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Integration of Taxanes in the Management of Breast Cancer. Jean-Marc A. Nabholtz, MD, MSc Professor of Medicine, Univ. of California at Los Angeles Director, Cancer Therapy Development Program Director, Solid Tumor Program, Jonsson Comprehensive Cancer Center, UCLA Chairman, CIRG and BCIRG.

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Integration of taxanes in the management of breast cancer

Integration of Taxanes in the Management of Breast Cancer

Jean-Marc A. Nabholtz, MD, MSc

Professor of Medicine, Univ. of California at Los Angeles

Director, Cancer Therapy Development Program

Director, Solid Tumor Program, Jonsson Comprehensive Cancer Center, UCLA

Chairman, CIRG and BCIRG


Development of chemotherapy breast cancer
Development of Chemotherapy Breast Cancer

1970s

  • Before anthracyclines

    • CMF, CMFVP

  • With anthracyclines

    • Combinations: AC, FAC, AVCMF, FEC, CEF

    • Sequence and Alternating (Milan A & B)

    • Dose intensity,dose density, HDCT

  • Taxanes (Paclitaxel/Docetaxel)

    • Sequential: A T C or AC T

    • Combinations: TA, TAC

  • Biologic Modifiers (Herceptin)

    • Integration in chemotherapy strategies

1980s

1990s

2000s


Chemotherapy drug development
Chemotherapy Drug Development

NEW SINGLE AGENT

2nd LINE

NEW

COMBINATIONS

1st LINE

ADJUVANT


Single agents first line breast cancer
Single agents First-line breast cancer

Vogel CL, Nabholtz Oncologist 1999; 4: 17-33.

Nabholtz et al. Exp. Opin Pharmacother 2000; 1: 187-206.


Adjuvant chemotherapy breast cancer 1990s 2000s emergence of taxanes
Adjuvant Chemotherapy Breast Cancer1990s-2000s: Emergence of Taxanes

  • Paclitaxel and Docetaxel

  • Differences accounting for existing adjuvant strategies

    • Ratio efficacy / toxicity / practicality

    • Ability to integrate with anthracyclines

    • Synergism with Herceptin


Paclitaxel phase ii metastatic breast cancer
Paclitaxel Phase II Metastatic Breast Cancer

Studies Pts RR

  • First-Line:

    • 3 Hour-infusion 6 273 46%

      (175-250 mg/m2) (32-60)

    • 24 Hour-infusion 3 59 50%

      (135-250 mg/m2) (32-62)

  • Second-line:

    • 3 Hour-infusion 6 202 25%

      (135-250 mg/m2) (6-42)

    • 24 Hour-infusion 6 273 46%

      (175-250 mg/m2) (24-33)

    • 96 Hour-infusion 2 53 39%

      (125-140 mg/m2) (30-48)


Randomized phase ii trials paclitaxel p metastatic breast cancer
RANDOMIZED PHASE II TRIALS PACLITAXEL (P) METASTATIC BREAST CANCER

TTF or TTP Overall Survival

Patients ORR (%) Median Months Median Months

Study Design (nb) P value P value P value

Nabholtz et alP 135 mg/m2 47122 3 10.5

1993/JCO 1996 vs

P 175 mg/m2 29 4.2 11.7

Schedule: 3 hr infusion NS .02 NS

Peretz et al P as 3-hr infusion 521 29 No difference NA

ECCO 95 vs

P as 24-hr infusion 31 NA NS

Dose: 175 mg/m2

Winer et al P 175 mg/m2 475 21 3.8 9.8

ASCO 98 vs

P 210 mg/m2 28 4.1 11.8

vs

P 250 mg/m2 22 4.8 11.9

Schedule: 3-hr infusion NS .03 NS


Randomized phase ii trials paclitaxel p metastatic breast cancer1
RANDOMIZED PHASE II TRIALS PACLITAXEL (P) METASTATIC BREAST CANCER

TTF or TTP Overall Survival

Patients ORR (%) Median Mos Median Mos

Study Design (nb) P value P value P value

Smith et al P as 3-hr infusion 563 40 NA No Difference

NSABP B26 vs

JCO 1999 P as 24-hr infusion 50

Dose: 250 mg/m2 0.02

Holmes et al P as 3-hr infuson 179 23 NA 11

ASCO 98vs

P as 96-hr infusion 29 10

Dose: 3-hr Arm: 250mg/m2 NS NS

96-hr Arm: 140 mg/m2


Paclitaxel
Paclitaxel CANCER

Schedule and Dose are important

  • High Dose and Long Schedule (250 mg/m2, 24 Hours), : Efficacy (RR=50%) but Toxicity and Practicality…

  • Low Dose and Short Schedule (175 mg/m2, 3 Hours): Low Efficacy (RR=25-30%), but good toxicity profile and practicality.

