Integration of Taxanes in the Management of Breast Cancer Jean-Marc A. Nabholtz, MD, MSc Professor...

Integration of Taxanes in the Management of Breast Cancer

Jean-Marc A. Nabholtz, MD, MSc

Professor of Medicine, Univ. of California at Los AngelesDirector, Cancer Therapy Development Program

Director, Solid Tumor Program, Jonsson Comprehensive Cancer Center, UCLAChairman, CIRG and BCIRG

Development of Chemotherapy Breast Cancer

• 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

1970s1970s

1980s1980s

1990s1990s

2000s2000s

Chemotherapy Drug Development

NEW SINGLE AGENTNEW SINGLE AGENT

2nd LINE

1st LINE

ADJUVANT

NEW COMBINATIONS

NEW COMBINATIONS

Drug Year of publication

CR + PR (%)

Taxotere (75-100mg/m²) 1993 - 95 48 - 68 Taxol (175 - 250 mg/m² : 3-24hr) 1991 - 95 29 - 63 Doxorubicin (60-75mg/m²) 1974 - 94 43 - 54 Capecitabine 1995 - 99 35 - 50 Navelbine 1992 - 94 30 - 41 Gemcitabine 1995 - 97 25 - 37 Carboplatin 1985 - 93 7 - 35 Cisplatin 1978 -88 9 - 50 Cyclophosphamide 1959 - 68 36 Fluorouracil 1961 - 81 28 Methotrexate 1952 - 81 26 Mitomycin C 1976 - 85 32

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

• 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

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)



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 al P 135 mg/m2 471 22 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 NAECCO 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 9.8ASCO 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 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 vsJCO 1999 P as 24-hr infusion 50 Dose: 250 mg/m2 0.02

Holmes et al P as 3-hr infuson 179 23 NA 11ASCO 98 vs P as 96-hr infusion 29 10 Dose: 3-hr Arm: 250mg/m2 NS

NS 96-hr Arm: 140 mg/m2

Paclitaxel

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 StudiesPaclitaxel Neoadjuvant StudiesPaclitaxel Neoadjuvant StudiesPaclitaxel Neoadjuvant Studies

Nabholtz; May, 2002

MD Anderson Study DesignGreen et al, Proc. ASCO 2002 (Abst 135)

MD Anderson Study DesignMD Anderson Study DesignGreenGreen et al, Proc. ASCO 2002 (et al, Proc. ASCO 2002 (Abst Abst 135)135)

FAC x 4FAC x 4

N=236N=236

Pre and PostPre and Post--menopausal menopausal

RANDO MI

ZATION

Pac = Pac = PaclitaxelPaclitaxel

Pac weekly Pac weekly NN--: 80 mg : 80 mg / m2 x12/ m2 x12NN--: 150 mg: 150 mg/m2 x3 /m2 x3

q.4w: 4 cyclesq.4w: 4 cycles

Pac q.3w Pac q.3w 250250 mgmg/m2/24 h /m2/24 h

q.3w x 4q.3w x 4

SURGERY

236 pts236 pts evaluableevaluablepCRpCR: W N+: 28.0%: W N+: 28.0% NN--: 29.4%: 29.4%

3W N+: 13.7% N3W N+: 13.7% N--: 13.4%: 13.4%

Docetaxel

Worldwide: 8 Phase I

Dose and schedule for Phase II,III

• Dose: 100mg/m2

• One hour infusion

• Every three weeks

Phase II Studies: Breast

Final Results – ITT

Type Authors Patients ResponseRate

First Line FumoleauTrudeauSeidman

117 56.4%(47.4-65.4%)

Second Line Ten BokkelValeroRavdin

111 48.6%(39.4-57.9%)

Anthracyclineresistant

ValeroRavdinBonneterre

105 41.7%(32.0-59.4%)

Pivotal Phase III Trials Monochemotherapy

Taxotere vs: RR TTP OS

Second Line after anthracycline

MV (Nabholtz JCO 99)

30 vs 12% p<.001

19 vs 11 wks p<.001

11.4 vs 8.7 mos p<.0097

MF (Sjostrom EJC 99)

42 vs 21% p<.0001

27 vs 13 wks p<.0001

NS

(crossover)

First and Second line after alkylating agent

Doxorubicin

(Chan JCO ‘99) 48 vs 33% p=.008

26 vs 21 wks NS

NS

Nabholtz, May, 2001.

