILL RECUR AT 10 YEARS

How many women with ER+, N- disease will benefit from the addition of chemotherapy?

ESTABLISHED ROLE OF GEP IN DE-ESCALATING CTH

IN HR+ HER2- EBC

Prospective data in low-risk patients

Prospective WSG Phase III PlanB trial: Clinical outcome at 5-year follow-up and impact of

21 Gene Recurrence Score® result, central/local-

pathological review of grade, ER, PR and Ki-67 in

HR+/HER2- high risk node-negative and -positive

breast cancer patients

Oleg Gluz, Ulrike Nitz, Matthias Christgen, Ronald E. Kates, Michael Clemens, Stefan Kraemer, Benno

Nuding, Bahriye Aktas, Sherko Kuemmel, Toralf Reimer, Fatemeh Lorenz-Salehi, Petra Krabisch, Marianne

Just, Doris Augustin, Cornelia Liedtke, Christer Svedman, Steven Shak, Rachel Wuerstlein, Hans H. Kreipe,

and Nadia Harbeck

PlanB: Design HER2-negative primary breast cancer

23.04.2018 7

▪ pT>2

▪ G2-3

▪ uPA/PAI-1↑

▪ HR-

▪ age <35 years

▪ Age<75 years

▪ free margins

▪ M0

▪ pN+

▪ pN0 high risk

R

A

N

D

O

MI

Z

A

TI

O

N

Doc75C600 x 6*

E90C600x4 Doc100 x4*

R

E

C

U

R

R

E

N

C

E

S

C

O

R

E

Endocrine therapy*0-3 LN and

RS<11

0-3 LN and

RS>11

or >/= 4 LN

HR+

HR-

• endocrine therapy and RT according to national guidelines

• E: Epirubcin; Doc: Docetaxel; C: Cyclophosphamid

PlanB: Five-year disease-free survival in

per-protocol population (n=2160)(no chemotherapy in pN0-1 RS 0-11)

23.04.2018WSG GmbH

8

5-Y DFS 94%

5-Y DFS 94%

5-Y DFS 84%

5-Y DFS 94%

5-Y DFS 95%

5-Y DFS 88%

94%

94%

84%N0 N1

PlanB trial (HR+/HER2- population;

5-year median follow-up): Conclusions I

23.04.2018WSG GmbH

9

▪ Excellent 5-year DFS (94%) in clinically high-risk patients (pN0 or pN1) with

RS <12 treated by endocrine therapy alone

▪ Overtreatment by chemotherapy likely in patients with RS 12-25 (pN0 or pN1)

)



EBC

Her2+ BC

CTH + T

HR+ Her2-

ET +/- CTH

TNBC

CTH


•Do all patients need anthracyclines??

ADJUVANT TC VS ECT IN HIGH-RISK HER2-NEGATIVE

EARLY BREAST CANCER:

BACKGROUND

Role of anthracycline-containing regimens for pts with early BC still debated

EBCTCG meta-analysis: reduced BC mortality with anthracycline + taxane regimens,

increased cardiac mortality with anthracyclines[1]

USOR 9735: superior DFS and OS with TC x 4 vs AC x 4[2]

ABC joint analysis: improved iDFS with taxane + AC regimens vs TC x 6[3]

PlanB: prospective, randomized, open-label phase III trial of TC vs ECT in HER2-

negative pts with early BC

Current analysis reports final 5-yr results[4]

1. EBCTCG, et al. Lancet. 2012;379:432-444. 2. Jones S, et al. J Clin Oncol. 2009;27:1177-1183. 3. Blum JL, et al. J Clin Oncol. 2017;[Epub ahead of print]. 4. Harbeck N, et al. ASCO 2017. Abstract 504.

PlanB: Design HER2-negative primary breast cancer

23.04.201812

▪ pT>2

▪ G2-3

▪ uPA/PAI-1↑

▪ HR-

▪ age <35 years

▪ Age<75 years

▪ free margins

▪ M0

▪ pN+

▪ pN0 high risk

R

A

N

D

O

MI

Z

A

TI

O

N

Doc75C600 x 6*

E90C600x4 Doc100 x4*

R

E

C

U

R

R

E

N

C

E

S

C

O

R

E

Endocrine therapy*0-3 LN and

RS<11

0-3 LN and

RS>11

or >/= 4 LN

HR+

HR-

• endocrine therapy and RT according to national guidelines

• E: Epirubcin; Doc: Docetaxel; C: Cyclophosphamid

(n = 1222)

(n = 1227)Primary endpoint: DFS, noninferiority : 4.4% Secondary endpoints: safety, OS

PlanB: Baseline Characteristics

Characteristic, n (%)TC

(n = 1222)

ECT

(n = 1227)

Surgery

▪ BCS

▪ Mastectomy

995 (81.6)

224 (18.4)

990 (80.8)

235 (19.2)

Triple negative (central) 214 (18.9) 211 (18.7)

HR+ (local) 1005 (82.2) 999 (81.4)

Recurrence score (HR+)

▪ ≤ 25

▪ > 25

703 (72.5)

266 (27.5)

710 (73.8)

252 (26.2)

Ki-67 (central, semiquantitative)

▪ 0-10

▪ 15-35

▪ ≥ 40

364 (33.5)

567 (52.1)

157 (14.4)

384 (35.4)

560 (51.6)

141 (13.0)

Characteristic, n (%)TC

(n = 1222)

ECT

(n = 1227)

Premenopausal 439 (39.2) 429 (37.8)

pN

▪ 0

▪ 1

▪ 2

▪ 3

727 (59.5)

404 (33.1)

72 (5.9)

19 (1.6)

714 (58.2)

428 (34.9)

63 (5.1)

22 (1.8)

pT

▪ 1

▪ 2

▪ 3

▪ 4

637 (52.3)

532 (43.6)

41 (3.4)

9 (0.7)

705 (57.6)

471 (38.4)

42 (3.4)

7 (0.6)

Grade

▪ 1-2 (central)

▪ 1-2 (local)

▪ 3 (central)

▪ 3 (local)

659 (56.0)

782 (64.2)

518 (44.0)

437 (35.8)

664 (56.3)

787 (64.2)

516 (43.7)

438 (35.8)

Data missing for some subgroups; discordance between

local/central labs.

Harbeck N, et al. ASCO 2017. Abstract 504.