  • Weekly: Phase II data


Paclitaxel Neoadjuvant Studies CANCER

Nabholtz; May, 2002


Docetaxel
Docetaxel CANCER

Worldwide: 8 Phase I

Dose and schedule for Phase II,III

  • Dose: 100mg/m2

  • One hour infusion

  • Every three weeks



Pivotal phase iii trials monochemotherapy
Pivotal Phase III Trials Monochemotherapy CANCER

Nabholtz, May, 2001.


Paclitaxel phase iii trial monochemotherapy
Paclitaxel Phase III trial Monochemotherapy CANCER

  • Second line chemotherapy after Failure of Doxorubicin

    • No self standing trial

    • Cross Over only

      • Paclitaxel 3 Hours: RR: 13-14% (EORTC JCO 2000)

      • Paclitaxel 24 Hours: RR: 20% (Intergroup ASCO 97)

  • First Line Chemotherapy

    • 3 Hours: Worse than Doxo 75 mg/m2

      Gamucci, EORTC JCO 2000

    • 24 Hours: Equal to Doxo 60 mg/m2

      Sledge,Intergroup ASCO 97


Ability to integrate CANCERTaxanes and Anthracyclines

  • Paclitaxel:

    • 3 hour schedule: efficacious, but pharmacokinetic Interaction with potential cardiac toxicity

      • 16-24 interval between paclitaxel and doxorurubicin

      • Maximum cumulative dose of doxorubicin 360 mg/m2

      • 24 hour schedule: no cardiac toxicity, but low efficacy (ECOG)

      • Use of epirubicin in Europe: ITALY: EC vs ET, N+

  • Docetaxel:

    • 1 hour infusion (AT/TAC):

      • No added cardiac toxicity to doxorubicin (No pharmacokinetic interaction)

      • Recommended doses: 75/50 or 60/60 mg/m2

      • Efficacious


Randomized Trials of Taxane-Anthracycline Combinations vs Polychemotherapy

Paclitaxel

Docetaxel

* ASCO 2000 in all pts. ** ASCO 2001 in HER2 positive pts. *** ASCO 2002


Development of adjuvant chemotherapy breast cancer
Development of Adjuvant Chemotherapy Polychemotherapy Breast Cancer

1970s

  • Before anthracyclines

    • CMF, CMFVP

  • With anthracyclines

    • Combinations: AC, FAC, AVCMF, FEC, CEF

    • Sequence and Alternating (Milan A & B)

    • Dose intensity,dose density, HDCT

  • Taxanes (Paclitaxel/Docetaxel)

    • Sequential: A T C or AC T

    • Combinations: TA, TAC

  • Biologic Modifiers (Herceptin)

    • Integration in chemotherapy strategies

1980s

1990s

2000s


Treatment of adjuvant breast cancer
Treatment of Adjuvant Breast Cancer Polychemotherapy

  • First Generation Trials:

    • comparing taxane / anthracycline to non-taxane / anthracycline

      • polychemotherapy

      • sequential

  • Second Generation Trials:

    • comparing taxanes in both arms

      • polychemotherapy

      • sequential


Taxane adjuvant trials
Taxane Adjuvant Trials Polychemotherapy


Paclitaxel Adjuvant Studies Polychemotherapy

Nabholtz; May, 2002


Calgb 9344 update
CALGB 9344 Update Polychemotherapy

ASCO sNDA NIH CDC 5/98 4/99 11/00

Median F/U (mos) 18 30 52

Number of Events Recurrences 453 624 901 Deaths 200 342 589

Reduction in Hazard of recurrence 22%* 22%* 13%* Hazard of death 26%* 26%* 14%*p<0.05


CALGB 9344: PolychemotherapyDisease Free Survival by Subgroup

1.00

AC  T

AC

Receptor Status Positive

0.75

0.50

Proportion Disease-Free

1.00

AC  T

AC

Receptor Status Negative / Unknown

0.75

0.50

0

1

2

3

4

5

6

Years

Adapted from the 2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer.


Nsabp b 28 disease free survival and survival all patients
NSABP B-28 PolychemotherapyDisease-free Survival and Survival All Patients

AC ACT RR* P n=1525 n=1528 (95%CI) value

Events 282 269 0.93 0.38 (0.78-1.10)

Deaths 133 136 1.00 0.98 (0.78-1.27)

*RR adjusted for # (+) nodes, operation, and TAM use


Large Taxane Trials Reported as of 11/2000 Polychemotherapy

NSABP-B28

CALGB 9344

T x 4

Nil

T x 4

Nil

A (↑ doses) C x 4

A (fixed dose) C x 4

± Tamoxifen X 5 Y (given to 70%)

Delayed Administration

± Tamoxifen X 5 Y (given to 85%)

