QOL primary endpoint primary endpoint NSABP B-18 AC(60/600) surgery surgery AC(60/600) Primary end points: disease free survival NSABP B-18 primary ch

(1)

乳がん臨床試験概説

愛知県がんセンター中央病院乳腺科

岩田広治

診断

乳癌治療（昔）

手術

薬物療法 RT

診断

乳癌治療（現在）

薬物療法

手術

RT

手術

薬物療法

放射線照射

薬物療法

手術

放射線照射

薬物療法

放射線照射

手術

薬物療法の位置づけ

• 術前薬物療法

• 術後薬物療法

• 再発薬物療法

術前薬物療法

手術不能乳癌を手術可能に

温存手術を目指して

一般臨床

pCRをprimary endpointにした

新しいレジメンの開発

臨床試験

(2)

術後薬物療法

一般臨床

臨床試験

生存率、無再発生存期間を

primary endpointにおいた

新規治療の評価

生存率向上を目指して

標準的治療の遵守

再発薬物療法

奏効率をprimary endpointに

新規薬剤の開発、

新規併用療法の開発

一般臨床

生存期間の延長を目指して（QOLも重視）

臨床試験

術前薬物療法の臨床試験

NSABP B-18

AC(60/600)

surgery

Primary end points: disease free survival

NSABP B-18の結果

JCO 16:2672-2685,1998

PSTとadjuvantでDFS, 生存率に差はない

Docetaxel primary chemotherapy

in breast cancer: a five year update of the

Aberdeen Trial

Andrew W Hutcheon on behalf of the Aberdeen

Breast Group

University of Aberdeen and Grampian University Hospitals

(3)

All Patients 4 cycles of CVAP (n=162) 4 cycles of docetaxel (n=55) 4 cycles of docetaxel (n=52) 4 cycles of CVAP (n=52) No R espo nse Re_sp onse Ra_n d o m is e

First Phase Second Phase

Tax301 Study

Conducted by the Aberdeen Breast Group

Fi nal A ssessme n t / Sur g ery 5 2 15 31* 17 15 11 4 23 27 24 3 17 19 20 2 2 19 27 1 Docetaxel n = 52 % CVAP n = 52 % No Initial Response Docetaxel n = 55 % Miller & Payne

Grade of Pathological Response Initial Response pNR pCR

Tax301

Pathological Response Rates

Not Evaluable 16 4 10 (*P=0.06)

Time (months)

S

u

rv

iv

a

l

(%

)

1.0 0.9 0.8 0.7 20 40 60 80 100 Log rank p=0.04 Docetaxel CVAP

Tax 301 Overall Survival

Median Follow - up: 60 months

97%

78%

NSABP B-27

R

AC(60/600) x 4

surgery

Docetaxel 75 x 4

surgery

Docetaxel 75 x 4

3.7 9.2 12.9％ 30 25 20 15 10 5 0 7.2 18.9 4.4 10.1 DCIS only No Tumor Grp.l (n=762) Grp.ll (n=752) Grp.lll (n=772)

Journal of Clinical Oncology, Vol 21, No 22(November 15), 2003: pp 4165-4174

％ 14.5％

26.1％*

Complete Phathologic Tumor Response

NSABP B-27

Overall Survival

40 50 60 70 80 90 100 0 1 2 3 4 5 Group I Group II Group III TRT N Deaths 801 803 799 150 143 163 HR=0.694 p=0.57 HR=1.07 p=0.53

Years after Surgery

% S u rv iv in g 3-31-04

(4)

NSABP B-27: Disease-Free Survival

Patients with cPR after AC

40 50 60 70 80 90 100 0 1 2 3 4 5 % Disease-free

Years after Surgery

TRT N Events Group I 353 133 Group II 378 103 HR=0.68 p=0.003 Group III 350 120 HR=0.90 p=0.40 3-31-04 PR = Partial Response

B-18

Disease-Free and Overall Survival

According to Response

0 20% 40% 60% 80% 100% 2 4 6 8 Year P=0.00005 pINV cPR cNR pCR 2 4 6 8 pINV cPR cNR pCR P=0.0008 Wolmark N: CDC, 2000

