oncology journal club clinical review of current treatment strategies for breast cancer ruth m....

Oncology Journal Club

Clinical Review of Current Treatment Strategies for Breast Cancer

Ruth M. O’Regan, MDAssociate Professor

Emory University School of MedicineWinship Cancer Institute

Physician, Emory University HospitalGrady Memorial Hospital

Atlanta, Georgia

Topics To Be Covered

• Endocrine therapy

– Update of ATAC

– Molecular profiling of ER-positive cancers

– Tamoxifen metabolism

– Bone support measures

• Chemotherapy

– AC vs. TC

– Novel chemotherapeutics

• Biologics in triple negative disease

ATAC

• Recruitment July 1996 – March 2000• Median follow up 100 months

Tamoxifen (N=3,116)

Surgery+/- RT

+/- Chemo (20%)

Anastrozole (N=3,125)

5 years

• 84% HR positive• 61% node negative

Discontinued following initial analysis as no efficacy or

tolerability benefit compared with tamoxifen arm

Lancet Oncology, 2008

Effect of Anastrozole and Tamoxifen as Adjuvant Treatment for Early-stage Breast Cancer:

100-month Analysis of the ATAC Trial

Forbes JF, et al.

Disease-free Survival HR+ Patients

Tamoxifen (T) Anastrozole (A)

Pat

ient

s (%

)

30

25

20

15

10

5

0

26182598

25412516

24532400

23612306

22782196

21592075

19951896

18011711

14921396

608547

At risk:AT

13.9%

16.4%

25.8%

29.9%

0 1 2 3 4 5 6 7 8 9

30

25

20

15

10

5

0

HR+

HR

0.85

95% CI

(0.76, 0.94)

P-value

0.003

Follow-up time (years)

Absolute difference 2.5% 4.1%

HR, hazard ratio; CI, confidence interval Forbes et al Lancet Oncology 2008

Time to Recurrence HR+ Patients

Forbes et al Lancet Oncology 2008

26182598

25412516

24532400

23612306

22782196

21592075

19951896

18011711

14921396

608547

At risk:AT


Pat

ient

s (%

)

30

25

20

15

10

5

0

0 1 2 3 4 5 6 7 8 9

30

25

20

15

10

5

0

12.5% 17.0%

21.8%

9.7%

2.8% 4.8%Absolutedifference

HR+

HR

0.76

95% CI

(0.67, 0.87)

P-value

0.0001


Time to Distant RecurrenceHR+ Patients

26182598

25512533

24702440

23932363

23202263

22012151

20421982

18541809

15361484

636591

At risk:AT

Pat

ient

s (%

)

30

25

20

15

10

5

0

0 1 2 3 4 5 6 7 8 9

30

25

20

15

10

5

0

7.8%

9.1% 13.2%

15.6%


HR+

HR

0.84

95% CI

(0.72, 0.97)

P-value

0.022

Absolute difference 1.3% 2.4%



Death: All CausesHR+ Patients

26182598

25672549

25112504

24452432

23892339

22742227

21022068

19111888

15861551

659620

At risk:AT

Pat

ient

s (%

)

30

25

20

15

10

5

0

0 1 2 3 4 5 6 7 8 9

30

25

20

15

10

5

0


HR+

HR

0.97

95% CI

(0.86, 1.11)

P-value

0.70



Use of Oncotype DX® in Node-positive ER-positive Breast Cancer

• The 21-gene Recurrence Score assay (RS) is prognostic for women with node (-), ER+ breast cancer on 5 years of tamoxifen*

• A high RS predicts large benefit from chemotherapy in node (-) disease, but no improvement if the RS is low**

• There are no RS data in a N+ population with a tamoxifen-alone control

• SWOG 8814 is an ideal trial to explore this question

*Paik, et al. NEJM, 2004

**Paik, et al. J Clin Oncol, 2006

SABCS 2007, Abstract 10

Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in

Postmenopausal, Node-Positive (N+), ER-Positive (ER+) Breast Cancer

SWOG 8814, TBCI 0100

K. Albain et al.

Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+

CAF x 6, then tamoxifen

RANDOMIZE N = 1477

tamoxifen x 5 yrs CAF x 6, with concurrent tamoxifen

Superior Disease-Free Survival (DFS) and Overall Survival (OS) over 10 Years

(N = 361) (N = 550) (N = 566)

Albain K, et al. SABCS 2007. Abstract 10.