PlanB: DFS

▪ Difference in DFS within margin of noninferiority from original trial design

HR

Favors ECTFavors TC

Subgroup

All pts

Recurrence score ≤ 25

Recurrence score > 25

pN0

pN1

pN2/3

Ki-67 0-10

Ki-67 15-35

Ki-67 > 40

Local grade 1/2

Local grade 3

Central grade 1/2

Central grade 3

Triple negative


Mos

DF

S (

%)

HR: 0.996

(95% CI: 0.77-1.29)

Pts at Risk, n

TC 90

ECT 90

5-Yr DFS, %

100

80

60

40

20

00 12 24 36 48 60 72

TC

ECT

1153

1128

1126

1105

1065

1051

1003

993

952

936

736

729

25

32

0.1 1.0 10

PlanB: OS

Slide credit: clinicaloptions.comHarbeck N, et al. ASCO 2017. Abstract 504. Reproduced with permission.

Mos

OS

(%

)

Pts at Risk, n

TC 95

ECT 95

5-Yr OS, %

100

80

60

40

20

00 12 24 36 48 60 72

TC

ECT

1153

11281137

1112

1087

10631032

1016

979

963

751

751

16

25

HR: 0.94

(95% CI: 0.66-1.35)

http://www.clinicaloptions.com/

PlanB: Safety

▪ Tx-related deaths (P = .2):

– TC: 5 (0.4%)

– ECT: 1 (0.1%)

– Due to infectious complications (n = 5); pulmonary embolism (n = 1)

▪ Dose reductions (P < .001):

– TC: 78 (6.6%)

– ECT: 230 (19.7%)

▪ Cycle delays > 7 days (P = .004)

– TC: 47 (4.0%)

– ECT: 78 (6.7%)

Slide credit: clinicaloptions.com

Grade 3/4 AE of Interest, n (%) TC (n = 1178) ECT (n = 1167) P Value

Leukopenia 598 (50.8) 671 (57.5) .001

Neutropenia 598 (50.8) 676 (57.9) .001

▪ Febrile neutropenia 63 (5.3) 45 (3.9) .09

Infection 82 (7.0) 62 (5.3) .1

Nausea 20 (1.7) 44 (3.8) .002

Vomiting 5 (0.4) 23 (2.0) < .001

Peripheral polyneuropathy 10 (0.8) 26 (2.2) .007

HFS/palmar syndrome 9 (0.8) 33 (2.8) < .001

Diarrhea 37 (3.1) 39 (3.3) .8

Mucositis/stomatitis 20 (1.7) 43 (3.7) .003

Arthralgia/myalgia 18 (1.5) 35 (3.0) .02

Pain 37 (3.1) 61 (5.2) .01

Cardiac failure 3 (0.3) 3 (0.3) 1.0

Fatigue 35 (3.0) 68 (5.8) .001


http://www.clinicaloptions.com/

PlanB: Conclusions

▪ In pts with clinically high-risk or genomically intermediate-/high-risk HER2-negative early BC, TC noninferior to ECT for DFS

– Similar 5-yr DFS and OS for TC vs ECT

– No subgroup-specific benefit with anthracycline-containing ECT

▪ Fewer grade 3/4 AEs, dose reductions/cycle delays with TC vs ECT

▪ Study investigators conclude 6 x TC represents effective CT option for HER2-negative early BC, evaluation of novel therapeutics needed in subgroup of pts with high-RS tumors




EBC

Her2+ BC

CTH + T

HR+ Her2-

ET +/- CTH

TNBC

CTH


•Do all patients need anthracyclines??

•Optimizing duration of adjuvant ET

WHAT IF YOUR PATIENT HAS JUST FINISHED

ADJUVANT ET FOR 5 YEARS AND SHE IS NED?

What Is The Risk of Recurrence

Following 5 Years of Adjuvant Tamoxifen?

Hongchao Pan et al , ASCO 2016

~55-60% T3-4/ N≥1055%

Hongchao Pan et al , ASCO 2016

MA.17: Trial Design

Eligibility criteria: postmenopausal, hormone receptor–positive/unknown, recurrence-free, completed 4.5-6 years’ tamoxifen, ECOG PS 0-2

Primary end point: DFS (ipsilateral, chest wall, local, metastatic, contralateral new)

Secondary end points: OS, rate of CBC, safety, QOL

Substudies: BMD/bone markers, lipid profile

EGOG = Eastern Cooperative Oncology Group; PS = performance status; DFS = disease-free survival; OS = overall survival; CBC = contralateral breast cancer; QOL = quality of life; BMD = bone mineral density.

Goss et al. J Natl Cancer Inst. 2005;97:1262.Goss et al. N Engl J Med. 2003;349:1793.

Randomization(all patients disease-free)

Tamoxifen

Approx. 5 years adjuvant 5 years extended adjuvant

0-3

months

Letrozole 2.5 mg qd (n=2582)

Placebo qd (n=2586)

MA.17: DFS—Letrozole Significantly Decreased Risk of Recurrence by 42%...At a median follow-up of 2.4 years

No. at risk (letrozole)

No. at risk (placebo)

2583

2587

2497

2489

1905

1874

1110

1075

541

519

176

164

6

8

Goss et al. Proc Am Soc Clin Oncol. 2004;23:87. Abstract 847 and oral presentation.

Goss et al. J Natl Cancer Inst. 2005;97:1262.

HR 0.58; P<0.001

Letrozole Placebo

0

20

40

60

80

100

Months from randomization

0 10 20 30 40 50 60

% o

f p

atie

nts

MA.17: 4-Year DFS*—All Patients and By Nodal Status At a median follow-up of 2.4 years

Letrozole

(n=2582)

Placebo

(n=2586) Abs. Difference

Estimated 4-y DFS (total

population)

94.4 89.8 4.6%

(P<0.001)

4-y DFS/N- 95.9 93.5 2.4%

4-y DFS/N+ 92.7 85.2 7.5%

Update of Goss et al. Proc Am Soc Clin Oncol. 2004;23:87. Abstract 847.

Goss et al. J Natl Cancer Inst. 2005;97:1262.

*Study powered to show a 2.5% improvement in the estimated risk of relapse at 4-year (9.5% to 12%)

48% reduction of the risk for relapse

MA.17

On the basis of these findings, postmenopausal women with hormone-receptor–positive tumors who have completed about five years of adjuvant tamoxifen therapy should be considered for letrozole treatment

These results, which necessitated the discontinuation of the study ( at a median follow-up period of 30 months), have left the optimal duration of treatment undefined and the question of long-term toxicity unanswered

– Increasing Benefit of Letrozole With Longer Duration of Treatment has been strongly suggested

Goss et al. N Engl J Med. 2003;349:1793.

