neues aus san antonio 2017...with her2‐positive early breast cancer after 5 years’...

ONKOLOGIEFrauenklinik Taxisstraße

2018

Neues aus San Antonio2017

Therapie des frühen Mammakarzinoms(neo‐)adjuvant

C.A. Hanusch


2018

Topics 1

• GS3‐05: Survival analysis of the prospectively randomized phase III GeparSepto trial

• GS3‐04: A randomized phase III study of adjuvant trastuzumab for a duration of 9 weeksversus 1 year, combined with adjuvant taxane‐anthracycline chemotherapy, for earlyHER2‐positive breast cancer (the SOLD study).

• Incidence and management of diarrhea with adjuvant Pertuzumaband Trastuzumab in HER2‐positive breast cancer


2018

Topics 2• Pharmacokinetic results of a subcutaneous injection of Trastuzumab into the thigh versus into the abdominal wall in patients with HER2‐positive primary breast cancer (BC) treated within the neo‐/adjuvant GAIN‐2 study

• Efficacy and safety of subcutaneous or intravenous Trastuzumab in patients with HER2‐positive early breast cancer after 5 years’ treatment‐free follow‐up: Final analysis from the phase III, open‐label, randomized HannaH study

• A phase Ib dose‐finding study of subcutaneous Pertuzumab in combination with subcutaneous Trastuzumab in healthy male volunteers and female patients with early breast cancer


2018

GS3‐05: Survival analysis of the prospectively randomized phase III GeparSepto trial

GeparSepto: Überträgt sich die signifikant höhere pCR Rate mit nab-Pac in ein besseres DFS?


2018

Schneeweiss A, et al. SABCS 2017 (GS3-05)


2018


2018

pCR Rate gesteigert mit nabPaclitaxel vs. lösl. Paclitaxel als Teil einer sequenziellen Anthracyclin/Taxan‐basierten Chemotherapie

Höhere pCR‐Rate übersetzt sich in ein signifikant und klinisch relevant verbessertes rezidivfreiesÜberleben (HR=0.69, log rank p=0.0044)

Auch Pat. mit Ki67 <20% bzw. non‐pCR profitieren bez. DFS von nab‐Paclitaxel

Rate peripherer Neuropathien unter nabPaclitaxel nach Dosisreduktion gesenkt:Grad ¾: 150/ 125 (mg/m2 KOF) 15%/ 8% (nach 464 rekrutierten Pat.)

Fazit


2018

A randomized phase III study of adjuvant Trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant Taxane‐Anthracycline chemotherapy, for

early HER2‐positive breast cancer The Synergism Or Long Duration (SOLD)

trialJoensuu H et al. Oral Session – General Session 3

Abstract No. GS3‐04


2018

SOLD – Hypothesis

Administration of Trastuzumab concomitantly with a Taxane for a brief time period is not inferior in terms of DFS as compared with the standard treatment*, and may be less cardiotoxic

*Standard: Chemotherapy plus 12 months of anti‐HER2‐directed treatment ± endocrine therapy

Mod. Joensuu H et al. SABCS 2017, Oral Session – General Session 3, Abstract No. GS3‐0417


2018

SOLD – Design

*Wkly iv, or 3‐wkly either iv or sc; **14 times 3 weekly, either iv or sc


In both groups:

• Locoregional RT given according to the institutional practice

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

Docetaxel (D)

80/100 mg/m2

iv 3‐wkly

F600E75C600iv 3‐wkly

Trastuzumab (T)

T for 9 wks*

T for 9 wks* T to complete 1 year of administration**

DFEC

D D

D D D

FEC

FEC

FEC

FEC

FEC

R

18


2018

SOLD – Patient disposition


Category 9 weeksno. (%)

1 yearno. (%)

Randomized (Jan 2008 to Dec 2014) 1,087 1,089

Included ITT Population* 1,085 1,089

Withdrew consent 0 (0) 0 (0)

Had distant metastases at study entry 2 (0) 0 (0)

Received study treatment (Safety Population) 1,084 1,089

*ITT, Intention to treat


2018

SOLD – Key baseline characteristics


Characteristic 9-week group(n=1,085)