SWOG 8814/TBCI 0100 Sample Size for This Analysis

Patients with samples - 666(45% of parent trial)

RT-PCR obtained - 601 (90%)Tamoxifen alone 148

CAFT (concurrent) 234

CAF-T (sequential) 219

Final sample for primary analysis148 + 219 = 367 (40% of parent trial)


SWOG 8814/TBCI 0100 Correlative Science Study

1) provides prognostic information for women with N+ disease treated only with tamoxifen, and

2) allows prediction of a N+ group that does not derive benefit from chemotherapy

Two co-primary objectives were to determine if the RS:


0.00

0.25

0.50

0.75

1.00

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10Years since registration

Tamoxifen (N = 148, 63 events)CAF-T (N = 219, 74 events)

Stratified log-rank P = 0.054 at 10 years

(adjusted for nodal status)

Outcomes in RS Subset Mirror Those Reported in Main Trial: Superiority of CAF-T

Disease-free Survival


Comparative Distribution of RS SWOG 8814 Less Low RS, More High RS

Study Low Risk

(RS < 18)

Int. Risk

(RS 18-30)

High Risk

(RS ≥ 31)

NSABP B14* 51% 22% 27%

NSABP B20* 54% 21% 25%

Kaiser controls* 56% 19% 25%

ECOG 2197** 49% 31% 20% SWOG

8814*** 40% 28% 32%

*node(-): Paik, et al. NEJM 2004 & JCO 2006; Habel, et al. Breast Ca Res Treat 2006 **node- or 1-3+: Goldstein, et al. Proc ASCO 2007

***node+, postmenopausal: this analysis - no difference by age

SWOG 8814/TBCI 0100 21-Gene Recurrence Score is Prognostic for

DFS and OS in Tamoxifen Arm

0.0

00

.25

0.5

00

.75

1.0

0

Dis

ea

se-f

ree

su

rviv

al

0 2 4 6 8 10

Years since registration

Low RS <18 (n=55)

Intermediate RS 18-30 (n=46)

High RS ≥31 (n=47)


Disease-Free Survival by Risk Group (tamoxifen alone)

10-yr: 60%, 49%, 43%

0.0

00

.25

0.5

00

.75

1.0

0O

vera

ll S

urv

ival

0 2 4 6 8 10


Low RS <18 (n=55)

Intermediate RS 18-30 (n=46)

High RS ≥31 (n=47)


Overall Survival by Risk Group(tamoxifen alone)

10-yr: 77%, 68%, 51%


Strong benefit if high RS

0.0

00

.25

0.5

00

.75

1.0

0

Dis

ea

se-f

ree

sur

viva

l

0 2 4 6 8 10


Tamoxifen (n=55, 15 events)CAF-T (n=91, 26 events)


Low risk (RS < 18)

Disease-Free Survival by Treatment0.

000.

250.

500.

751

.00

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10




High risk (RS ≥31)

Disease-Free Survival by Treatment

0.0

00

.25

0.5

00

.75

1.0

0

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10




Intermediate risk (RS 18-30)

Disease-Free Survival by Treatment

Prediction of Chemotherapy Benefit

No benefit to CAF

over time if low RS


SWOG 8814/TBCI 0100 Ten-Year DFS Point Estimates (95% CI)

Recurrence Score

Risk Category

Tamoxifen

Alone

CAF followed

by tamoxifen

Low (< 18)*60%

(40%, 76%)

64%

(50%, 75%)

Intermediate (18-30)49%

(32%, 63%)

63%

(48%, 74%)

High (≥ 31)43%

(28%, 57%)

55%

(40%, 67%)

*40% event rate over 10 years and resistance to CAF

DFS: distant and local metastasis, CBC, deaths from other causes


CAF Benefit Greatest in Higher RS for Both Nodal Subsets, with No Benefit in Lower RS

Five-Year Probability of Death or Disease RecurrenceLinear model for Recurrence Score and interactions with treatment

