Do we need a Taxane in the treatment of breast cancer

Yes But not yet No Im not convinced

Do we need a Taxane in breast cancer

Single

agent With Anthracycline With other drugs With biological therapy

Do we need a Taxane in breast cancer

Adjuvant ? Neoadjuvant ? Metastatic ?

Single agents in Breast Cancer (First-line)

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

Vogel CL, Nabholtz Oncologist 1999; 4: 17-33. Nabholtz et al. Exp. Opin Pharmacother 2000; 1: 187-206.

TAX 306 AT vs AC Efficacy: Response Rate

All Randomized AT AC

Overall*
Visceral Liver Lung 3 organs Adjuvant CT

60%
59% 62% 59% 60% 54%

47%
42% 43% 36% 41% 41%

P = .012

*Odds ratio AT/AC 1.7 [95%CI 1.1 -2.5]

Nabholtz et al 10/00 update of ASCO 99 abstract 485.

TAX306: AT vs AC: Overall Survival 40 months median follow-up

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54

Cumulative Probability

No Of pts Death Censored Median survival [95% CI] 1-yr survival [95% CI]

AT 214 155 (72%) 59 (28%) 22.5 mos [19.0, 26.4] 79% [74,85] Log-rank

AC 215 167 (78%) 48 (22%) 21.7 mos [19.8,25.2] 75% [70,81] p-value=0.2432

AT

AC
Survival Time (months)

Cut-off date: 22 Feb 01

Nabholtz, May, 2001

PROC, July 11, 2001

Metastatic Breast Cancer East-Central Europe study

AT(N=134) 87 (68%) 24 (19%) 1 8.3 m 23.3 m 42 % alive FAC(N=133) 72 (55 11 (8%) 0 6.2 m P=0.034 18.3 m P=0.013 26 % alive
Jassem et al, JCO 2001

Response rate

C.R
Early toxic death TTP

MST
At median follow Up period of 29 m

Taxanes As Adjuvant Therapy First Generation Of Randomized Clinical Trials Do we need a taxane?
Benefit of sequential Taxanes

Benefit of combining Taxanes with Anthracyclines

Benefit of substituting taxanes with Anthracyclines

Taxanes As Adjuvant Therapy Second Generation of Clinical Trials

Ok wed better use a Taxane, BUT we need to know:

Optimal taxane administration: sequence? combination Optimal taxane dose-density/dose-intensity Docetaxel versus Paclitaxel Benefit of combining taxanes with Herceptin

Taxanes in adj. treatment

1st Generation
Sequential taxanes A-T N19000 combinations N10000

2nd Generation
Dose N2250 & schedule N5000 Sequence Best vs Taxane combination Taxane N9300 Herceptin N8700

TC p53
N1016 N1400

N 55200 Paclitaxel 21700 Docetaxel 34500

CALGB 9344 Adjuvant Study Update 11/00: Henderson et al

N=3,170 Node+ Statification: Premenopausal and postmenopausal R A N D O M I Z E

A60 C 4 A75 C 4 A90+G-CSF C 4

TXL 4

No therapy

ER+ or PR+ patients received Tamoxifen 5 y

A=Dxoribicin C=cyclophosphane P=Pclitaxel
NIH Consensus Conference: Adjuvant Therapy for Breast Cancer, November 1-3, 2000, Bethesda, MD.

CALGB 9344
ASCO (98)
Median FU (mos) 21 453 200 22%* 26%*

NIH (2000)
52 901 589 13%* 14%

JCO (2003)
69 1054 742 17%* 18%*

Number of events Recurrences Deaths Reduction in Hazard of recurrence Hazard of death

CALGB
RECENT UPDATE

Add Taxol to AC (median follow up: 69%)

Reduced odds of recurrence Reduced Mortality 5-years DFS OAS

17% (p=0.0023) 18% (p=0.0064)

70% (vs 65%)

80% (vs 77%)
Henderson et al. JCO; 2003

Comparative Efficacy of Adjuvant Chemotherapy

EBCTCG Meta-Analysis
Reduction in Annual Odds, %
Therapy Polychemotherapy vs no chemotherapy (1995) Recurrence 23.5 (P < .00001) Death 15 (P < .00001)

Anthracyclines vs CMF (1995)

Anthracyclines vs CMF (2000)

12 (P = .006)
10.8 (P = .0005)

11 (P = .02)
15.7 (P < .00001)

Early Breast Cancer Trialists Collaborative Group. Lancet. 1998;352:930-942.