EXTENDED ADJUVANT AI

Gnant, SABCS 2017



EBC

Her2+ BC

CTH + T

HR+ Her2-

ET +/- CTH

TNBC

CTH

• Is the verdict out for optimal duration

of adjuvant Trastuzumab??

ADJUVANT TRASTUZUMAB

➢ One year of TRASTUZUMAB is the standard of care, according to international guidelines

▪ The One year duration was chosen on arbitrary basis ( a round figure assumption) , rather than a previously confirmed optimal duration

➢ One year of adjuvant TRASTUZUMAB is associated with :

▪ Reduction of the risk of relapse by 25% - 40%

▪ Reduction of the risk of death by 25%-35%

TRIALS EXPLORING TRASTUZUMAB DURATION IN

THE ADJUVANT SETTING

• PHARE : 1y vs 6 months

• SOLD: 1y vs 9 weeks

• ShortHER : 1y vs 9 weeks

• PERSEPHONE : 1y vs 6 months (ongoing)

N =13000

Trastuzumab 6 months

Trastuzumab up to 12 months

stop trastuzumab

Clinical examLVEF

3 6 9 12 15 18 21 24 30 mos

…0

R

R: Randomization after informed consent

Stratification1. ER pos / neg

2. Chemo: conco/ seq

Xavier Pivot et al SABCS 2012.

PHARE Trial

Study design

No restaging at the

time of randomization

0.00

0.25

0.50

0.75

1.00

DFS P

roba

bility

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-value

T 12m 176

T 6m 219 1.28 (1.05 – 1.56) 0.29


Conclusion : subgroup analysisHR (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

Pivot X, et al. Cancer Res. 2012;72(24 Suppl.): Abstract nr S5-3.

Trastuzumab 12 months Trastuzumab 6 months

Events N DFS-3 Events N DFS-3

Sequential 84 729 0.904 117 747 0.857

Concomitant 91 961 0.907 102 943 0.896

0.00

0.25

0.50

0.75

1.00

DFS

Prob

abili

ty

943 894 748 454 217 4T-6m961 922 774 478 220 1T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mConcomitant

HR = 1.15 : 95%CI: (0.88 - 1.53), p=0.32

0.00

0.25

0.50

0.75

1.00

DFS

Prob

abili

ty

747 692 605 485 309 19T-6m729 691 616 502 324 17T-12m

Trastuzumab

0 12 24 36 48 60Months

T-12m T-6mSequential

HR = 1.41 : 95%CI: (1.06 - 1.86), p=0.016

Sequential ConcomitantDefinitely

inferior

Definitely

non-inferior


Please remember concomitant T is the way it should be!!

A randomized phase III study of adjuvanttrastuzumab for a duration of 9 weeks versus 1 year,

combined with adjuvant taxane-anthracyclinechemotherapy, for early HER2-positive breast cancer

H Joensuu, J Fraser, H Wildiers, R Huovinen, P Auvinen, M Utriainen, P Nyandoto, KK Villman, P Halonen, H Granstam-Björneklett, L Lundgren, T Turpeenniemi-Hujanen, J Yachnin, D Ritchie, T Huttunen, R Paridaens, P Canney, VJ Harvey, PL Kellokumpu-Lehtinen, H

Lindman

San Antonio Breast Cancer Symposium – December 5-9, 2017

Joensuu, et al SABCS,2017

The Synergism Or Long Duration (SOLD) trial

FBCG

F600E75C600 iv 3-wkly

RANDOMIZE

T for 9 wks*

SOLD design

In both groups:

• Locoregional RT given according to theinstitutional practice

• Endocrine therapy for a minimum of 5 yrs when cancer ER/PR +ve

T for 9 wks*

T to complete 1 year of administration**

**14 times 3-weekly, either iv or sc

Docetaxel (D) 80/100mg/m2 iv 3-wkly Trastuzumab

(T)

*Wkly iv, or 3-wkly either iv or sc

D D D

D

FEC

FEC

D D

FEC

FEC

FEC

FEC

Joensuu, et al SABCS,2017

Disease-free survival

HR 1.39 (90% CI 1.12-1.72)

Non-inferiority could not be demonstrated

(%)

Disease free

1 year

9 weeks

90.5%*

88.0%*

. Joensuu, et al SABCS 2017

Non-inferiority margin 1.385

SOLD trial

Distant disease-free survival

without distant

recurrence (%)

HR 1.24 (90% CI 0.93-1.65)

94.2%*

93.2%*

1 year

9 weeks


SOLD trial

Overall survival

1 year

9 weeks

*5-year survival estimate

HR 1.36 (90% CI 0.98-1.89)

Proportion

alive (%)

95.9%*

94.7%*

Years

SOLD trial

DFS: Docetaxel dose 100 mg/m2

Years

Proportion alive

without recurrence

(%)

HR 0.71 (90% CI 0.44-1.14)

92.2%*

87.8%*

1 year

9 weeks


SOLD trial

DFS: Docetaxel dose 80 mg/m2

Years

Proportion alive

without recurrence

(%)

HR 1.66 (90% CI 1.30-2.11)

91.3%*

86.8%*

1 year

9 weeks


SOLD trial

Cardiac safety

Less cardiac toxicity was observed in the 9-week group

Event 9-week groupn (%)

1-year groupn (%)

Any protocol-defined cardiac adverse event*

22 (2.0) 42 (3.9)*

Congestive heart failure 21 (1.9) 36 (3.3)**

*Any Gr. 3 or 4 cardiac event; symptomatic cardiac failure; cardiac failure requiring medical

management; LVEF decrease >10 percentage points and to a value <50%; LVEF decrease to <45%

from any baseline value

*P = 0.012

**P = 0.046


9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: results of the phase III multicentric Italian Short-HER study

Presented By Pier Conte at 2017 ASCO Annual Meeting

Short-HER: Study Design


Total planned amount of chemotherapy and trastuzumab in the two treatment arms

Conte et al ASCO 2017

100% higher dose of Epirubicin and 33% higher dose of Docetaxel were given in patient

receiving 1 year of T versus 9 weeks

Short-HER: Disease Free Survival


DFS – Subgroup analysis


PFS Subgroup analysis



EBC

Her2+ BC

CTH + T

HR+ Her2-

ET +/- CTH

TNBC

CTH

• Is the verdict out for shorter duration

of adjuvant Trastuzumab??

•Do we need more Her2 blockade??