00

.20

.40

.60

.81

.0

Fiv

e Y

ear

Pro

bab

ility

of

an E

vent

0 20 40 60 80 100

Recurrence Score

Tam, 4+ nodes (n=54)CAF-T, 4+ nodes (n=86)Tam, 1-3 nodes (n=94)CAF-T, 1-3 nodes (n=133)

Chemo benefit 4+ nodes

Chemo benefit 1-3 nodes


The RS is Also Predictive for Overall Survival in SWOG 8814/TBCI 0100

• No benefit to CAF in low RS in first 5 years (HR 1.05) or over entire time period (HR 1.18)

• Strong impact of CAF in high RS first 5 years HR 0.43 (0.21, 0.90) and over entire period HR 0.56 (0.31, 1.01)

10-year estimates:

Tam 51% (35%, 65%)

CAF-T 68% (51%, 79%)

0.0

00

.25

0.5

00

.75

1.0

0

Ove

rall

surv

iva

l

0 2 4 6 8 10


Tamoxifen (N=47, 22 deaths)CAF-T (N=71, 20 deaths)

Stratified log-rank test P = 0.027 at 10 years

High risk (RS ≥31)

Overall Survival by Treatment



Value of Centrally-assessed Ki-67 Labeling Index as a Marker of Prognosis and Predictor of Response to

Adjuvant Endocrine Therapy in the BIG 1-98 Trial of Postmenopausal Women with Estrogen Receptor-

positive Breast Cancer

Viale G, et al.

BIG 1-98 Central Assessment of Ki-67

Viale G et al. Presented at: SABCS 2007, San Antonio, Tex. Abs 64.

TAM

LET

LET

LET TAM

RANDOMIZE

0 2 5Years

AB

C

D

TAM

N = 4,922 monotherapy

N = 3,088 sequential

N = 8,010 randomized

• IBCSG Central Pathology Laboratory assessed:

– Ki-67 immuno-reactivity by IHC (median 11%)

– ER, PgR by IHC; HER2 by IHC; confirmed by FISH

• Analysis cohort: 2,685 of 4,922 (55%) with material evaluable for Ki-67 and with ER-expressing tumors (≥1%), centrally confirmed

• Retrospective tissue collection

Disease Free Survival by Ki-67 LI

• 1,252 (47%) expressed Ki-67 LI > 11% (high)

• High Ki-67 LI associated with: (each P<0.01)

– Larger tumors

– Higher tumor grade

– Vessel invasion

– HER2 +

• No association with PgR

Viale G et al. SABCS 2007, Abs 64.

Ki-67 LI by Treatment

• High Ki-67: hazard of DFS event for letrozole was half the hazard for tamoxifen

– HR(L:T) = 0.53 (95% CI, 0.39 to 0.72)

• Low Ki-67: hazard also less for letrozole (HR(L:T)=0.81; 95% CI, 0.57 to 1.15)

Viale G et al. SABCS 2007, Abs 64.

CYP2D6 Genetic Variations

• Caucasians and Western Europeans:

– 1-2% have multiple copies (Ultra-rapids = UM)

– 70% have two wild type alleles (Extensive = EM)

– 20% have one variant (CYP2D6*4) allele (Intermediate = IM)

– ~8% have two variant alleles (Poor = PM)

• CYP2D6 is responsible for the conversion of tamoxifen to its most abundant active metabolite: endoxifen

Kaplan Meier Plots for Patient by CYP2D6*4 Genotype

Goetz J Clin Oncol 23: 9312-9318, 2005

Disease-free Survival Overall Survival

Hot flashes36/177

Hot flashes0/13

Hypothesis: CYP2D6 Activity Influences Patient Adherence to Therapy

• Women with reduced CYP2D6 activity on chronic tamoxifen therapy:

– Have lower endoxifen concentrations

– Will experience fewer side effects

– Will be more likely to adhere to tamoxifen therapy.


Cytochrome P450 2D6 Activity Predicts Adherence to Tamoxifen Therapy

Rae JM, et al.