現在の至適レジメン(pCRで）

アンスラサイクリン→タキサン

Randomised trial in HER2-positive BC:

trial design

H qw x 12 + P q3w x 4

Appropriate endocrine therapy for patients with ER+ disease

Stage II–IIIA breast cancer; HER2 positive

P q3w x 4

FEC q3w x 4 H qw x 12 + FEC q3w x 4

Local therapy Randomisation

FEC = fluorouracil, epirubicin, cyclophosphamide

H = Herceptin®; P = paclitaxel Buzdar A, et al. Proc ASCO 2004;23:7 (Abstract 520)

Randomised trial in HER2-positive

operable BC: pCR rates

0 10 20 30 40 50 60 70 80 90

DSMB reviewed data Final results 26.3% n=19 65.2% n=23 25.0% n=16 66.7% n=18 95% CI (41–87%) p=0.02 95% CI (43–84%) p=0.016 (n=34) (n=42) pC R (% ) P + FEC alone H + (P → FEC)

Buzdar A, et al. Proc ASCO 2004;23:7 (Abstract 520)

Herceptin

®

PST compares favourably with

anthracycline plus taxane-based PST

Study Author n Regimen

CR (%)

pCR (%) NSABP B-27 Bear 2003 752 AC x 4 → Doc x 4 64 26 GeparDuo Minckwitz 2003 197 AT x 4 → Doc x 4 57 22 Aberdeen Smith 2002 55 CVAPd x 4 → Doc x 4 94 34 AGO Untch 2002 242 (E x 3 → Pac x 3) q2w NA 18 ECTO Gianni 2002 270 APac x 4 → CMF x 4 52 22

MD Anderson* Buzdar 2004 23 Herceptin + (P → FEC) NA 65

(5)

FEC 100

x 4 Cyclophosphamide 500 mg/m2 Epirubicin 100 mg/m2 5FU 500 mg/m2

Docetaxel

x 4 75 mg/m2

Surgery

The trial was initiated June 2002, and closed June 2004 with a recruitment of 202 patients

JBCRG001

Clinical response （n=90)

0% 50% 100

Changes of effects : Improvement 30 pts (34.1%)

(FEC → Docetaxel) No change 49 pts (55.7%)

Progress 9 pts (10.2%) CR PR SD PD NE 12% 18 41 23 39% 43% 4% 6 2 1% FEC Docetaxel 11 39 35 4 11% 20% 46% 26% 7% 2%

Pathologic effects (n=90)

pCR

pSR/pNR

15.6% 57.8%

NE

5.6% pCR : 14 Near pCR : 8 pPR : 11 SR*/NR: 52 NE : 5 8.9%

Near pCR

multiple cross-section specimens: median 21.5 (3-77)

12.2%

pPR

* Slight Response

pCR + Near pCR 24.4 %

Primary Chemo Radiation therapy

for Breast Cancer

（PRICRA-BC）

腫瘍径2cm以上のI-III期原発乳癌に対する

術前化学療法とそれに続く放射線照射の

有効性・安全性試験

原発乳癌 5cm≧腫瘍径（US計測）≧2cm stageI-IIIA 年齢:20-70, PS:0-1, 適性臓器機能針生検・画像評価 PTX(80mg/m2)×12 q1W

乳房照射 45Gy/25 Fr + Boost 10Gy

AC(60/600) ×4 q3W 手術

JBCRG 003

FEC 100

x 4 Cyclophosphamide 500 mg/m2 Epirubicin 100 mg/m2 5FU 500 mg/m2

Docetaxel

x 4 75 mg/m2

Surgery

(6)

TBCRG 001

Docetaxel 75mg/m2 Herceptin

surgery

Locally advanced breast cancer

IMAGE-BC（JCOG)

針生検＋画像診断

PST

画像診断でcPR+cCR

針生検

Surgery

最終病理結果

効果判定

一致率

術後薬物療法の臨床試験

Cancer 85:104-111,1999

再発１０年後の生存率：3.8%

1581例/M.D. Anderson Cancer Center

IC

でのポイント

・再発すれば癌を完治させることが難しくな

ります。だから再発をさせないことが重要

です。

そのためには今出来る最善の治療をしま

しょう。

副作用や辛いことがあるかも知れません

が、頑張りましょう。

Adjuvant chemotherapy

俺の経験ですべきではない

Evidenceに基づいた薬剤の選択

(7)

The First Milan Trial

386 node positive Breast Cancer Radical Mastectomy R A N D O M I Z E No Treatment CMF 12 cycles (179 pts) (207 pts)