CALGB 9344: Disease Free Survival by Subgroup

1.00

Proportion Disease-Free

AC TXL AC

0.75

Receptor Status Positive

0.50 1.00

AC TXL AC

0.75

Receptor Status Negative / Unknown

0.50 0 1 2 3 4 5 6
Adapted from the 2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer.

Years

Lessons from CALGB 9344 (N=3121)

MORE IS NOT ALWAYS BETTER

Increase ADRIAMYCINE dose from 60mg/m2 90mg/m2 didnt improve treatment outcome in any subset

Lessons from CALGB 9344 (N=3121)

Better outcome may be achieved using PACLITAXEL x 4 following AC x 4 or simply by using 8 cycles

Lessons from CALGB 9344 (N=3121)

Do we need molecular selection for adjuvant cases ??

ER +ve

NO benefit

NSABP B-28: Study Design

R A N D O M I Z E

N=3,060 Node+ Stratification: Premenopausal and postmenopausal

AC 4

AC 4

TXL 4

All patients 50 years and those <50 with ER+ or PR+ tumors received Tamoxifen 5 y
A=Doxorubicin C=Cyclophosphamide P=Paclitaxel
NIH Consensus Conference: Adjuvant Therapy for Breast Cancer, November 1-3, 2000, Bethesda, MD.

NSABP-B28 EARLY RESULTS

Disease-Free Survival
100 80

Overall Survival
100 80

RR = 0.93 p= 0.38
60 40 20 0 0

60 40

RR = 1.00 p= 0.98

AC 1525 pts, AC T 1528 pts,

6

282 events
269 events

20 0 0

AC 1525 pts, ACT 1528 pts,

6

133 deaths 136 deaths

12 18 24 30 36 42 48

12 18 24 30 36 42 48

NSAPB B-28 F/U 1-3 (+) LN 4 (+) LN Tamox < 50 Recur/Death 40 mos 70% 30% 85% 51% 561 / 269

CALGB 9344 69 mos 46% 54% 67% 60% 1054/742

Hazard Ratio for Relapse: No Tamoxifen Tamoxifen

.86 (.62-1.19)

0.69 (.57-.84)

.96 (.78-1.16)

0.92 (.79-1.08)

MD Anderson Adjuvant Trial n=524 (67% post-op)

# Est. 4 yr DFS:
P F A C

265 259

86% 83%
p=0.09

F A C

(No Impact By Receptor Status)

Buzdar, et al, Clin Cancer Res, 2002. 8(5): p. 1073-9.

BCIRG 001: TAC vs FAC 3 Year F/U: Adjuvant Rx for Node (+) BC
n
A C D A C F

DFS

OS

745

82%
74%
0.68 0.0011

92%
87%
0.76 0.11

746
RR p

Nabholtz et al Proc ASCO 2002 abs # 141

Disease Free Survival by Nodal Status

100 % Alive and Disease Free 90

90% 79%

TAC

80

1-3
FAC

70

FAC
RR p-value 0.0002
0.33
18 24 Months
427 393 227 212

TAC
67%

69%

60

1-3 Nodes
4+ Nodes

0.50
0.86
12
452 438 258 261

4+

50 0
Number at Risk TAC 463 1-3 FAC 459 4+ TAC 282 FAC 287

6
462 454 274 275

30
250 224 123 110

36
103 98 49 52

42
14 26 9 5

48
1 0 0 0

437 417 241 239

Nabholtz et al. ASCO 2002 (Abs 141).