CYP2D6 Poor Metabolizers are Most Likely to Adhere to Tamoxifen

Score Phenotype #Stayed on

N (%)

Dropped out

N (%)

0 PM 10 10 (100) 0 (0)

0.5 IM 15 14 (93.3) 1 (6.7)

1 IM 72 65 (90.3) 7 (9.2)

1.5 EM 50 43 (86) 7 (14)

2 EM/UM 120 107 (89.2) 13 (10.8)

Total 267 240 (89.9) 28 (10.5)

Rae JM, et al. SABCS 2007 Rae JM, et al. SABCS 2007


The Effect of Zoledronic Acid on Aromatase Inhibitor-associated Bone Loss in

Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole:

The Z-FAST Study 36-month Follow-up

Brufsky A, et al.

Z-FAST: Zoledronic Acid for AI-Related Bone Loss: 36-Month Follow-up

Primary Objective: % change in lumbar spine (LS) BMD at 12 months

Secondary Objective: % change LS BMD at 24, 36, 60 months % change total hip (TH) BMD at 12, 24, 36, 60 months

Bone markersIncidence of fractures (36 months)Time to disease progression

Brufsky, SABCS 2007, Abstract 27

Stratification:- Adjuvant chemo (yes or no)- T score (> -1 or

b/w 1 and -2)

Zoledronic acid (delayed) 4 mg IV q 6 monthsLetrozole 2.5 mg po qd

N = 602

Zoledronic acid (up front) 4 mg IV q 6 monthsLetrozole 2.5 mg po qd

RANDOMIZE

Eligibility:- Early ER+ or

PgR+ BC- PMW- T score ≥ -2

Z-FAST Efficacy Results: Upfront vs. Delayed Zoledronic Acid

Significant positive percentage change in LS (P < .0001) and TH (P < .0001) bone mineral density for upfront compared to delayed zoledronic acid after 12, 24, and 36 months follow-up

Fracture Rates

Clinical Sig.

Trauma

Minimal or No

TraumaAsymp. Other

Radiological Spine

Total

Upfront ZA (N = 300)

11 (3.7%) 2 (0.7%) 2 (0.7%) 1 (0.3%) 1 (0.3%) 17 (5.7%)

Delayed ZA (N = 300)

12 (4.0%) 3 (1.0%) 1 (0.3%) 2 (0.7%) 1 (0.3%) 19 (6.3%)

Brufsky, SABCS 2007, Abstract 27


A Phase 3 Study of the Effect of Denosumab Therapy on Bone Mineral Density in

Women Receiving Aromatase Inhibitors for Non Metastatic Breast Cancer

Ellis G, et al.

Phase III Study of the Effect of Denosumab on Bone Mineral Density in Women Receiving Aromatase

Inhibitors for Nonmetastatic Breast Cancer

• Background:– Bone loss is mediated by osteoclasts whose formation, function, and

survival depend on receptor activator of NF-κB ligand (RANKL).

• Objective: – To evaluate denosumab, a fully human monoclonal antibody to

RANKL, compared with placebo in women with nonmetastatic breast cancer who are receiving aromatase inhibitor adjuvant therapy

• Study details:– Patients randomized to receive denosumab 60 mg s.c. every 6

months × 4 doses or placebo on the same schedule

– All patients were instructed to take daily supplements of calcium (1000 mg) and vitamin D ( 400 IU).

Ellis, SABCS 2007, Abstract 47

Effect of Denosumab on Lumbar Spine Bone Mineral Density (BMD)


* P < 0.0001 versus placebo

Per

cen

tag

e C

han

ge (

± 95

% C

I) F

rom

Bas

elin

e in

Lum

bar

Spi

ne

Bon

e M

iner

al D

ensi

ty

8

6

4

2

0

-2

7

5

3

1

-1

-3

**

**

*

7.6% Differenceat Month 24

1 3 6 12 24Months


• Not influenced by the duration of aromatase inhibitor therapy (≤ 6 months or > 6 months)

Denosumab (N = 123)Placebo (N = 122)

Effect of Denosumab on Bone Mineral Density at the Total Hip and Distal 1/3 Radius

* P < 0.0001 versus placebo


Total Hip (Proximal Femur)

Per

cen

tag

e C

han

ge (

± 95

% C

I) F

rom

Bas

elin

e in

Bon

e M

iner

al D

ens

ity

Distal 1/3 Radius

1 3 6 12 24

Months

4

2

0

-2

5

3

1

-1

Placebo (N = 122) Denosumab (N = 123)