Paclitaxel Phase III trial Monochemotherapy

• 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

• 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

Ability to integrate Taxanes and Anthracyclines

Randomized Trials of Taxane-Anthracycline Combinations vs Polychemotherapy

Study Status AT vs AC Nabholtz et al, 1999

AT>AC

TAC vs FAC Nabholtz et al, 2001 Mackey et al, 2002***

TACFAC

ET vs FEC Bonneterre et al, 2001

ET>FEC

Docetaxel Paclitaxel

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

Development of Adjuvant Chemotherapy Breast Cancer

• 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

1970s1970s

1980s1980s

1990s1990s

2000s2000s

Treatment of Adjuvant Breast Cancer

• First Generation Trials: comparing taxane / anthracycline to

non-taxane / anthracycline polychemotherapysequential

• Second Generation Trials: comparing taxanes in both arms

polychemotherapysequential

Taxane Adjuvant Trials

Number of patients

First Generation 31,000

Paclitaxel 10,000

Docetaxel 21,000

Second Generation

25,000

Paclitaxel 12,000

Docetaxel 13,000

Total 56,000

CALGB 9344 Study DesignCALGB 9344 Study DesignCALGB 9344 Study Design

PP175/3h175/3h x 4 x 4

NoneNone

N=3170N=3170

Node+Node+

Pre and Pre and PostPost--menopausal menopausal

ER+ or PR+ER+ or PR+

RANDO MI

ZATION

A =A = DoxorubicinDoxorubicinC = C = CylophosphamideCylophosphamideP = P = PaclitaxelPaclitaxel

AA6060C x 4 C x 4

AA7575C x 4C x 4

AA90+G90+G--CSFCSFC x 4C x 4

ER+ or PR+ patients received Tamoxifen x 5 yrs

NSABP B-28 Study DesignNSABP BNSABP B--28 28 Study DesignStudy Design

N=3060N=3060

Node+Node+

Pre and Pre and PostPost--menopausal menopausal

ER+ or PR+ER+ or PR+

A =A = DoxorubicinDoxorubicinC = C = CylophosphamideCylophosphamideP = P = PaclitaxelPaclitaxel

PP225/3h225/3h x 4 x 4 RANDO MIZATION

AC x 4 AC x 4

AC x 4AC x 4

All patients 50 years and those <50 with ER+ or PR+ tumors received Tamoxifen x 5 yrs

Paclitaxel Adjuvant StudiesPaclitaxel Adjuvant StudiesPaclitaxel Adjuvant StudiesPaclitaxel Adjuvant Studies

Nabholtz; May, 2002

CALGB 9344 Update

ASCO sNDA NIH CDC5/98 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:Disease Free Survival by Subgroup

Receptor Status Positive

Receptor Status Negative / Unknown

0.50

0

Pro

po

rtio

n D

ise

as

e-F

ree

AC T

AC

Years

AC T

AC

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

0.75

1.00

0.50

0.75

1.00

1 2 3 4 5 6

NSABP B-28 Disease-free Survival and Survival All Patients

AC ACT RR* Pn=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 11/2000Large Taxane Trials Reported as of 11/2000

CALGB 9344 NSABP-B28

T x 4

Nil

4 N+ 1-3 N+ 4 N+ 1-3 N+

A (↑ doses) C x 4

N=3170 N=3060

Premenopausal: 62 %ER+: 58%

< 50 y of age: 51 %ER+: 66 %

54 % 30 %

± Tamoxifen X 5 Y (given to 70%)Delayed Administration

± Tamoxifen X 5 Y (given to 85%)Concomitant Administration

A (fixed dose) C x 4 T x 4

Nil

Deaths 52 39 0.75 0.20 (0.49-1.16)