1-year group(n=1,089)

Median age (range) – years (range) 56 (23-82) 56 (27-79)

Premenopausal 33% 33%

Breast tumor diameter≤10 mm 12% 14%11-21 mm 44% 42%21-50 mm 41% 42%>50 mm 3% 3%

Axillary lymph nodes with cancer0 60% 60%1-3 30% 29%>3 11% 11%

Ductal histological type 92% 92%Estrogen receptor-positive 66% 66%Progesterone receptor-positive 46% 47%


2018

SOLD – DFS events and deaths (ITT)


Event9-wk group(n=1,085)

n (%)

1-yr group(n=1,089)

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)

Death from any cause 58 (5) 44 (4)Death from BC 34 (3) 33 (3)Death from another cause 24 (2) 11 (1)


2018

SOLD – Disease‐free survival

22 Mod. Joensuu H et al. SABCS 2017, Oral Session – General Session 3, Abstract No. GS3‐04

Alive, norecurren

ce(%

)

90.5%*

88.0%*

HR 1.39 (90% Cl 1.12‐1.72)

Non‐inferiority could not be demonstrated

51 weeks9 weeks

Years

Non‐inferiority margin 1.385

Hazard Ratio

• Chemo: 3 x Doc q3w 3 x FEC q3w, N=2,176

• Non‐inferiority instead of superiority study design

*5‐year DFS estimate

Number at risk10851089

10131047

707742

373394

7682

00

0 2 4 6 8 10 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8

0

20

40

60

80

100


2018

SOLD – Overall survival


Prop

ortio

n alive(%

)

Number at risk10851089

10471078

761786

408421

8187

00

95.9%*

94.7%*

HR 1.36 (90% Cl 0.98‐1.89)

Years

*5‐year survival estimate

51 weeks9 weeks


2018

HR 1.24 (90% Cl 0.93‐1.65)

SOLD – Distant disease‐free survival


94.2%*

93.2%*Prop

ortio

n with

outd

istant

recurren

ce(%

)

*5‐year DDFS estimate

51 weeks9 weeks

YearsNumber at risk

10851089

10251056

723760

393409

8083

00


2018

Subgroup Hazard Ratio(90% Cl)

p (interaction)

ER status NegativePositive

1.57 (1.14‐2.17)1.28 (0.96‐1.69) 0.424

Docetaxel dose 80 mg/m2

100 mg/m21.66 (1.30‐2.11)0.67 (0.41‐1.10) 0.007

Nodes with cancer 01‐33+

1.31 (0.95‐1.80)1.83 (1.22‐2.74)1.24 (0.82‐1.85) 0.460

Centre accrual <100 patients≥100 patients

1.40 (1.06‐1.83)1.37 (0.98‐1.93) 0.949

Age <50 yrs≥50 yrs

1.08 (0.76‐1.53)1.61 (1.23‐2.11) 0.137

Stage IIIIII

1.46 (0.96‐2.22)1.54 (1.12‐2.11)1.21 (0.81‐1.79) 0.724

SOLD – Predefined subgroup analyses for DFS


Favors 9 weeks Favors 1-year10.5 1.5 20 2.5 3


2018

Prop

ortio

n alivewith

outrecurrence(%

)

SOLD – DFS: Docetaxel dose 80 mg/m2


91.3%*

86.8%*

HR 1.66 (90% Cl 1.30‐2.11)

YearsNumber at risk843835

765808

545568

309317

7077

00


51 weeks9 weeks


2018

SOLD – DFS: Docetaxel dose 100 mg/m2


92.2%*

87.8%*

242254

228239

162174

6477

55

00

Prop

ortio

n alivewith

outrecurrence(%

)


51 weeks9 weeks

Number at risk

HR 0.71 (90% Cl 0.44‐1.14)

Years


2018

• Chemotherapy‐related toxicity generally similar and expected in the 2 groups

SOLD – Treatment safety


9-weekgroupn (%)

1-yeargroupn (%)

Discontinued Chemotherapy 44 (4.1) 51 (4.7)