**

**



Placebo (N = 106) Denosumab (N = 115)

12 24

Months

4

2

0

-2

3

1

-1

-3

-4

-5

* *



Adverse Events at 24 Months

EventPlacebo

(N = 120)

Denosumab

(N = 129)

Arthralgia 30 (25%) 31 (24%)

Pain in Extremity 14 (12%) 19 (15%)

Back Pain 15 (13%) 18 (14%)

Fatigue 17 (14%) 17 (13%)

Constipation 11 (9%) 15 (12%)

Cough 5 (4%) 13 (10%)

Insomnia 14 (12%) 12 (9%)

• There were no treatment-related serious adverse events, and although 1 death occurred in each treatment arm, these were not considered treatment related.

• Overall, denosumab appears to increase bone mineral density in patients who have received AIs for nonmetastatic breast cancer with minimal drug-related toxicities.


Summary Endocrine Agents

• The superior effects of anastrozole over tamoxifen have persisted over time but there is still no survival difference

• Molecular profiling and pharmacodynamic studies can optimize the selection of endocrine agents

• Bisphosphonates and denosumab appear beneficial in preventing AI-induced bone loss


Extended Follow-up and Analysis by Age of the US Oncology Adjuvant Trial 9735:

Docetaxel/Cyclophosphamide is Associated with an Overall Survival Benefit Compared to Doxorubicin/Cyclophosphamide and is Well-

tolerated in Women 65 or Older

Jones, et al.

US Oncology 9735 Follow-up Analysis: AC vs. TC

Eligibility: Stage I, II, or III diseaseMedian follow up: 7 years

16% of patients 65 years or older

Tamoxifen for all ER+ patients after chemotherapy +/- radiation

• N = 1016• 67% ER+• 48% N–

4 x AC q3wDoxorubicin (60 mg/m2)Cyclophosphamide (600 mg/m2)

N = 510

4 x TC q3wDocetaxel (75 mg/m2) Cyclophosphamide (600 mg/m2)N = 506

RANDOMIZE

Jones et al. J Clin Oncol. 2006;24:5381-87.Jones, SABCS 2007, Abstract 12

Efficacy by TreatmentAC vs. TC: 7 year Median Follow-up

AC (N = 510)

TC(N = 506)

Overall DFS75% 81%

HR 0.74, P = 0.033

Overall Survival82% 87%

HR 0.69, P = 0.032

• TC effective in HER2+ (N=46) as well as HER2- (N=124) patients

AC TC

DFS < 65 yearsN = 428 N = 428

HR 0.76, P-value NR

DFS ≥ 65 yearsN = 82 N = 78

HR 0.70, P-value NR

Jones, SABCS 2007, Abstract 12

AC vs. TCDisease-free Survival by Treatment

At Risk TC 506 495 473 454 442 434 425 420 418 AC 510 498 477 442 422 412 401 396 392

0 12 24 36 48 60 72 84 96

Months

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Pro

po

rtion

DF

S

P = 0.033HR = .74

TC

AC

81%

75%


AC vs. TC: Exploratory Analysis of DFS Hazard Ratios (CI) for Key Subgroups

Overall HR for DFS = 0.74


AC vs. TCOverall Survival by Treatment

At Risk TC 506 502 495 481 466 461 454 449 448 AC 510 504 493 476 459 448 432 429 427

0 12 24 36 48 60 72 84 96

Months

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Pro

po

rtion

Su

rviv

ing

P = 0.032HR = .69

TC

AC

87%

82%


Major Grade 3/4 Toxicities by Age: AC vs. TC

< 65 years ≥ 65 years

Adverse EventAC (%)

(n = 428)TC (%)

(n = 428)AC (%)(n = 82)

TC (%)(n = 78)

Anemia 1 <1 5 <1

Neutropenia 54 60 59 52

Febrile Neutropenia 2 4 4 8

Asthenia 4 3 9 6

Fever 3 4 4 6

Infection 10 7 2 6

Diarrhea 1 2 1 5

Nausea 7 2 5 3

Vomiting 6 1 0 0

3 Long-Term Fatal Toxicities on AC Arm: CHF, MDS, Myelofibrosis


• New antineoplastic class - the natural epothilones and their analogs

• Low susceptibility to tumor resistance mechanisms

– MRP-1 and P-gp efflux pumps

– b (III) tubulin overexpression

– b tubulin mutations

• Activity in multiple tumor models

• Demonstrated pre-clinical synergy with capecitabine

Epothilones: Ixabepilone (BMS-247550)