APHINITY (BO25126): Phase III adjuvant study

CCOD, clinical cut-off date; DRFI, distant relapse-free interval; FPI, first patient in; LN, lymph node; LPI, last patient in; RFI, relapse-free interval.

von Minckwitz G, et al. N Engl J Med 2017 (Epub ahead of print);www.clinicaltrials.gov/ct2/show/NCT01358877.

• Primary endpoint: IDFS • Secondary endpoints: IDFS with second non-breast primary

cancers included, DFS, OS, RFI, DRFI, safety and HRQoL• Stratification factors: Chemotherapy regimen, HR status, nodal

status, geographic region, Protocol version (A vs. B)

Chemotherapy* + Herceptin + Placebo

Chemotherapy* + Herceptin + Pertuzumab

Randomisation and treatmentwithin 8 weeks

of surgery

Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)

Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

Central confirmation

of HER2 status(N = 4805 )

FOLLOW-UP

10

YEARS

R

S

U

R

G

E

R

Y

* Standard anthracycline or non-anthracycline (TCH) regimens were allowed

Timelines:• FPI 8 Nov 2011; LPI 31 Aug 2013• Protocol Amendment B (Nov 2012): Capped LN-negative

enrolment, increased target sample size from 3800 to 4800• Primary Analysis at 379 IDFS events (CCOD is 19 Dec 2016)

Baseline characteristics by stratification factors

* Protocol A only von Minckwitz G, et al. N Engl J Med 2017 (Epub ahead of print).

Pertuzumab–Herceptinn = 2400

Placebo–Herceptinn = 2404

Nodal status, n (%)0 positive nodes and T ≤1 cm*0 positive nodes and T >1 cm*1–3 positive nodes≥ 4 positive nodes

90 (3.8)807 (33.6)907 (37.8)596 (24.8)

84 (3.5)818 (34.0)900 (37.4)602 (25.0)

Adjuvant chemotherapy regimen (randomised), n (%)Anthracycline-containing regimenNon-anthracycline-containing regimen

1865 (77.7)535 (22.3)

1877 (78.1)527 (21.9)

Hormone receptor status (central), n (%)Negative (ER- and PR-negative)Positive (ER- and/or PR-positive)

864 (36.0)1536 (64.0)

858 (35.7)1546 (64.3)

Protocol version, n (%)Protocol AProtocol Amendment B

1828 (76.2)572 (23.8)

1827 (76.0)577 (24.0)

Primary analysis: IDFS

Stratification factors are: nodal status and protocol version, intended adjuvant chemotherapy and central hormone receptor status* The p value shown in this table is based on stratification factor data taken from the eCRF. In a sensitivity analysis based on stratification factor data from the IxRS system (FDA Preferred Analysis), the p-value from stratified log-rank rest was 0.0471. Hazard ratio was estimated by Cox regression.

von Minckwitz G, et al. N Engl J Med 2017 (and supplementary information;

Epub ahead of print).

No. of patients at risk

2400 2309 2275 2236 2199 2153 2101 1687 879

2404 2335 2312 2274 2215 2168 2108 1674 866

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n e

ven

t-fr

ee

0 6 12 18 24 30 36 42 48Time (months)

93.2%94.1%

3 years

95.7%96.4%

98.8%98.6%

90.6%92.3%

4 years

1 year2 years

IDFSPertuzumab–

Herceptin (n = 2400)

Placebo–Herceptin(n = 2404)

Events, n (%) 171 (7.1) 210 (8.7)

Stratified HR (95% CI) 0.81 (0.66, 1.00)

p value 0.0446*

Median FU, months 45.4

APHINITY met the primary efficacy objective, IDFS, with a 19% reduction of the risk of an IDFS event with Pertuzumab–Herceptin vs. Herceptin (HR 0.81; 95% CI 0.66–1.00; p =

0.0446)

IDFS results: Lymph node-positive subgroup

Hazard ratios were estimated by Cox regression. von Minckwitz G, et al. N Engl J Med 2017 (Epub ahead of print).

Pertuzumab–Herceptin (n = 1503)


Events, n (%) 139 (9.2) 181 (12.1)

Unstratified HR (95% CI) 0.77 (0.62, 0.96)

p value 0.0188



1503 1444 1419 1387 1358 1327 1283 912 423

1502 1453 1439 1408 1359 1319 1264 882 405

0 6 12 18 24 30 36 42 48Time (months)

90.2%

92.0%

3 years 4 years

86.7%

89.9%

Pro

po

rtio

n e

ven

t-fr

ee

0.8

0.6

0.4

0.2

0.0

1.0

93.7%

94.9%

98.2%

98.1%1 year 2 years

Patients with node-positive disease, a clinically high-risk subgroup, showed a clear benefit with

Pertuzumab-Herceptin (HR = 0.77)


897 865 856 849 841 826 818 775 456

902 882 873 866 856 849 844 792 461

IDFS results: Lymph node-negative subgroup




Events, n (%) 32 (3.6) 29 (3.2)


p value 0.6436


98.4%

97.5%

3 years 4 years

96.7%

96.2%99.0%

99.1%

99.5%

99.7%

1 year 2 years

0 6 12 18 24 30 36 42 48Time (months)

Pro

po

rtio

n e

ven

t-fr

ee

0.8

0.6

0.4

0.2

0.0

1.0

In this relatively low risk subgroup with node-negative disease, HR was 1.13; however fewer than 4% of patients

experienced an IDFS event, making the confidence intervals

very wide

IDFS results: HR-negative subgroup


91.2%

92.8%

3 years4 years

88.7%

91.0%



Events, n (%) 71 (8.2) 91 (10.6)


p value 0.0847

93.7%

96.2%

97.9%

98.1%

1 year 2 years

Pro

po

rtio

n e

ven

t-fr

ee

0.8

0.6

0.4

0.2

0.0

1.0

Time (months)0 6 12 18 24 30 36 42 48


864 836 821 813 797 774 755 600 314

858 827 811 793 771 758 730 569 302

The HR-negative patients, also a high risk subgroup, showed a marked

benefit from treatment with Pertuzumab–Herceptin (HR = 0.76)

Longer follow-up will likely confirm the benefit in this subgroup

IDFS results: HR-positive subgroup1

Hazard ratios were estimated by Cox regression.1. von Minckwitz G, et al. N Engl J Med 2017 (Epub ahead of print);