Concomitant Administration

N=3060

N=3170

30 %

54 %

1-3 N+

 4 N+

1-3 N+

 4 N+

Premenopausal: 62 %

ER+: 58%

< 50 y of age: 51 %

ER+: 66 %


B-28 Polychemotherapy

Survival

Patients Not Receiving Tamoxifen

p-

value

AC

n=237

AC T

n=237

RR

(95%CI)

Deaths 52 39 0.75 0.20

(0.49-1.16)

* RR Adjusted for # (+) nodes and operation


B-27 Schema Polychemotherapy

Operable Breast Cancer

Randomization

AC x 4

Tam X 5 Yrs

AC x 4

Tam X 5 Yrs

AC x 4

Tam X 5 Yrs

Surgery

Docetaxel x 4

Surgery

Surgery

Docetaxel x 4

I

II

III

Mamounas, Dec 2001


B-27 Polychemotherapy

Pathologic Response (pCR) in Breast

No Tumor

Non-Invasive

30%

P < 0.001

20%

18.7%

9.8%

10%

25.6%

13.7%

6.9%

3.9%

0

AC

(1,492 pts)

AC Taxotere

(718 pts)

Mamounas, Dec 2001


Tax301 Study PolychemotherapyConducted by the Aberdeen Breast Group

First Phase

Second Phase

4 cycles of docetaxel

No Response

All Patients

Final Assessment / Surgery

Final Assessment / Surgery

4 cycles of CVAP

Response

4 cycles of docetaxel

Randomise

4 cycles of CVAP

Hutcheon et al. SABCS 2001, abs 506


Tax301 Polychemotherapy

Pathological Response Rates

Miller & Payne Grade of Pathological Response

Initial Response

No Initial Response

Docetaxel

n = 45

CVAP

n = 50

Docetaxel

n = 47

1

25%

22%

4%

pNR

2

31%

18%

20%

3

29%

26%

23%

4

13%

16%

19%

pCR

5

2%

18%

34%

Hutcheon et al. SABCS 2001, abs 506


Taxotere First Generation Trials: Polychemotherapy Polychemotherapy

6 x TAC

(75,50,500)

BCIRG 001

N+

6 x FAC

1500 patients

(500,50,500)

4 x AT

(60,60)

North American

Intergroup

N+ 1-3/N0

4 x AC

(60,600)

3200 patients


BCIRG 001 Polychemotherapy

F

A

C

T

A

C

Design

5-FU 500 mg/m2Doxorubicin 50 mg/m2

Cyclophosphamide 500 mg/m2

R

Every 3 weeks x 6 cycles

  • Stratification:

  • Nodes: 1-3 4+

  • Center

Docetaxel 75 mg/m2

Doxorubicin 50 mg/m2

Cyclophosphamide 500 mg/m2

Dexamethasone premedication, 8 mg bid, 3 days

Prophylactic Cipro500 mg bid, day 5-14

Nabholtz et al, ASCO 2002 (Abs 141)


Disease Free Survival (ITT) Polychemotherapy

82%

74%

BCIRG 001

Median follow-up: 33 months / n=1,491

100

90

TAC

80

% Alive and Disease Free

FAC

70

60

50

0

6

12

18

24

30

36

42

48

Months

Number at Risk

TAC

745

736

710

678

654

373

152

23

1

FAC

746

729

699

656

605

334

150

31

0

Nabholtz et al, ASCO 2002 (Abs 141)


Confirmatory analyses dfs

BCIRG 001 Polychemotherapy

Confirmatory Analyses: DFS

*Controls for nodes, age, tumor size, histology, ER/PR, HER2

Nabholtz et al, ASCO 2002 (Abs 141)


Sites of first events

BCIRG 001 Polychemotherapy

Sites of First Events

Nabholtz et al, ASCO 2002 (Abs 141)


Planned additional analyses disease free survival and overall survival

BCIRG 001 Polychemotherapy

Planned Additional Analyses Disease Free Survival and Overall Survival

  • Prospectively defined and powered at 5 years

    • By nodal status

  • Prospectively defined but not powered

    • By Hormonal Receptor

    • By HER2 status (FISH)

Nabholtz et al, ASCO 2002 (Abs 141)


Disease free survival by nodal status prospectively defined and powered at 5 years

BCIRG 001 Polychemotherapy

100

100

90%

TAC

90

90

79%

80

80

1-3

% Alive and Disease Free

TAC

69%

FAC

FAC

70

70

67%

4+

60

60

4+ Nodes

0.86

0.33

50

50

0

0

6

6

12

12

18

18

24

24

30

30

36

36

42

42

48

48

Months

Number at Risk

TAC

463

462

452

437

427

250

103

14

1

1-3

FAC

459

454

438

417

393

224

98

26

0

TAC

282

274

258

241

227

123

49

9

0

4+

FAC

287

275

261

239

212

110

52

5

0

Disease Free Survival by Nodal StatusProspectively defined and powered at 5 years