CMFの効果 (Milan Trial)

reduces the risk of recurrence by 24%

Recurrence

Death

無再発生存率

アンスラサイクリン vs CMF

Lancet. 1998;352:930-942. アンスラサイクリンレジメン CMF 57.3% 54.1% 3.2% (log-rank 2p = 0.006) Follow-up (Years) 0 1 2 3 4 ≥ 5 0 20 40 60 80 100 P e rc e n ta ge Re la ps e F re e CEF:q4Wk x 6 CPA:75mg/m2 po,14d EPI:60mg/m2, d1&8 5-FU:500mg/m2 d1&8 CMF: q4Wk x 6 CPA:100mg/m2 po, 14d MTX:40mg/m2, d1&8 5-FU:600mg/m2, d1&8

N+, Pre

JCO 19:602-611,2001 DFS OS

FASG trial

N+ cases JCO 19:3103-3110,2001

EC: 60/500 q3W x 8

HEC:100/830 q3W x 8

CMF:classical CMF x 6

OS DFS

(8)

適切な量のanthracyclinを投与する

Evidences of Chemotherapy (including Taxans

)

結果：未

ECOG1199

dose dense AC→P ＞ AC→P

CALGB9741

AC ＝ AC→D

NSABP B-27

weekly P ＞3 week P

CALGB9840

DFS, OS共にFECx3→Dx3 ＞FECx6

PACS-01

DFSでTAC＞FAC

BCIRG001

OSに差はなし

NSABP B-28

DFSがER(-)でP=0.001, RR:0.75

ER(+)でP=0.13, RR:0.88

CALGB9344

results

Trial

Hudis

結論

リンパ節転移陽性：

Ｔaxanの十分な上乗せ効果がある。

ホルモン陽性：

Taxanの上乗せ効果は減少する

Trial Strategies in Early Adjuvant

Therapy: Aromatase Inhibitors

ATAC ARNO / ITA TAMOXIFEN ANASTROZOLE LETROZOLE PLACEBO BIG 1-98 (BIG FEMTA) MA-17 EXEMESTANE ICCG / IES TEAM EXEM 027 NSABP B33

Early Adjuvant setting

• 0 – 5 years

Extended Adjuvant setting

• 5 – 10 years

3

2

3

3 Chronology of endocrine therapy

Future

S

U

R

G

E

R

Y

• 5y

• 10y

• 15y

Tamoxifen No treatment Anastrozole Exemestane Tamoxifen Letrozole

• Early Adjuvant• Extended Adjuvant

Letrozole Placebo • ARNO • TEAM Letrozole • BIG 1.98

(9)

NSABP B-31

NCCTG N9831

Arm 1 Arm 2 Arm A Arm B Arm C = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2_{q 3 wk x 4} = paclitaxel (T) 175 mg/m2_{q 3 wk x 4} = paclitaxel (T) 80 mg/m2_{/wk x 12} = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Control: AC

→T

Investigational: AC

→T+H

Disease-Free Survival

87% _85% 67% 75% N Events ACÆT 1679 261 ACÆTH 1672 134 % HR=0.48, 2P=3x10-12 ACÆTH ACÆT

Years From Randomization B31/N9831

B-31/N9831 Survival

ACÆTH 94% 91% 87% 92% ACÆT N Deaths ACÆT 1679 92 ACÆTH 1672 62 HR=0.67, 2P=0.015

Years From Randomization _B31/N9831

Perez E. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followed by 2mg/kg);

doxorubicin dose 60mg/m2; cyclophosphamide, 600mg/m2; paclitaxel, 80mg/m2

q3w=every 3 weeks; qw=weekly

NCCTG N9831 Schema

R A N D O M I Z E

Radiation and/or hormonal therapy as indicated Paclitaxel qw x 12 Arm A: AC q3w x 4 Paclitaxel qw x 12 Arm B: AC q3w x 4 H qw x 52 AC q3w x 4 Paclitaxel qw x 12 + H qw x 12 Arm C: H qw x 40

Disease-Free Survival: A vs C

From the Joint Analysis

100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 Years AC →T Events=261 AC →T + H →H Events=134 % Hazard ratio=0.48 Stratified logrank 2P=3x10-12

Number of patients followed

A 1162 689 374 193 59 C 1217 766 427 238 74

Disease-Free Survival: A vs B

N9831

100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 Years

Number of patients followed

A 979 629 353 168 15 B 985 637 403 169 20 AC →T Events=117 Hazard ratio=0.87 Stratified logrank 2P=0.2936 AC →T →H Events=103 %

(10)

A randomized three-arm multi-centre comparison of:

• 1 year Herceptin®

• 2 years Herceptin®

• or no Herceptin®

in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapy

Martine J. Piccart-Gebhart, MD, PhD on behalf of:

The Breast International Group (BIG), NON-BIG participating groups, Independent sites, F. Hoffmann – La Roche Ltd.