2. Slamon D, et al. N Engl J Med 2011; 3. Romond E, et al. SABCS 2012.



Events, n (%) 100 (6.5) 119 (7.7)


p value 0.2771

94.4%

94.8%

3 years 4 years

91.6%

93.0%96.8%

96.5%

99.3%

98.9%

1 year2 years

In the hormone receptor-positive subgroup, the HR is 0.86, consistent

with the ITT analysis.KM separation starts later

(at ~4 years) reflecting the known biology and recurrence pattern

of HR-positive BC2,3

Pro

po

rtio

n e

ven

t-fr

ee

0.8

0.6

0.4

0.2

0.0

1.0

Time (months)0 6 12 18 24 30 36 42 48


1536 1473 1454 1423 1402 1379 1346 1087 565

1546 1508 1501 1481 1444 1410 1378 1105 564

Secondary efficacy endpoints

A testing hierarchy was used to control the overall type I error rate of the secondary endpoints at 5%.* First OS IA at 26% of the target events for the final OS analysis† DFRI not included in the hierarchical testing procedureAnalyses were based on the ITT population.DRFI, distant recurrence-free interval

von Minckwitz G, et al. ASCO 2017 (Abstract LBA500 & oral presentation);von Minckwitz G, et al. N Engl J Med 2017 (and supplementary information; Epub ahead of print).

3-year absolute rates



Hazard ratio (95% CI) p value

IDFS (primary endpoint), % 94.1 93.2 0.81 (0.66, 1.00) 0.0446

Key secondary efficacy endpoints, %

IDFS incl. second primary non-BC events (STEEP definition)

93.5 92.5 0.82 (0.68, 0.99) 0.0403

DFS 93.4 92.3 0.81 (0.67, 0.98) 0.0327

OS (first interim analysis)* 97.7 97.7 0.89 (0.66, 1.21) 0.467

DRFI† 95.7 95.1 0.82 (0.64, 1.04) 0.101

Pertuzumab–Herceptin demonstrated a significant IDFS (STEEP definition) and DFS benefit over Herceptin

The first interim analysis of OS is immature (hierarchical testing procedure)

Cardiac toxicity (1)

* Reported reasons for cardiac deaths in the Herceptin arm: acute myocardial infarction (AMI) and heart failure (HF); in the Pertuzumab–Herceptin arm: cardiogenic shock and mitral valve disease** Asymptomatic or mildly symptomatic (NYHA II) significant drop in LVEF confirmed within approximately 3 weeks or as confirmed by CAB and only counted for patients who did not have a primary cardiac event. Note: Secondary cardiac events only counted for patients with no primary cardiac eventCAB, Cardiac Advisory Board; HF, heart failure; NYHA, New York Heart Association

von Minckwitz G, et al. ASCO 2017 (Abstract LBA500 & oral presentation);

von Minckwitz G, et al. N Engl J Med 2017 (Epub ahead of print).

Note: Only one death due to heart failure occurred in the Herceptin arm


Pertuzumab–Herceptin vs. placebo–Herceptin

(95% CI)


Primary cardiac, n (%)Heart failure NYHA III/IV + LVEF drop

Recovered according to LVEFCardiac death*

17 (0.7)15 (0.6)

72 (0.08)

0.4 (0.0, 0.8) 8 (0.3)6 (0.2)

42 (0.08)

Secondary cardiac**Identified from LVEF assessments

Identified by CAB

64 (2.7)50 (2.1)14 (0.6)

-0.1 (-1.0, 0.9) 67 (2.8)47 (2.0)20 (0.8)

Low incidence of HF NYHA III/IV and significant LVEF decline in both armsIncidence of heart failure was numerically higher in the PH arm

Cardiac toxicity (2)

* Recovered according to Investigator = outcome of ‘resolved’ in eCRF† Recovered according to LVEF = 2 consecutive LVEF assessments where the LVEF is >50%‡ Three patients included in the safety population were excluded from the outputs of safety by chemotherapy since they did not receive any carboplatineCRF, electronic case report form

von Minckwitz G, et al. N Engl J Med 2017 (Epub ahead of print); Roche. Data on file.

Patients, n (%)Pertuzumab–Herceptin

n = 2364Placebo–Herceptin

n = 2405

HF NYHA III/IV + LVEF drop 15 (0.6) 6 (0.2)

Recovered according to either Investigator or LVEF *†

10 6

Events by chemo regimen, n (%)Anthracycline

n = 1834

TCH‡

n = 528

Anthracyclinen = 1894

TCH‡

n = 510

HF Event (NYHA III/IV) 13 (0.7) 2 (0.4) 5 (0.3) 1 (0.2)

Recovered according to either Investigator or LVEF *†

7 2 3 1

HF was reversible, with the majority of patients recovering in both armsHeart failure was more common on anthracycline chemotherapy



EBC

Her2+ BC

CTH + T

HR+ Her2-

ET +/- CTH

TNBC

CTH

•More intense NACT

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib

for Early TNBC: Background

▪ Achieving pCR with neoadjuvant therapy correlates with improved EFS and OS in TNBC vs pts with residual disease[1]

▪ Veliparib: potent, orally available PARP 1/2 inhibitor

– Preclinical evidence for increasing chemotherapy antitumor activity[2]

▪ I-SPY2 pilot study suggested high probability for successful phase III trial of veliparib + carboplatin added to weekly T AC as neoadjuvant therapy in TNBC[3]

▪ Current phase III study evaluated addition of carboplatin ± veliparib to neoadjuvant T AC in early stage TNBC, with particular interest in veliparibcontribution to increased pCR rate[4]

1. Cortazar P, et al. Lancet. 2014;384:164-172. 2. Donowho CK, et al. Clin Cancer Res. 2007;13:2728-

2737. 3. Rugo HS, et al. N Engl J Med. 2016;375:23-34. 4. Geyer CE, et al. ASCO 2017. Abstract 520.

Neoadjuvant Chemotherapy + Carboplatin ±

Veliparib for Early TNBC: Phase III Study Design

▪ Primary objectives: pCR in breast and ipsilateral axillary nodes (ypT0/Tis, pN0)

▪ Secondary objectives: conversion to BCS eligibility, EFS, OS, safety

▪ Tertiary objectives: clinical response rate at Wk 12, pCR + MRD, QoL

Previously untreated

women with

resectable

stage II-IIIA TNBC

with documented

gBRCA testing

(N = 634)

Veliparib + Carboplatin + Paclitaxel

(n = 316)

Placebo + Carboplatin + Paclitaxel

(n = 160)

Placebo + Placebo + Paclitaxel

(n = 158)

Geyer CE, et al. ASCO 2017. Abstract 520.