S.cellulosum Epothilone B Ixabepilone

Study Design International, Randomized, Open-label, Phase III Trial

Ixabepilone(40 mg/m2 IV over 3 hr d1 q3wk)

+Capecitabine

(2000 mg/m2/day PO 2 divided doses d1-d14 q3wk)

Capecitabine(2500 mg/m2/day PO 2 divided doses

d1-d14 q3wk)

Metastatic or locally advanced breast cancer

RESISTANT to anthracyclines

and taxanes

Stratification • Visceral metastases• Prior chemotherapy for MBC

• Anthracycline resistance• Study site

Median 95% CI

Ixabepilone + Capecitabine 5.8 mo (5.5–7.0)

Capecitabine 4.2 mo (3.8–4.5)

Progression-free Survival by Independent Radiologic Review

P = 0.0003

HR: 0.75 (0.64–0.88)

Pro

port

ion

Pro

gres

sion

Fre

e

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24 28 32 36

Months

Thomas et al J Clin Oncol 2007

Response Rate

% Response

Investigator IRR

Ixabepilone + Capecitabine

(N = 375)

Capecitabine

(N = 377)

Ixabepilone + Capecitabine

(N = 375)

Capecitabine

(N = 377)

ORR (CR + PR) 42 23 35 14

P < 0.0001 P < 0.0001

Stable disease 36 38 41 46

Progressive disease

14 29 15 27

Unable to determine

8 10 9 12


SABCS 2007, Poster 6069

Combination Therapy with the Novel Epothilone B Analog, Ixabepilone, Plus Capecitabine has

Efficacy in ER/PR/HER2-negative Breast Cancer Resistant to Anthracyclines and Taxanes

Rugo HS, et al.

Ixabepilone + Capecitabine in ER/PR/HER2-Negative MBC Resistant to Anthracyclines and Taxanes

Efficacy Results

Rugo H, et al. SA BCS 2007. Poster 6069.

On-Study Deaths

Ixabepilone +Capecitabine

(N = 369)

Capecitabine

(N = 368)

Number of patients

Deaths within 30 days 35 39

Disease progression 18 32

Treatment-related toxicity 12 2

Other/unknown causes 5 5

• All toxicity-related deaths with ixabepilone plus capecitabine were attributable to neutropenia

– Incidence with baseline ≥Grade 2 LFTS was 31% (5/16 patients)

– Incidence with baseline ≤Grade 1 LFTS was 2% (7/353 patients)

• Protocol amended to exclude patients with baseline ≥ Grade 2 liver dysfunction


Grade 3/4 Hematologic Toxicities

(%)*Ixabepilone + Capecitabine

(N = 369)

Capecitabine

(N = 368)

P-value

Leukopenia 57 6 <0.0001

Anemia 10 4 0.005

Neutropenia 68 11 <0.0001

Thrombocytopenia 8 4 0.011

Febrile neutropenia 4 <1 0.001


*By worst CTCAE v.3 grade

Grade 3/4 Non-hematologic ToxicitiesP

erip

hera

l

neur

opat

hy

23

0

Mya

lgia

8

0.3

Han

d-fo

ot

synd

rom

e

18 17

Dia

rrhe

a6

9

Muc

ositi

s

3 2

Vom

iting

42

Fatig

ue

9

3

Nau

sea

3 2

Art

hral

gia

30

0

% o

f P

atie

nts

Ixabepilone + Capecitabine (N=369)

Capecitabine (N=368)

20

40

60

80



EGFR Inhibition with Cetuximab in Metastatic Triple Negative (Basal-like) Breast Cancer

Carey LA , et al.