ACn=237

SurvivalPatients Not Receiving Tamoxifen

AC Tn=237

RR(95%CI)

p-value

* RR Adjusted for # (+) nodes and operation

B-28

B-27 SchemaB-27 Schema

Operable Breast CancerOperable Breast Cancer

RandomizationRandomization

II IIII IIIIII

AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs



SurgerySurgery Docetaxel x 4Docetaxel x 4 SurgerySurgery

SurgerySurgery Docetaxel x 4Docetaxel x 4

Mamounas, Dec 2001

B-27B-27Pathologic Response (pCR) in BreastPathologic Response (pCR) in Breast

P < 0.001P < 0.001

AC TaxotereAC Taxotere(718 pts)(718 pts)

ACAC(1,492 pts)(1,492 pts)

3.9%

9.8%

No TumorNo Tumor Non-InvasiveNon-Invasive

6.9%

18.7%

13.7%13.7% 25.6%25.6%

20%20%

10%10%

00

30%30%

Mamounas, Dec 2001

All Patients

4 cycles of CVAP

4 cycles of docetaxel4 cycles of docetaxel

4 cycles of docetaxel4 cycles of docetaxel

4 cycles of CVAP4 cycles of CVAP

No Response

ResponseR

and

om

ise

First Phase Second Phase

Fin

al Assessm

ent / S

urg

eryTax301 Study

Conducted by the Aberdeen Breast Group F

inal A

ssessmen

t / Su

rgery

Hutcheon et al. SABCS 2001, abs 506

34%18% 2%5

19%16%13%4

23%26%29%3

20%18%31%2

4%22%25%1

Docetaxeln = 47

CVAPn = 50

No Initial Response Docetaxel

n = 45

Miller & Payne Grade of

Pathological Response

Initial Response

pNR

pCR

Tax301Tax301Pathological Response RatesPathological Response Rates

Hutcheon et al. SABCS 2001, abs 506

Taxotere First Generation Trials: Polychemotherapy

BCIRG 001N+ 6 x FAC

6 x TAC

North AmericanIntergroup N+ 1-3/N0

4 x AC

4 x AT

(75,50,500)

(500,50,500)

(60,600)

(60,60)

1500 patients

3200 patients

Design

Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2

Cyclophosphamide500 mg/m2

5-FU 500 mg/m2

Doxorubicin 50 mg/m2

Cyclophosphamide500 mg/m2

FAC

TAC

R

Dexamethasone premedication, 8 mg bid, 3 days Prophylactic Cipro 500 mg bid, day 5-14

Every 3 weeks x 6 cycles

Stratification:• Nodes:

1-3 4+

• Center

Nabholtz et al, ASCO 2002 (Abs 141)

BCIRG 001

TAC

FAC

0 6 12 18 24 30 36 42 48Months

Number at RiskTACFAC

745 736 710 678 654 373 152 23 1746 729 699 656 605 334 150 31 0

50

60

70

80

90

100

% A

live

and

Dis

ease

Fre

e

# Events RR p-value

TAC 1190.68 0.001

FAC 170

Total 289

Disease Free Survival (ITT)BCIRG 001

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

82%

74%


Confirmatory Analyses: DFS

Analysis Cohort RR p

Main Analysis(Stratified by nodes)

ITT0.68

(0.54 – 0.86)0.001

Unadjusted ITT0.67

(0.53 – 0.85)0.0008

Cox Model* ITT0.64

(0.50 – 0.81)0.0002

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


BCIRG 001

Sites of First Events

TACn= 745

FACn= 746

number of events

Metastatic 80 119

Local/Regional 23 31

Contralateral 3 6

Other 2nd Primary 6 10

Death NED 7 4

119 170


BCIRG 001

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)