Doxorubicin +

Cyclophosphamide

(4 cycles)

Stratified by BRCA status (mut vs no mut vs unknown),

node stage (N0 vs N1-2), AC schedule (Q2W vs Q3W)

Veliparib 50 mg PO BID; carboplatin AUC 6 mg/mL Q3W;

paclitaxel 80 mg/m2 Q1W.

12 weeks

Surgery


Veliparib for Early TNBC: Pt Characteristics

Characteristic Veliparib + Carboplatin +

T AC

(n = 316)

Carboplatin +

T AC

(n = 160)

T AC

(n = 158)

Median age (range), yrs

▪ > 50 yrs, %

51.0 (26-79)

52.2

49.0 (23-76)

45.6

50.0 (22-75)

48.7

Deleterious gBRCA mutation, % 14.2 15.6 14.6

Tumor stage, %

▪ T1

▪ T2

▪ T3-T4a

11.7

72.5

15.8

12.5

66.9

20.6

9.5

74.1

16.5

Lymph node stage N0/N1-N2, % 57.0/43.0 57.5/42.5 59.5/40.5

Planned AC schedule Q2W/Q3W, % 54.7/44.3 55.0/43.8 56.3/43.7

Longest tumor diameter > 30 mm, % 54.1 55.6 50.0


Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for

Early TNBC: Efficacy

Geyer CE, et al. ASCO 2017. Abstract 520. Reproduced with permission.

V + Cb

+ T → AC

(n = 316)

Cb + T → AC

(n = 160)

T → AC

(n = 158)

Pts

(%

)

100

75

50

25

0

pCR

53.2 31.0

P < .001

P = .357

57.5

V + Cb

+ T → AC

(n = 316)

Cb + T → AC

(n = 160)

T → AC

(n = 158)

Pts

(%

)

100

75

50

25

0

Rate of Clinical Response

83.4 55.7

P < .001

P = .961

83.3

V + Cb

+ T → AC

(n = 73)

Cb + T → AC

(n = 34)

T → AC

(n = 34)

Pts

(%

)

100

75

50

25

0

Rate of Intent for BCS

61.6 44.1

P = .139

P = .132

44.1

V + Cb

+ T → AC

(n = 268)

Cb + T → AC

(n = 140)

T → AC

(n = 125)P

ts (

%)

100

75

50

25

0

Rate of MRD

68.3 47.2

P < .001

P = .739

70.0


Veliparib for Early TNBC: pCR by Subgroup

Geyer CE, et al. ASCO 2017. Abstract 520. Reproduced with permission.

Risk Difference (95% CI)

-50 -40-30-20-10 0 10 20 30 40 50


-4.34 (-13.8 to 5.1)

6.52 (-18.1 to 31.1)

-6.23 (-16.4 to 4.0)

-1.15 (-13.7 to 11.4)

-8.39 (-22.5 to 5.7)

-0.50 (-13.2 to 12.2)

-9.15 (-23.3 to 5.0)

Favors V + Cb + T → ACFavors Cb + T → AC

All Pts

BRCA1 and/or BRCA2 mutation

No mutation in BRCA1 or BRCA2

N0

N1-2

Q2W

Q3W

Lymph node stage

AC dose


-50 -40-30-20-10 0 10 20 30 40 50


22.15 (13.1 to 31.2)

15.61 (-9.4 to 40.7)

23.18 (13.5 to 32.9)

27.96 (15.8 to 40.2)

15.09 (1.7 to 28.5)

25.00 (12.9 to 37.1)

18.57 (4.9 to 32.2)

Favors V + Cb + T → ACFavors T → AC

All Pts

BRCA1 and/or BRCA2 mutation

No mutation in BRCA1 or BRCA2

N0

N1-2

Q2W

Q3W

Lymph node stage

AC dose


Veliparib for Early TNBC: TEAEs


TEAE in ≥ 10% of

pts in any arm during T

tx segment, %

Veliparib + Carboplatin +

T AC (n = 313)

Carboplatin +

T AC (n = 158)

T AC

(n = 157)

Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4

Neutropenia 70.0 57.2 61.4 53.2 9.5 2.5

Anemia 61.0 24.6 69.6 17.1 10.8 0

Thrombocytopenia 47.9 10.5 37.3 6.3 0 0

Leukopenia 12.8 4.2 15.9 5.1 3.8 0.6

Nausea 60.4 1.3 62.0 0 28.7 0

Diarrhea 32.3 1.9 26.0 1.3 26.1 0

Vomiting 20.1 1.3 28.4 0.6 5.1 0

Stomatitis 19.5 0 14.6 1.3 9.5 0.6

Fatigue 51.8 1.3 52.6 1.3 42.7 0

Peripheral neuropathy 37.7 1.0 40.5 0 40.1 2.5

Myalgia 18.5 0 16.5 0 17.8 0

Arthralgia 10.2 0.6 10.1 0 17.8 0

Hem

eG

IO

ther

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib

for Early TNBC: Conclusions

▪ Veliparib + carboplatin + T AC significantly increased pCR rate over T AC alone (53.2% vs 31.0%; P < .0001)

▪ Addition of veliparib did not increase pCR rate over carboplatin + T AC (53.2% vs 57.5%; P = .36)

– pCR improvement likely due to carboplatin, without additional benefit with veliparib

▪ Some toxicities, including hematologic and GI, increased with carboplatin addition

– Carboplatin use increased T dose reductions and administration time


CARBOPLATIN IN TNBC (Neoadjuvant)

Trial Type n Drugs Population pCR

DFCI1 Single arm Ph 2 21 CDDP x 4 TNBC 21%

DFCI2 Single arm Ph 2 51 CDDP+bev TNBC 15%

GeparSixto Randomized

Ph 3

165 PM/bev

PMCb/bev

TNBC (subset) 38%

59%

CALGB 40603 Randomized

Ph 2

455 T-AC(bev)

T/carbo-

AC(bev)

TNBC 41%

54%

Unselected TNBC

Silver et al, JCO’12; Ryan et al, ASCO’09; Byrski et al, JCO’10; Alba et al, BCRT’12; von Minckwitz et al, ASCO’13 ; Telli et al, ASCO’13; Sikov et al, SABCS’13

CREATE-X: STUDY DESIGN

CREATE-X: 5-YR EFFICACY

Capecitabine achieved significantly higher 5-yr DFS and OS in HER2- BC pts with

residual disease

Outcome, %Capecitabine

(n = 440)

No Capecitabine

(n = 445)

HR

(95% CI)P Value

5-yr DFS 74.1 67.70.70

(0.53-0.93).00524

5-yr OS 89.2 83.90.60

(0.40-0.92)< .01

Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X: 5-YR EFFICACY

Masuda, et al. NEJM,2017.