FIRST RESULTS OF THE

HERA TRIAL

ASCO, Scientific Session, May 16, 2005

EU 71.5% EASTERN EUROPE: ≅ 11% JAPAN ≅ 12% ASIA PACIFIC CENTRAL & SOUTH AMERICA 5.5%

ACCRUAL: 5090 WOMEN

478 centers from 39 countries (2002-2005)

CANADA NORDIC COUNTRIES SOUTH AFRICA AUSTRALIA – NEW ZEALAND

HERA TRIAL DESIGN

Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed

Surgery + (neo)adjuvant chemotherapy (CT) ± radiotherapy

Stratification

Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region Randomization Trastuzumab 8 mg/kg Æ 6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg Æ 6 mg/kg 3 weekly x 1 year Observation

DISEASE-FREE SURVIVAL

% alive and disease free Months from

Months fromrandomizationrandomization 0 0 55 1010 1515 2020 2525 1693 1693 14281428 994994 580580 280280 8787 1694 1694 14721472 10671067 629629 303303 102102 Events Events 2 2--yryr DFS

DFS%% HRHR [95% CI][95% CI] p valuep value 127 127 85.885.8 0.540.54[0.43, 0.67][0.43, 0.67]<0.0001<0.0001 220 220 77.477.4 1 year trastuzumab 1 year trastuzumab Observation Observation 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 No. No. at risk

at risk Months fromMonths fromrandomizationrandomization

0 0 55 1010 1515 2020 2525 1693 1693 14281428 994994 580580 280280 8787 1694 1694 14721472 10671067 629629 303303 102102 Events Events 2 2--yryr DFS

DFS%% HRHR [95% CI][95% CI] p valuep value 127 127 85.885.8 0.540.54[0.43, 0.67][0.43, 0.67]<0.0001<0.0001 220 220 77.477.4 1 year trastuzumab 1 year trastuzumab Observation Observation 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 No. No. at risk at risk

ACKNOWLEDGEMENTS

T. Suetoe M. Jahn C. Bernard M. Mano P. Wermuth C. Ward G. Demonty S. Jonas A. Spence M. Procter L. Dal Lago S. Dolci E. McFadden R. Gelber

STATISTICS & DATAMANAGEMENT & MEDICAL SUPERVISION

J. Rueschoff, O. Stoss CENTRAL HER-2 TESTING

C. Straehle S. Guillaume, V. Greatorex

BIG COORDINATION MONITORING COORD C. Lohrish, H. Weber WRITING OF HERA PROTOCOL

IDMC MEMBERS T. Suter CARDIAC ADVISORY BOARD

M. Lichinitser, I. Lang, U. Nitz, H. Iwata, C. Thomssen INVESTIGATORS WITH LARGEST ACCRUAL A. Goldhirsch, M. Piccart, B. Regeer, B. Vanhauwere J. Baselga, R. Bell, D. Cameron, M. Dowsett, L. Gianni, C.

Jackisch, B. Leyland-Jones, I. Smith, M. Untch TRIAL DESIGN / DAY TO DAY SUPERVISION

BIG GROUPS ABCSG ACCOG ANZ BCTG BOOG BREAST CEEOG DBCG EORTC GABG GEICAM NON BIG GROUPS AGO ASG&WSG BIOMED NO GIM IBCG MICHELANGELO NBCG SOLTI TCOG 91 Independent centers GOCCHI GOIRC GONO IBCSG ICCG NCIC-CTG NCRI SAKK SBCG YBCRG

Evidence (guideline)

St Gallen recommendation

NIH consensus conference

(11)

9th_{International Conference on Primary Therapy of}

Early Breast Cancer at St. Gallen,2005

Annals of On

NCCN (The National Comprehensive Cancer network) 全米で１９施設

遺伝子解析による臨床試験の時代

Prognosis estimate by microarray

gene expression profiling

Van’t veer LJ, et al: Nature 2002:31:530-536

Van de Vijver MJ, et al: N Engl J Med 2002:347;1999-2009

New clinical trial (MINDACT Trial)