Discontinued Trastuzumab 96 (8.9)-53% for toxicity

217 (19.9)-66% for toxicity

Died from treatment-related cause 2 (0.2) 2 (0.2)

28


2018

• Less cardiac toxicity was observed in the 9‐week group

SOLD – Cardiac safety

*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


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)***

29


2018

SOLD – Mean LVEF stratified by the treatmentgroup

LVEF, Left ventricular ejection fraction


LVEF (%

)

p<0.001

Time after study entry

9 weeks

51 weeks

30


2018

SOLD – Conclusions

• Non‐inferiority of 9‐weeks of adjuvant Trastuzumab plus Chemotherapy could not be demonstrated as compared to 1‐year of Trastuzumab plus Chemotherapy in terms of DFS

• Patients treated with the 9‐week duration had fewer cardiac events and had the LVEF better maintained

• Docetaxel dosing with Trastuzumab requires further study• Chemotherapy plus 1‐year of anti‐HER2 therapy should remain the standard



2018

Incidence and management of diarrheawith adjuvant Pertuzumab and

Trastuzumab in HER2‐positive breast cancer

Bines J et al. Poster Session 1 – Treatment: Adjuvant Therapy

Abstract No. P1‐13‐07


2018

Mod. Bines J et al. SABCS 2017, Poster Session 1 – Treatment: Adjuvant Therapy, Abstract No. P1‐13‐0733

APHINITY – Inzidenz der Diarrhoe nachTherapiezyklus

De Azambuja E et al., SABCS 2017

Targeted treatment cycle

Percen

tage of p

atients w

ith an even

t

Pertuzumab + Trastuzumab + Chemotherapy

Placebo + Trastuzumab + Chemotherapy

2,3642,335

2,2532,241

2,2332,225

2,2652,257

1,6581,700

2,1852,190

2,0512,051

2,3062,302

2,2462,231

2,3292,317

2,2852,281

2,2102,211

2,1932,194

2,1512,169

2,1362,159

2,1092,129

2,1652,178

2,2002,200

No. at risk


2018

APHINITY – Inzidenz der Diarrhoe nach Therapiezyklus und Art der Chemotherapie


De Azambuja E et al., SABCS 2017

Targeted treatment cycle

1,8341,824528510

1,7551,751496489

1,7411,742490482

1,7641,765499491

1,3121,336345364

1,7031,713480476

1,6081,602441448

1,7981,806506495

1,7511,744493486

1,8131,815514501

1,7831,788500492

1,7211,730487480

1,7081,716483477

1,6771,692472476

1,6661,685468473

1,6461,659461469

1,6891,701474476

1,7131,719485480

No. at risk

Pertuzumab + Trastuzumab + Anthracycline

Placebo + Trastuzumab + Anthracycline

Pertuzumab + Trastuzumab + Non‐Anthracycline

Placebo + Trastuzumab + Non‐Anthracycline

Percen

tage of p

atients w

ith an even

t


2018

APHINITY – Inzidenz und Management der Diarrhoe


De Azambuja E et al., SABCS 2017All presented data based on the preferred term “diarrhea“; *The incidence of diarrhea is based on anthracycline‐based chemotherapy only as no Pertuzumab or Placebo was given concurrently with an

Anthracycline. ¹Docetaxel only in the Non‐Anthracycline groups.

Anthracycline-based chemotherapy Non-Anthracycline-based chemotherapy

Pertuzumab + Trastuzumab n=1,834

Placebo + Trastuzumab n=1,894

Pertuzumab + Trastuzumab n=528

Placebo + Trastuzumab n=510

Incidence and severityTotal number of patients with at least one event (%) 1,235 (67.3) 772 (40.8) 447 (84.7) 314 (61.6)Total number of events 2,527 1,282 883 508Total number of patients with at least one NC1-CTCAE grade ≥3 event (%) 137 (7.5) 59 (3.1) 95 (18.0) 31 (6.1)