BCIRG 001

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

RR p-value

1-3 Nodes 0.50 0.0002

TAC

FAC

0 6 12 18 24 30 36 42 48Months

Number at RiskTACFAC

463 462 452 437 427 250 103 14 1459 454 438 417 393 224 98 26 0

50

60

70

80

90

100

% A

live

and

Dis

ease

Fre

e

1-3

1-3

90%

79%

TACFAC

0 6 12 18 24 30 36 42 48

4+ TACFAC

282 274 258 241 227 123 49 9 0287 275 261 239 212 110 52 5 0

50

60

70

80

90

100

0.330.864+ Nodes

4+

69%

67%


BCIRG 001

TAC

FAC

0 6 12 18 24 30 36 42 48MonthsNumber at Risk

TACFAC

463 462 459 453 449 261 112 14 1459 457 453 444 422 243 107 28 1

50

60

70

80

90

100

% A

live

Overall Survival by Nodal Status Prospectively defined and powered at 5 years

96%

89%

RR p-value

1-3 Nodes 0.46 0.006

1-3

1-3

TAC

0 6 12 18 24 30 36 42 48

4+ TACFAC

282 279 273 265 251 132 59 10 0287 281 275 269 256 132 64 5 0

50

60

70

80

90

100

0.751.084+ Nodes

4+

86%84%


BCIRG 001

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Hazard Ratio

TAC Better FAC Better

10+

4-9

1-3

All

Number of Positive Nodes

(N=149)

(N=420)

(N=922)

(N=1491)

BCIRG001 - DFS: Comparison by Nodal StatusOriginal Analysis: 1-3 versus 4+ Nodes

DFS Relative Risk Reduction by Nodal Status

5 Year Recurrence and Survival by number of Lymph Nodes

Number of Pathologically Positive Axillary Lymph Nodes

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6-10 16-20 >2011-15

= survival

= recurrence

Results of a national survey by the ACS. Cancer 1980;45:2917 Nabholtz; May, 2002

Disease Free Survival by Hormonal Status

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

231 217 188 47 0228 202 158 34 0

50

60

70

80

90

100

% A

live

and

Dis

ease

Fre

e

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

514 493 466 105 1518 497 447 116 0

50

60

70

80

90

100

Negative Positive

RR = 0.62p = 0.005

RR = 0.68p = 0.02


BCIRG 001

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

485 467 433 102 1478 455 402 108 0

40

50

60

70

80

90

100

% A

live

and

Dis

ease

Fre

e

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

138 131 118 32 0148 135 107 26 0

40

50

60

70

80

90

100

Disease Free Survival by HER2 status

Negative (FISH) Positive (FISH)

RR = 0.74p = 0.06

RR = 0.59p = 0.02


BCIRG 001

Study Design

Intergroup(led by ECOG)

AC (x4) P 175/3h/d1 q3wks (x4) vsAC (x4) P 90 weekly (x12) vsAC (x4) T 100/1h/d1 q3wks (x4) vsAC (x4) T 35 weekly (x12)

NSABP-B30AC (x4) T 100 (x4) vsAT 50/75* (x4) vs TAC 75/50/500* (x4)

BCIRG 005AC (x4) T 100 (x4) vsTAC 75/50/500 (x6)

Taxanes Second Generation Pivotal Adjuvant Trials

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

Current BCIRG Adjuvant Program

Adjuvant SettingScreen by FISH ~15-18,000 patients

Her 2 negative~12,000 pts

N+

Her 2 positive N+/High risk N-

BCIRG 0063,150 ptsBCIRG 005

3,130 pts

Her 2 negative~9,000 pts

N-

Pilot Phase II (TCH)

BCIRG 101BCIRG 102

BCIRG 0XX

Nabholtz; May, 2002

BCIRG 005Adjuvant Breast Cancer

Node Positive

Her2 –FISH

4 x AC 60/600 mg/m2 4 x Docetaxel 100 mg/m2

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

N=3150345 centres

BCIRG 006Adjuvant Breast Cancer

Node Positive and High Risk Node Negative

HER2 +FISH

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Platinum salts75 mg/m2 75 mg/m2 or AUC 6

1 Year Trastuzumab

N=3150480

centres

1 Year Trastuzumab

ACT

ACTH

TCH

Conclusion

Taxanes: chemotherapies of the 1990’s for breast cancer

• Established role in advanced breast cancer

• Entering adjuvant setting…

Integration of Taxanes in the Management of Breast Cancer Jean-Marc A. Nabholtz, MD, MSc Professor...

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