TAKE HOME MESSAGEIn HR+ Her2- BC:

➢ GEP has established it’s role in omitting chemotherapy in low/Intermediate risk patients.

➢ Some patients can be safely spared adjuvant anthracyclines.

➢ Duration of extended adjuvant hormonal treatment…5 years is not a must

In Her2 positive BC:

➢ One year adjuvant Trastuzummab remains the standard of care…The verdict is not out yet

for shorter durations of adjuvant Trastuzumab

➢ Adjuvant Trastuzumab/Pertuzumab dual blockade improves iDFS especially in N+ patients

In TNBC

➢ The addition of Carboplatin to NACT significantly improves PCR rates.

➢ In TNBC pts not achieving PCR after NACT, adjuvant Capecitabine improves DFS & OS.

PlanB: Patient characteristics

HR-positive population (n=2642)

▪ Age

▪ Median 56 years

▪ Tumor size

▪ Median 19 mm

▪ Ki-67

▪ Median 15%

▪ Nodal status

▪ N0: 59%

▪ N1: 35%

▪ N2-3: 6%

▪ Local grade

– 1: 6.2%

– 2: 61.7%

– 3: 19.9%

– Unknown: 12.2%

▪ Central ER/PR

▪ ER+: 90.5%

▪ PR+: 74.5%

▪ HR+: 91.6% HR-: 2.4%

▪ Unknown: 5.9%

▪ Recurrence Score (RS)

▪ 0-11: 17.4%

▪ 12-25: 58.4%

▪ 26-100: 20.8%

▪ Unknown: 3.4%

▪ Central grade

–1: 5.1%

–2: 61.9%

–3: 31.2%

–Unknown: 1.8%

PlanB: Shared decision making based on Recurrence

Score

Dropout/

non-compliance

rates

▪ RS>25: 10%

▪ RS 12-25: 21%

▪ N0 patients 25%

▪ N1 patients 15%

▪ RS 0-11: 1.5%; CT in 5.5% N0 and 25% N1 patients

▪ 18% of patients potentially spared chemotherapy

(n=404 post-amendment)

86% acceptance

PlanB: Recurrence Score by (central) Ki-67

23.04.2018 WSG GmbHGluz et al. JCO 2016

PlanB trial (HR+/HER2- population; 5-year

median follow-up): Conclusions II

23.04.2018 WSG GmbH88

▪ Both local and central grade 3 are independent prognostic markers, despite

their significant assesment discordance

▪ Ki-67 correlates well with Recurrence Score in (central) Ki-67 ranges <10% and

>40%

▪ Highest prognostic utility from a multigene assay can be expected in cases with

intermediate Ki-67

▪ Only pN2-3, continuous RS, grade 3 and tumor size >2cm are independent

predictors for DFS and should be used together for treatment decisions in early

HR+ HER2- breast cancer

PlanB: DFS by Recurrence Score (HR+)

▪ Analysis in ITT pts with RS measurement after early protocol amendment

Recurrence Score ≤ 25 Recurrence Score > 25

Harbeck N, et al. ASCO 2017. Abstract 504. Reproduced with permission.

Mos

DF

S (

%)

Pts at Risk, n

TC 94

ECT 95

5-Yr DFS, %

100

80

60

40

20

00 12 24 36 48 60 72

TC

ECT

657

649

649

638

615

616

588

591

559

561

431

448

19

21

Mos

DF

S (

%)

Pts at Risk, n

TC 86

ECT 85

5-Yr DFS, %

100

80

60

40

20

00 12 24 36 48 60 72

TC

ECT

254

231

251

227

237

212

220

195

210

183

169

149

1

5

Fin HER: Study Design

R

HER 2 +veHER 2 -ve

HER 2 +veHER 2 -ve

3 x Taxotere (100)q3w

8 x Vinoralbine (25)qw

3 x FEC (600/60/600)

3 x FEC (600/60/600)

Herceptin x 9 weeks (2mg/kg, 1st

dose 4mg/kg)qw

Total 1010 BC patients

(n=232 HER2 amplification)

Herceptin x 9 weeks (2mg/kg, 1st

dose 4mg/kg)qw Joensuu H, et al. N Engl J Med 2006;354:809–20

FinHER: St Gallen 09 5 year DDFS update

Joensuu H et al. Breast 2009; 18 (Suppl 1): S10 (Abstr S24).

94.492.5

77.674.1

Hazard ratio 0.32 (95% CI, 0.12-0.89)

P = 0.029

Docetaxel/FEC, trastuzumab

Docetaxel/FEC

Years0 1 2 3 4 5 6 7

%

0

40

60

80

100

Chemotherapy, no trastuzumab

90.4

77.6

83.3

73.0

% Chemotherapy, with trastuzumab

Hazard ratio 0.65 (95% CI, 0.38-1.12)

P = 0.12

0 1 2 3 4 5 6 7

0

20

40

60

80

100

Sustained benefits

for the docetaxel

subgroup

Years

What is smart about the FinHER Study Design ?

• Give Trastuzumab

– very early adminstration (on D1 of cycle 1)

– concurrently with the most synergistic drugs

– Prior to Anthracyclines…which would reduce cardiotoxicity

DFS events and deaths (ITT)

Event 9-wk group 1-yr group (n=1,085) (n=1,089)

n (%) n (%)

Any recurrence or death 140 (13) 105 (10)

Distant recurrence 73 (7) 61 (6)

Locoregional recurrence 17 (2) 13 (1)

Contralateral BC 15 (1) 7 (1)

Second cancer 27 (3) 24 (2)

Death without cancer 14 (1) 5 (0)

SOLD trial

Not related to treatment efficacy

Breast cancer specific events: 105 (9.6%) 81 (7.4%)Cardiac serious events : 21 (1.9) 36 (3.3)

Total breast cancer serious events 126 (11.5%) 112 (10.7%)

Interpreted by Hamdy Azim March 2018

Placebo–Herceptin + chemo

(n = 2404)

Pertuzumab–Herceptin + chemo

(n = 2400)