Total number of NCI-CTCAE grade ≥3 events 147 60 113 35Treatment period, total number of patients with at least one event (%)Anthracycline* 296 (16.1) 278 (14.7) – –HER2-targeted therapy + Taxane¹ 1,006 (54.9) 513 (27.1) 444 (84.1) 301 (59.0)HER2-targeted treatment post-chemotherapy 373 (20.3) 175 (9.2) 55 (10.4) 46 (9.0)


2018

Safety of adjuvant treatment with Pertuzumab plus Trastuzumab after neoadjuvant Anthracycline‐based

chemotherapy in patients with HER2‐positive localized breast cancer: Updated results from the

BERENICE study

Dang C et al. Poster Session 5 – Treatment: Her2‐targeted therapy

Abstract No. P5‐20‐04


2018

Cohort A(ddAC TPH)

Cohort B(FEC DPH)

Overalltreatment period n=199

Adjuvant treatment period n=181

Overall treatment period n=198

Adjuvant treatment period n=190

Any AE 198 (99.5) 171 (94.5) 198 (100.0) 171 (90.0)Grade ≥3 AE 109 (54.8) 23 (12.7) 126 (63.6) 40 (21.1)Serious AE 54 (27.1) 15 (8.3) 61 (30.8) 17 (8.9)

AE leading to P or H discontinuation 19 (9.5) 9 (5.0) 14 (7.1) 11 (5.8)

Diarrhea (any grade) 144 (72.4) 26 (14.4) 148 (74.7) 45 (23.7)Diarrhea (grade ≥3) 6 (3) 0 (0) 22 (11.1) 2 (1.1)

Mod. Dang C et al. SABCS 2017, Poster Session 5 – Treatment: Her2‐targeted therapy, Abstract No. P5‐20‐04 37

BERENICE StudieAdjuvantes Trastuzumab/Pertuzumab nach anthrazyklinhaltiger NACT (ddAC q2w Pacli q1w vs. FEC q3w Docetaxel q3w, N=397)

Data are number of patients (%).AE. adverse events; ddAC. dose‐dense Doxorubicin plus Cyclophosphamide; DPH. Docetaxel. Pertuzumab. and Trastuzumab; FEC. Fluorouracil. Epirubicin. and Cyclophosphamide; TPH. Paclitaxel,

Pertuzumab. and Trastuzumab.

General AEs (safety population)


2018

Take Home Message

38

• Die Rate der Diarrhoe unter CTX plus Trastuzumab + Pertuzumab ist im Vgl. zu Trastuzumab erhöht

• Erhebliche Verbesserung nach Absetzen der CTX• APHINITY: Gesteigerte Diarrhoe unter Anthrazyklin‐freier CTX durch den alleinigen Einsatz von Docetaxel bedingt


2018

Pharmacokinetic results of a subcutaneous injection of Trastuzumab into the thigh versus into the abdominal wall in patients with HER2‐positive primary breast cancer (BC) treated within the neo‐/adjuvant GAIN‐2 study

Möbus V et al. Poster Session 5 – Treatment: Her2‐targeted therapyAbstract No. P5‐20‐09


2018

40

GAIN‐2 StudiePK Resultate s.c. Applikation von Trastuzumab

Mod. Möbus V et al. SABCS 2017, Poster Session 5 – Treatment: Her2‐targeted therapy, Abstract No. P5‐20‐09

N=2886

Neo

‐/Ad

juvant

(∑ 100

0 pa

ents)

Trastuzumab i.v.**

Pertuzumab i.v.*

Pertuzumab i.v.*

Trastuzumab i.v.**

EpirubicinStarting dose. 90 mg/m² q2wDose levels (min./max.)‐ Level – 3: 38 mg/m² q2w‐ Level + 2: 120 mg/m² q2w

CyclophosphamideStarting dose: 600 mg/m² q2wDose levels (min./max.)‐ Level – 3: 450 mg/m² q2w‐ Level +2: 1200 mg/m² q2w

DocetaxelStarting dose: 75 mg/m² q2wDose levels (min./max.)‐ Level – 1: 60 mg/m² q2w‐ Level + 2: 100 mg/m² q2w

Epirubicin150 mg/m²

q2w

nab‐Paclitaxel330 mg/m²

q2w

Cyclophos‐phamide

2000 mg/m² q2w

N=220

1 week

rest

*Pertuzumab i.v.(if HER2‐positive and neoadjuvant): Starting dose 840 mg q3w, thereafter 420 mg q3w.