Overall Survival by Nodal Status

100

96% 89% 86% 84%

TAC
1-3

90

% Alive

80

FAC

70

TAC
RR p-value
0.006
0.75
18 24 Months
449 422 251 256

4+

60

1-3 Nodes
4+ Nodes

0.46
1.08
12
459 453 273 275

50
0
Number at Risk 1-3 TAC 463 FAC 459 4+ TAC 282 FAC 287

6
462 457 279 281

30
261 243 132 132

36
112 107 59 64

42
14 28 10 5

48
1 1 0 0

453 444 265 269

Nabholtz et al. ASCO 2002 (Abs 141).

Disease Free Survival by Hormonal Status

Negative
100 % Alive and Disease Free 100

Positive

90

90

TAC
80 80

FAC

70

TAC
RR = 0.62 p = 0.005
0 12
217 202

70

60

FAC

60

RR = 0.68 p = 0.02
0 12
493 497

50 24 Months
188 158

50 36
47 34

48
0 0

24 Months
466 447

36
105 116

48
1 0

N at Risk TAC 231 FAC 228

N at Risk TAC 514 FAC 518

Nabholtz et al. ASCO 2002 (Abs 141).

Pre vs Post Operative AC NSABP B-18

-More Breast Conservation -Response Predicts Outcome

S
No Difference in DFS or OS through 5 years f/u

Fisher et al, JCO 1997 15:2483

B-18 Disease-Free and Overall Survival According to Response

100%
80% 60% 40% 20% 0 Year

pCR pINV cPR cNR

2 4

P=0.00005

pCR pINV cPR cNR

8 2

P=0.0008

Wolmark N: CDC, 2000

NSABP B-27
n
A C

pCR
9.8 19.7

DFS/OS
? ?

1492
T

718

Bear et al, SABC Proceedings 12/2001 69:210. Abstract 5

Tax 301 Study Conducted by the Aberdeen Breast Group

First Phase Second Phase
Final Assessment / Surgery

4 cycles of docetaxel
All Patients
N= 167

4 cycles of CVAP

N= 47

4 cycles of docetaxel
N= 50

4 cycles of CVAP

Tax 301 Study Survival

1.0

Survival probability

docetaxel
.9

Patients who responded to CVAP Randomized to: docetaxel x4 or CVAP x 4

p=0.05
.8

CVAP Log Rank Test

.7
0 10 20 30 40 50 60

Time (months)

Survival increased in docetaxel group

Taxanes as Adjuvant or Neo-Adj. Rx: Available Randomized Trials

Study CALGB 9344 NSABP B-28 MD Anderson BCIRG 001 NSABP B-27 Aberdeen Design AC +/-P AC +/-P P->FAC vs FAC TAC vs FAC AC +/-D CAVp +/D Result POSITIVE NEG. / EARLY Too Small...?POS. POSITIVE POSITIVE POSITIVE
P = paclitaxel D = docetaxel

Taxanes in Breast Cancer

How to Improve Outcome ??
1. 2. 3. 4.

5.
6.

Better scheduling Dose Dense programs Synergy with other drugs Synergy with biological therapy Predict benefit Newer generation of Taxanes

Scheduling of Taxol
Weekly Taxol Advantages: 1- Better toxicity profile - Less alopecia - Less neuropathy - Less myelosuppression
Perez et.al. Proc. ASCO, 1998 Abs #480

Weekly Taxol
Advantages:
2- Better Tumour cell kill - More frequent drug exposure Dose dense (Seidman et.al., JCO, 1998) - Enhancement of Anti Angiogenic property of Taxol (Belotti et.al., Cancer Res.,1998) - Enhancement of Apoptosis induction by Taxol (Milross et.al., JNCI, 1996)

Dose-dense Paclitaxel Via Weekly 1-hour Infusion: Lack Of Cumulative Neutropenia

14 12 ANC (1000/L) 10 8 6 4 2 0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Week
Seidman et al: JCO16:3353-61, 1998

Weekly vs q 3 Week Paclitaxel MD Anderson Neo-Adjuvant Trial

mg/m2

80 Node Neg. 225/24h

N= 258 patients

150 (3/4 wks)

Node Pos. 225/24h
Green MC, et al, Proc ASCO 2002 abs # 135

Weekly vs q 3 Week Paclitaxel MD Anderson Neo-Adjuvant Trial

mg/m2 Path CR

80 Node Neg 225/24h

29%
13% 28% 14%

150 (3/4 wks) Node Pos 225/24h

Green MC, et al, Proc ASCO 2002 abs # 135

Taxanes in Breast Cancer

How to Improve Outcome ??
1. 2. 3. 4.