Pertuzumab–Herceptin + chemotherapybetter

Placebo–Herceptin + chemotherapybetterBaseline risk factors

Totaln

Patients per group

Eventsn

Patients per group

Eventsn Hazard Ratio 95% CI

All patients 4804 2404 210 2400 171 0.82 (0.67, 1.00)

Nodal status0 positive nodes, tumour ≤1 cm0 positive nodes, tumour >1 cm1-3 positive nodes≥4 positive nodes0 positive nodes≥1 positive nodes

17416251807119817993005

84818900602902

1502

42575

10629

181

90807907596897

1503

230558432

139

0.481.230.730.791.130.77

(0.09, 2.60)(0.72, 2.10)(0.52, 1.04)(0.59, 1.05)(0.68, 1.86)(0.62, 0.96)

Adjuvant chemotherapy regimenAnthracyclineNon-anthracycline

37421062

1877527

171 39

1865535

13932

0.820.82

(0.66, 1.03)(0.51, 1.31)

Central HR statusPositive (ER- and/or PgR-positive)Negative (ER- and PgR-negative)

30821722

1546858

11991

1536864

10071

0.860.76

(0.66, 1.13)(0.56, 1.04)

Protocol versionProtocol AProtocol Amendment B

36551149

1827577

14367

1828572

12051

0.840.77

(0.66, 1.1.08)(0.53, 1.11)

Tumour size (cm)<22 - <5≥5

19212556321

9441283174

6411531

9771273147

4110822

0.620.960.85

(0.42, 0.92)(0.74, 1.24)(0.49, 1.47)

IDFS pre-planned subgroup analyses

von Minckwitz G, et al. N Engl J Med 2017 (Epub ahead of print).1/10 10

Pre-planned subgroup analyses were generally consistent with the ITT population

All patients refers to the unstratified analysis for the ITT population

ExteNET: Background

▪ In pts with HER2+ breast cancer, relapse has occurred in up to 26.3% of pts within 8.4 yrs of follow-up after adjuvant trastuzumab[1-4]

– Highest risk of relapse within first year after trastuzumab[4]

– Relapse risk lower among those without nodal metastases[5]

▪ Neratinib, oral TKI of HER1, HER2, and HER4

– Data suggest efficacy in pts with HER2+ metastatic breast cancer treated with trastuzumab[6]

– Diarrhea most common AE, within first mo of treatment

▪ Current report is 3-yr exploratory analysis of neratinib after adjuvant chemotherapy with trastuzumab in pts with local HER2+ breast cancer enrolled in phase III ExteNET study[7]

1. Goldhirsch A, et al. Lancet 2013;382:1021-1028. 2. Joensuu H, et al. J Clin Oncol. 2009; 27:5685-5692. 3. Slamon D, et al. N Engl J Med. 2011;365:1273-1283. 4. Perez E, et al. J Clin Oncol. 2014;32:3744-3752. 5. Slamon D, et al. SABCS 2009. Abstract 62. 6. Burstein H, et al. J ClinOncol. 2010;28:1301-1307. 7. Chan A, et al. SABCS 2015. Abstract S5-02. 2-7..

ExteNET: Phase III Study Design

▪ Primary endpoint: iDFS in ITT population at 2 yrs

▪ Results of primary analysis: 2-yr iDFS improved with neratinib vs placebo (93.9% vs 91.6%, HR: 0.67; P = .009)

– Hormone receptor+ (n = 1631): HR: 0.51; P = .001

Chan A, et al. SABCS 2015. Abstract S5-02.

Pts with HER2+

local BC; adj. trastuzumab

completed ≤ 1 yr before study

entry plus chemo; lymph node+

disease or no pCR;

known ER and PgR status

(N = 2840)

iDFS: 2- and 5-yr F/U

OS: 5-yr F/U

Neratinib 240 mg/day

Placebo

1 yr

ExteNET: Baseline Characteristics (3-Yr Analysis)

Chan A, et al. SABCS 2015. Abstract S5-02.

Characteristic, %Neratinib

(n = 1420)

Placebo

(n = 1420)

Median age, yrs (range) 52 (25-83) 53 (24-81)

Negative nodal status 23.6 23.7

Positive hormone receptor status 57.7 57.3

Earlier trastuzumab regimen concurrent with chemo 60.3 63.3

Neoadjuvant anthracycline or anthracycline + taxane 80.6 79.7

Median time from trastuzumab, mos (range) 4.2 (0.4-30.9) 4.3 (0.3-40.6)

100

90

80

70

60

50

0

Neratinib

(n = 1420)

Placebo

(n = 1420)

48

ExteNET Analysis: 3-Yr iDFS*

Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission.

2-sided P = .023

HR: 0.74 (95% CI: 0.56-0.96)

97.8%

95.6%

94.1%

91.6%

94.1%

89.9%

90.5%

88.6%

0 6 12 18 24 30 36 42

Dis

ease

-Fre

e S

urv

ival

(%)

Mos After Randomization

Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission.

ExteNET: 3-Yr iDFS by Hormone Receptor Status

Slide credit: clinicaloptions.com

100

90

80

70

60

50

0

100

90

80

70

60

50

00 6 12 18 24 30 36 42 48


0 6 12 18 24 30 36 42 48


Neratinib

(n = 816)

Placebo

(n = 815)

2-sided P = .003

HR: 0.57 (95% CI: 0.39-0.82)

Dis

ea

se

-Fre

e S

urv

iva

l (%

)

Dis

ea

se

-Fre

e S

urv

iva

l (%

)

98.0%

96.1%

95.4%

91.5%

93.6%

89.3%

Neratinib

(n = 604)

Placebo

(n = 605)

2-sided P = .938

HR: 0.57 (95% CI: 0.67-1.45)

97.5%

94.9%

92.5%

91.8%

90.6%

89.9%

Hormone Receptor Positive Hormone Receptor Negative

http://www.clinicaloptions.com/oncology

EXTENET: 5-YEAR ANALYSIS

M. Martin et al, ESMO 2017

HR (95% CI) = 0.73 (0.57–0.92)Two-sided P = 0.008

EXTENET: 5-YEAR ANALYSIS

ExteNET: Adverse Events

Diarrhea, main adverse event

Grade 3 diarrhea occurred in 39.9% of pts on neratinib

Median duration: 5 days (range: 1-139)

Most resolved in < 30 days; 1.4% pts hospitalized

26% dose reductions

17% ttt discontinuations

M. Martin et al, ESMO 2017

esmo summit middle east 2018€¦ · mucositis/stomatitis 20 (1.7) 43 (3.7) .003 arthralgia/myalgia...

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