**Trastuzumab i.v.(if HER2‐positive and neoadjuvant or adjuvant): Starting dose 8 mg/kg BW q3w, thereafter 6 mg/kg BW q3w

***Therapy durationTrastuzumab i.v. and s.c. totally 1 year

E E E nP nP nP C C C

E E ED D D D

R

EC C C C

3 weeks

Trastuzumab s.c.Thigh

Trastuzumab s.c.Abdominal wall

Trastuzumab s.c.600 mg q3w***

Trastuzumab s.c.600 mg q3w.***

R


2018

Mod. Möbus V et al. SABCS 2017, Poster Session 5 – Treatment: Her2‐targeted therapy, Abstract No. P5‐20‐09 41

GAIN‐2 Studie – PK Resultate s.c. Applikation von Trastuzumab

Mean plasma concentration‐time profile of the s.c. Trastuzumab

Concen

tration (ug/ml)

Time (days)

Thigh

Abdw


2018

Take Home Message – GAIN‐2

42

• Bestätigung der besseren Bioverfügbarkeit und daraus resultierenden Plasmaspiegel nach Applikation von TrastuzumabSC in den Oberschenkel vs. die Bauchdecke

• Damit Bestätigung der Zulassung von Trastuzumab SC


2018

Efficacy and safety of subcutaneous or intravenous Trastuzumab in patients with HER2‐positive early

breast cancer after 5 years’ treatment‐free follow‐up: Final analysis from the phase III, open‐label,

randomized HannaH study

Jackisch C et al., Poster Discussion – Novel Drugs / Predicting Response for HER2+ Breast Cancer

Abstract No. PD3‐11


2018

HannaH Trial – Trastuzumab s.c., 5‐J‐FU, finale AnalyseEFS by tpCR status (ITT population)

Mod. Jackisch C et al. SABCS 2017, Poster Discussion – Novel Drugs / Predicting Response for HER2+ Breast Cancer, Abstract No. PD3‐11

EFS, event‐free‐survival; H IV, intravenous Trastuzumab; H SC, subcutaneous Trastuzumab: ITT, intent‐to‐treat population: tpCR, total pathologic complete response

TreatmentH IV / tpCRH SC / tpCRH IV / non‐tpCRH SC / non‐tpCR

Estim

ated

Proba

bility

Months

94203108186

51524244

93170105159

741077992

70997687

7612486116

8114398133

0000

No. at risk

6‐year event‐free rate (95% Cl)

H IV H SC

tpCR 0.83(0.76, 0.91)

0.82(0.74, 0.89)

No tpCR 0.57(0.49, 0.64)

0.54(0.47, 0.62)

44


2018

Take Home Message – HannaH

45

• Überlebensvorteil (EFS/OS) nach pCR bestätigt• Konsistente Resultate hinsichtlich der Äquieffektivität von Trastuzumab s.c. vs. i.v.

• Keine neuen Safety‐Signale


2018

A phase Ib dose‐finding study of subcutaneous Pertuzumab in combination with subcutaneous Trastuzumab in healthy male volunteers and female patients with early breast cancer

Kirschbrown WP et al. Poster Session – 5 Treatment: Her2‐targeted therapy (presenter:

Whitney P)Abstract No. P5‐20‐07


2018

Take Home Message – Pertuzumab s.c.

47

• Pertuzumab s.c. ähnliche PK wie Pertuzumab i.v.• Kombination von Pertuzumab s.c. und Trastuzumab s.c. ohne beeinträchtigende Wirkung aufeinander

• Phase‐3‐Studie mit dualer Blockade s.c. als fixe Dosis in Planung– FPI Juni 2018


2018

Vielen Dank für Ihre Aufmerksamkeit!


2018

neues aus san antonio 2017...with her2‐positive early breast cancer after 5 years’...

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