MINDACT: Microarray In Node-negative Disease may Avoid ChemoTherapy

Recruitment 5,000 patients last quarter of 2005 Standardization and validation phase Oncotype DX

(12)

US intergroup PACT Trial

N(-), ER(+), PgR(+)

RS＜15

15≦RS＜30

30≦RS

H alone

R

H alone

H+Chemo

RS : Oncotype DX

(

Paik et al:NEJM, 2004:351;2817-2826

)

日本の臨床試験

N-SAS-BCの歩み

臨床研究支援事業

がん臨床研究支援事業骨粗鬆症至適療法研究支援事業生活習慣病臨床研究支援事業ヘルスアウトカムリサーチ支援事業

がん臨床研究支援事業

Comprehensive Support Project

for Oncology Research

(C-SPOR)

C-SPORのミッション

• 研究者主導の乳がん臨床研究の企画と実施

• がん患者のQOLに関する調査研究

• CRC(Clinical Research Coordinator)教育

• インターネットを利用した乳がん患者・医師・

CRCに対する情報提供と試験支援

組織化

• 諮問委員会

• 運営委員会

臨床試験小委員会

CRC支援/教育小委員会

ヘルスアウトカム評価小委員会

広報小委員会

• 事務局

• C-SPORデーターセンター

(13)

組織化

• 諮問委員会

• 運営委員会

臨床試験小委員会

CRC支援/教育小委員会

ヘルスアウトカム評価小委員会

広報小委員会

• 事務局

• C-SPORデーターセンター

N-SAS-BC 01

n0 high risk 術後補助療法 UFT 2Y CMF 6cycle RT TAM ± ± R

治療スキーマ

Stage I-IIIA 腋窩リンパ節転移陽性 70才以下 PS 0-1 paclitaxel A(E) C docetaxel paclitaxel docetaxel

ラ

ン

ダ

ム

化

割

付

術後乳がん N-SAS BC 02 放射線照射タモキシフェン

プロトコール治療

•Adriamycin (Epi) 60 (75) mg/m2 •Cyclophosphamide 600 mg/m2 N-SAS BC 02 ACP群 ACD群 PTX群 DTX群 q3wks x 4 Paclitaxel 175 mg/m2 _{q3wks x 4} Adriamycin (Epi) 60 (75) mg/m2 Cyclophosphamide 600 mg/m2 Docetaxel 75 mg/m2 q3wks x 4 q3wks x 4 Paclitaxel 175 mg/m2 _{q3wks x 8} Docetaxel 75 mg/m2 _{q3wks x 8}

プロトコール治療

基本的デザイン

•A(E)C N-SAS BC 02

Paclitaxel A(E)C Docetaxel

Paclitaxel Docetaxel 2 * 2 design

プロトコール治療

基本的デザイン

•A(E)C N-SAS BC 02

Paclitaxel A(E)C Docetaxel

Paclitaxel Docetaxel

2 * 2 design

(14)

N-SAS-BC03

TAM 5Y

TAM 1∼4Y

ANA 1∼4Y

目標症例数：2,500例

登録症例数：660例（8月末）

R

術後TAM内服

HR＋、閉経後

N-SAS-BC 04

TAM 5Y EXE 5Y TAM 5Y EXE 5Y ANA 5Y TEAM trial

TEAM Japan trial

R R 目標症例数：300例、登録症例数：203例（8月末）

n0 high risk, n＋

HR+、閉経後乳癌

N-SAS-BC 04 (new)

TAM 3Y EXE 5Y EXE 5Y ANA 5Y TEAM trial

TEAM Japan trial

R R EXE 2Y TAM 3Y EXE 2Y

再発薬物療法の臨床試験

JCOG trial

各地で乱立するphaseII

新規薬物療法治験（phaseII)

EPOCH注 BNP7787

支持療法

Lapatinib (GW572016) TSU-68

分子標的治療薬

Ixabepilone(BMS-247550) Gemcitabine (LY188011)

抗がん剤

TAS-108 Fuluvestlant (ICI182,780)

ホルモン剤

TBCRG002

ER+ or/and PgR+ and Her-2:3+ 再発乳癌 first line

ホルモン剤単独 Trastuzumab単独併用

uncertain

(15)