Nabholtz et al, ASCO 2002 (Abs 141)


Overall survival by nodal status prospectively defined and powered at 5 years
Overall Survival by Nodal Status PolychemotherapyProspectively defined and powered at 5 years

BCIRG 001

100

96%

89%

90

86%

84%

80

4+

TAC

70

60

4+ Nodes

1.08

0.75

50

0

6

12

18

24

30

36

42

48

TAC

282

279

273

265

251

132

59

10

0

4+

FAC

287

281

275

269

256

132

64

5

0

100

TAC

1-3

90

FAC

80

% Alive

70

60

50

0

6

12

18

24

30

36

42

48

Months

Number at Risk

TAC

463

462

459

453

449

261

112

14

1

1-3

FAC

459

457

453

444

422

243

107

28

1

Nabholtz et al, ASCO 2002 (Abs 141)


DFS Relative Risk Reduction by Nodal Status Polychemotherapy

BCIRG001 - DFS: Comparison by Nodal Status

Original Analysis: 1-3 versus 4+ Nodes

All

(N=1491)

Number of Positive Nodes

1-3

(N=922)

4-9

(N=420)

10+

(N=149)

TAC Better

FAC Better

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Hazard Ratio


5 year recurrence and survival by number of lymph nodes

= survival Polychemotherapy

= recurrence

5 Year Recurrence and Survival by number of Lymph Nodes

100%

80%

60%

40%

20%

0%

0

2

3

4

5

6-10

11-15

16-20

>20

1

Number of Pathologically Positive Axillary Lymph Nodes

Results of a national survey by the ACS. Cancer 1980;45:2917

Nabholtz; May, 2002


Disease free survival by hormonal status
Disease Free Survival by Hormonal Status Polychemotherapy

BCIRG 001

Negative

Positive

100

100

90

90

TAC

80

80

FAC

% Alive and Disease Free

TAC

70

70

FAC

60

60

RR = 0.62

p = 0.005

RR = 0.68

p = 0.02

50

50

0

12

24

36

48

0

12

24

36

48

Months

Months

N at Risk

N at Risk

TAC

231

217

188

47

0

TAC

514

493

466

105

1

FAC

228

202

158

34

0

FAC

518

497

447

116

0

Nabholtz et al, ASCO 2002 (Abs 141)


Disease free survival by her2 status
Disease Free Survival by HER2 status Polychemotherapy

BCIRG 001

Negative (FISH)

Positive (FISH)

100

100

90

90

TAC

80

80

% Alive and Disease Free

TAC

FAC

70

70

60

60

RR = 0.74

p = 0.06

RR = 0.59

p = 0.02

50

50

FAC

40

40

0

12

24

36

48

0

12

24

36

48

Months

Months

N at Risk

N at Risk

TAC

485

467

433

102

1

TAC

138

131

118

32

0

FAC

478

455

402

108

0

FAC

148

135

107

26

0

Nabholtz et al, ASCO 2002 (Abs 141)


Taxanes Second Generation Pivotal Adjuvant Trials Polychemotherapy

A = Adriamycin; C = Cyclophosphamide; T = Taxotere; P = paclitaxel; *recent change


Current bcirg adjuvant program
Current BCIRG Adjuvant Program Polychemotherapy

Adjuvant Setting

Screen by FISH ~15-18,000 patients

Her 2 negative

~9,000 pts

N-

Her 2 negative

~12,000 pts

N+

Her 2 positive N+/High risk N-

BCIRG 006

3,150 pts

BCIRG 0XX

BCIRG 005

3,130 pts

Pilot Phase II (TCH)

BCIRG 101

BCIRG 102

Nabholtz; May, 2002


BCIRG 005 Polychemotherapy

Adjuvant Breast Cancer

Node Positive

4 x AC 60/600 mg/m2

4 x Docetaxel 100 mg/m2

Her2 –

FISH

6 x TAC 75 75/50/500 mg/m2

N=3150

345 centres


BCIRG 006 Polychemotherapy

Adjuvant Breast Cancer

Node Positive and High Risk Node Negative

4 x Docetaxel

100 mg/m2

4 x AC60/600 mg/m2

ACT

ACTH

HER2 +

FISH

1 Year Trastuzumab

N=3150

480 centres

6 xDocetaxel and Platinum salts

75 mg/m2 75 mg/m2 or AUC 6

TCH

1 Year Trastuzumab


Conclusion
Conclusion Polychemotherapy

Taxanes: chemotherapies of the 1990’s for breast cancer

  • Established role in advanced breast cancer

  • Entering adjuvant setting…


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