5.
6.

Better scheduling Dose Dense programs Synergy with other drugs Synergy with biological therapy Predict benefit Newer generation of Taxanes

Why conventional sequential therapy may fail?

1012

Cell Number

108

104

100 0 20 Weeks 40 60

Dose dense sequential therapy Why it might succeed?

Intergroup Node (+) Trial

CALGB 9741
q 2 wk (w/G-CSF) 24 weeks q 3 wk 36 weeks

16 weeks doxorubicin 60 mg/m2 cyclophosphamide 600 mg/m2 paclitaxel 175 mg/m2 over 3 hours

24 weeks

Radiation therapy and tamoxifen follow as appropriate Closed March 31, 1999 with n~2005
Citron et al: SABCC 12/02 abs # 15

Disease-Free Survival by Density

Proportion Disease-Free 0.8 0.0 0 0.2 0.4 0.6 1.0

2 Years From Study Entry q 2 wks q 3 wks N= 988 N= 985

Events= 136 Events= 179

p=0.0072

Citron et al: SABCC 12/02 abs # 15

Overall Survival by By Density Overall Survival Density

0.8 Proportion Surviving 0.0 0 0.2 0.4 0.6 1.0

2 Years From Study Entry

q 2 wks q 3 wks

N= 988 N= 985

Events= 75 Events= 107

p=0.013

Citron et al: SABCC 12/02 abs # 15

I Seq

II

III Con

IV Con

q3

Seq

q2

q3

q2

No. No.

Treated Data < 0.5/ul

488 99 24% 3%

493 96 3% 2%

501 101 43% 5%

495 101 9% 2%

Granulocytes Febrile

Neutropenia Hospitalized
Red

Cell Transfusion Transfusion

0% 0% 1.9%

2% 0% 1.9%

3% 0% 3.9%

13% 0% 4.5%

Platelet

Neurologic:

Severe Sensory Loss or Motor Weakness

Citron et al: SABCC 12/02 abs # 15

Taxanes in Breast Cancer

How to Improve Outcome ??
1. 2. 3. 4.

5.
6.

Better scheduling Dose Dense programs Synergy with other drugs Synergy with biological therapy Predict benefit Newer generation of Taxanes

Potential mechanisms underlying Capecitabine plus Taxane synergy

Taxane
TP
upregulation
1

Bcl-2
downregulation
2

Capecitabine
2Fujimoto-Ouchi

N et al. Clin Cancer Res 1998;4:10139 K et al. Proc Am Assoc Cancer Res 2001 (Abst 463)
1Sawada

Lessons From The Past 5 Years

Novel Combinations in Metastatic Breast Cancer
Previous treatment by Anthracycline in 100%of patients for adjuvant/metastatic disease

Taxotere/Cap
N=255

Taxotere
N=256

42% 6.1 mons

PR + CR TTP

30% 4.2 mons

13.7 mons
32%

OAS (median)
IRC (PR+ CR)

11.1 mons
23%

OShaughnessy et al. Proc San Antonio; Abs#381, 2000

Rationale for capecitabine in combination: TP upregulation

(mg/kg) Paclitaxel 100 Docetaxel 15

* * * * *

Vinblastine
Vindesine Mitomycin C Doxorubicin Cisplatin Gemcitabine Vinorelbine

3
5 5 7.5 10

Cyclophosphamide 200 90 12 0
*p<0.05 p value not available

* *

2 3 4 5 6 7 8 TP upregulation (x control activity)

10

Ishitsuka H. Invest New Drugs 2000;18:34354 Sawada N et al. Proc Am Assoc Cancer Res 2002;43:1088 (Abst 5388)

Taxanes in Breast Cancer

How to Improve Outcome ??
1. 2. 3. 4.