Randomized Phase IICetuximab ± Carboplatin for Triple-Negative MBC

Carey et al. SABCS 2007, Abstract 307

RANDOMIZE

Cetuximab(N = 31)

Cetuximab + Carboplatin at Progression

(N = 22)

Cetuximab + Carboplatin(N = 49) (Not Reported)

Randomized Phase IICetuximab +/- Carboplatin for Triple-Negative MBC

• Arm 1 Closed – Response to single-agent cetuximab did not meet criteria for continuing

– Single-Agent Cetuximab

• 2 PR (6%), 5 SD (16%)

• Major SAEs: Rash (10%), Pain, Constitutional, Lab, Musculoskeletal (3% each)

– Cetuximab + Carboplatin at Progression

• 4 PR (18%), 5 SD (23%)

• Major SAEs: Rash (9%), Bone Marrow, Vascular, GI, Constitutional, Pain, Pulmonary (4.5% each)

• Arm 2 – Accrual complete, analysis ongoing

Carey et al. SABCS 2007, Abstract 307


Preliminary Results of a Randomized Phase II Study of Weekly Irinotecan/Carboplatin with or without Cetuximab in Patients with Metastatic

Breast Cancer

O'Shaughnessy J. et al.

Randomized Phase II:Weekly Irinotecan/Carboplatin ± Cetuximab for MBC

O’Shaughnessy et al. SABCS 2007, Abstract 308

Eligibility:0-1 Prior Therapies for MBC

Stratify:Triple Negative MBC

RANDOMIZE

Irinotecan*100 mg/m2 Carboplatin*AUC 2.5Days 1,8 q3w

Cetuximab alone at progression

* Starting doses decreased to 90 mg/m2 and AUC = 2.0 midway through enrollment due to diarrhea with triplet

Irinotecan* 100 mg/m2 D1,8 q3wCarboplatin* AUC 2.5 Days 1,8 q3wCetuximab 400 mg/m2 D1, then 250 mg/m2 weekly

Primary Objective: ORR

Randomized Phase II:Weekly Irinotecan/Carboplatin ± Cetuximab for MBC

I/Cb I/Cb + Cetuximab

Overall Response Rate 31% 38%

Triple Negative 30% 49%

HR+/HER2- 29% 25%

Median PFS 4.6 mo 4.8 mo

Triple Negative 5.1 mo 4.7 mo

HR+/HER2- 4.1 mo 4.6 mo

Median OS 12.8 mo 13.1 mo

Triple Negative 12.3 mo 15.5 mo

HR+/HER2- 12.8 mo 14.6 mo

138 Patients evaluable for efficacy

In subset analysis, starting dose triplet had higher ORR than doublet

O’Shaughnessy et al. SABCS 2007, Abstract 308

SABCS 2007, Abstract/Poster 4056

Trastuzumab Treatment Beyond Progression in Patients with HER-2 Positive Metastatic Breast

Cancer the TBP Study (GBG 26/BIG 3-05)

von Minckwitz G, et al.

Trastuzumab Treatment Beyond Progression in Patients with HER2 Positive MBC

Study Design and Treatment

Metastatic or locally advanced breast cancer

(N = 305)

Capecitabine 2,500 mg/m2 d1-14 q21 days(N = 78)

Capecitabine 2,500 mg/m2 d1-14 q21 days

+

Continuation of Trastuzumab 6mg/kg

every 3 weeks(N = 78)

• Primary Objective:

– TTP

• Secondary Objective:

– ORR

– Duration of response

– CR, PR, SD

– Safety

– Overall survivalVon Minckwitz G, et al. SA BCS 2007. Poster 4056.


Severe Toxicities (Grade 3/4)

Von Minckwitz G, et al. SA BCS 2007. Abst 4056.


Interim Efficacy Results

Von Minckwitz G, et al. SA BCS 2007. Poster 4056.

X

(N = 78)

XH

(N = 78)

Overall response rate (CR + PR)

24.8% 48.9%

Stable disease 49.1% 35.1%

PFS, mos. 5.6 8.5

OS, mos. 19.9 20.3

(HR: 0.71)

(HR: 0.79)


Progression-free Survival



Overall Survival


Summary of Chemotherapy and Biologics

• TC superior to AC in efficacy and in toxicity

• Ixabebilone has activity in heavily pretreated MBC, including triple negative cancers

• EGFR-directed therapies appear to have minimal single agent activity in triple negative cancers

• At last there is data to support continuing trastuzumab through progression

oncology journal club clinical review of current treatment strategies for breast cancer ruth m....

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