5.
6.

Better scheduling Dose Dense programs Synergy with other drugs Synergy with biological therapy Predict benefit Newer generation of Taxanes

Lessons From The Past 5 Years

Metastatic Breast Cancer
Herceptin in Combination with Chemotherapy as First Line in Metastatic Breast Cancer
Pivotal study (H0648g)

Addition of Herceptin to chemotherapy improves: Response rate 54% Response duration 58% TTP 65% OAS (at 30 months) 25%
Slamon Proc ICAT; Abs # 24, 2002

Mean Combination Index Values for Chemotherapeutic Drugs / Herceptin Combinations in-vitro
Drug
Vinorelbine Cisplatin Etoposide Thiotepa Docetaxel/Platinum Paclitaxel/carboplatin Doxorubicin Paclitaxel Methotrexate Vinblastine 5-fluorouracil

Combination index
0.34 0.56 0.15 0.54 0.15 0.67 0.12 0.34 0.64 1.16 0.18 0.91 0.23 1.36 0.17 1.09 0.19 2.87

Interaction
Synergy Synergy Synergy Synergy Synergy Synergy Addition Addition Addition Addition Antagonism

Pegram et al. Seminar Oncology, 2000

Advanced Breast Cancer First Line

TP Paclitaxel 175 mg/m
2

q 21d

HER2 +

Trastuzumab until progression

TPC Paclitaxel 175 mg/m /Carboplatin (AUC 6) q 21d
2

Trastuzumab until progression

Roberts et al; SABCC 2002

Estimated Progression-Free Survival by Treatment Arm

1.0 0.9

0.8

Progression Free

0.7 0.6

TPC Patients 96 Median TTP (Mos) 11.2 Range 1.2 - 36

TP 95 6.9 1.2 - 43

0.5
0.4 0.3

P=0.007

0.2
0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36

Months TPC (% Progression Free) TP (% Progession Free) 45 33

25 11

18 8 Roberts et al; SABCC 2002

Conclusions
The addition of Carboplatin to TP significantly increases the overall response and time to progression TP
RR

TPC
52%

TP3+
37%

TPC3+
57%

36%

TTP

6.9 mo

11.2 mo

7.2 mo

13.5 mo

Herceptin Platinum Combination(s) in HER2 +ve Metastatic Breast Cancer (prior exposure to Anthracyclines) Ongoing study CAIRO University Oncology Centre

patients previously treated By a Taxane

Herceptin 4mg/kg/week or 2mg/kg/week Cisplatinum 25 mg/m2 D1+D8+D15 Navelbine 25 mg/m2 D1+D8+D15 Recycle D28 x 6 then maintain on weekly Herceptin till progression

patients not treated By a Taxane

Herceptin 4mg/kg/week or 2 mg/kg/week Cisplatinum 25 mg/m2 D1+D8+D15 Taxol 60 mg/m2 D1+D8+D15 Recycle D28 x 6 then maintain on weekly Herceptin till progress

Herceptin Platinum Combination(s) in HER2 +ve Metastatic Breast Cancer Ongoing study CAIRO University Oncology Centre

CR :2 PR :7 OAR : 9 (60%) SD :4 DP : 2 (1 case HER2 +3) Response duration : 10 months TTP : 8.5 months ttt>1year : 4 cases

Breast Cancer International Research Group [BCIRG]

AC x 4

docetaxel x 4

Node-/+ HER2+ FISH +

C+T [carboplatin + docetaxel] x 6 Herceptin x 1 Year

N=3,000 Activated 2002

AC x 4

docetaxel x 4
Herceptin x 1 Year

Taxanes in Breast Cancer

How to Improve Outcome ??
1. 2. 3. 4.

5.
6.

Better scheduling Dose Dense programs Synergy with other drugs Synergy with biological therapy Predict benefit Newer generation of Taxanes

FUTUR PROMISES

Design of Treatment According to Molecular Profile of the Disease

CHANGING CONCEPTS

Design of treatment according to molecular profile of the disease

HER2/neu+ve ? Need for adequate doses of Anthracycline ? Need for a Taxane

Need for Herceptin in metastatic phase ?adjuvant phase

Herceptin synergy with other drugs

Survival HER2 negative (n = 170)

1.0 .9 .8 .7 Cum Survival .6 .5 .4 .3 .2 .1 0.0

Median Survival in Weeks ET 82 (95%CI 51-112) EC 90 (95%CI 79-101)

ET 31 / 91events EC 29 / 79 events

Log rank p = 0.8999

0 50 100
Weeks

150

200

Konecny et al., Proc ASCO 2001

Survival HER2 positive (n =102)

1.0 .9 .8 .7 Cum Survival .6 .5 .4 .3 .2 .1 0.0 0 50 100 Weeks 150 200

Median Survival in Weeks ET 103 (95%CI 64-142) EC 56 (95%CI 41-71) ET 14 / 49 events EC 27 / 53 events

Log rank p = 0.035

Konecny et al. Proc ASCO, 2001

Disease Free Survival by HER2 Status

Negative (FISH)
100 % Alive and Disease Free 90 100 90

Positive (FISH)

TAC
80 70 60 80

FAC

70 60

TAC

50
40

RR = 0.74 p = 0.06
0 12
467 455

50
40

RR = 0.59 p = 0.02
0 12
131 135

FAC
36
32 26

24 Months
433 402

36
102 108

48
1 0

24 Months
118 107

48
0 0

N at Risk TAC 485 FAC 478

N at Risk TAC 138 FAC 148

Nabholtz et al. ASCO 2002 (Abs 141).

Design of treatment according to molecular profile of the disease

Mutant P53

CHANGING CONCEPTS

?? Resistance to Anthracycline

?? Sensitivity to Taxanes

Taxanes may induce tumor cell apoptosis independent on P53 status

Lanni et cell biology;1997

Taxol induced rapid onset of P53 Independent apoptotic pathway

Wood et al Mol Med;1995

A potential for Predictive Value of P53

Patients with P53 deficient tumors may benefit from Paclitaxel

Kandiokr-Eckersberger Clin CancerRes;2000

Anthracycline and radiation therapy require Intact P53 for efficient tumor cell death
Lawe et cell biology;1993

P53 mutations are associated with de novo resistance to Anthracyclines In breast cancer patients
Aas et al Nat Med;1996

Design of treatment according to molecular profile of the disease

Overexpression of Topo II

CHANGING CONCEPTS

Sensitivity To Anthracycline

Taxanes in Breast Cancer

How to Improve Outcome ??
1. 2. 3. 4.

5.
6.

Better scheduling Dose Dense programs Synergy with other drugs Synergy with biological therapy Predict benefit Newer generation of Taxanes

Novel epothilone BMS-247550: Activity against clinical taxane resistance

Pat-21 (Breast)
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

Taxane resistant Pat-21 breast cancer

ADR + CMF (10 cycles)

TAXOL + Dexverapamil (4 cycles)

Years
1000

Biopsied

Median tumor weigh (mg)

Control

Paclitaxel (36 mpk x5)

100 BMS-247550 (10 mpk x3)

Rx

Rx 50 60 70 80

10
40

Time post tumor implantation (days)

Novel epothilone BMS-247550: Summary

O S N HN O OH O OH

BMS-247550

Microtubule stabilization is a clinically validated biological target Epothilone (BMS-247550) is active in vitro and in vivo against taxane-resistant tumor models Activity demonstrated in taxane-refractory patients in Phase I and II Phase 2 studies are in progress, in a broad program via BMS and NCI

Do We Really Need Anthracycline For All Patients?

Some tumors may not be sensitive to anthracycline

Some patients might not tolerate anthracycline

Some Combinations may be more effective but also more toxic Herceptin

Do we need a Taxane in the treatment of breast cancer

Cost
-Acute & ch. toxicity -Q.O.L

Benefit

Budget

Survival gain

How to minimize Adverse events?

How to predict Therapeutic benefit?

How to improve Treatment outcome?