ASCO 2006 UpdateNovel Therapeutics in Prevention and Treatment

for Breast Cancer

Hope S. Rugo, MDClinical Professor of Medicine

Director, Breast Oncology Clinical Trials ProgramUCSF Comprehensive Cancer Center

Discussion Outline• Endocrine Therapy

Prevention• 5: STAR NSABP P-2

Adjuvant therapy• Updates from IES, ARNO95, GROCTA4/ITA, MA17• Bone health substudy from ATAC

• Neoadjuvant Metronomic chemotherapy (SWOG 0012)

• Adjuvant trastuzumab Update on the HERA trial

• New treatments for HER2+ disease – Lapatanib Phase III trial with capecitabine 502: Inflammatory breast cancer 503: Treatment of CNS disease 583: Risk of cardiac toxicity

The Study of Tamoxifen and Raloxifene (STAR): Initial Findings from the NSABP P-2

Breast Cancer Prevention Study

Eligibility:

• Postmenopausal women at moderate to high risk

• 5-year breast cancer risk by modified Gail score = 1.66%

TAMOXIFEN 20 mg/day

X 5 years

RALOXIFENE 60 mg/day X 5 years

• Accrual (July 1999-Nov 2004) – 19,747 women randomized• Interim results at 327 invasive breast cancer cases• Average follow-up 47.3 months

Wickerham, ASCO 2006, LBA#5

NSABP P-2: Results• Patient Population

Age: <49: 9%; 50-59: 50%; 60-69: 32%; 70+: 9% Prior hysterectomy: 51.5% Prior LCIS: 9.2% Prior Atypical Hyperplasia: 22.7%

Tamoxifen Raloxifene Relative Risk P Value

Invasive Breast Cancer*

163 168 0.83 -

Noninvasive Breast Cancer

57 81 1.40 .052

* Gail Model Projected Incidence: 312 Wickerham, ASCO 2006, LBA#5

SAFETY

Wickerham, ASCO 2006, LBA#5

Tamoxifen Raloxifene Relative Risk

Uterine Cancer 36 23 0.62Endometrial Hyperplasia 84 14 -

Hysterectomy (non-cancer) 244 111 -

Thromboembolic Events 141 100 0.70*

Strokes 53 51 -Myocardial Infarction 48 37 0.77Severe Angina 51 63 1.23Acute Ischemic Syndrome 15 26 1.72

Osteoporotic Fractures 106 98 0.92Cataracts 394 313 0.79

*P=.01

STAR Trial: Summary• Raloxifene compared to tamoxifen for breast cancer prevention in

postmenopausal women was As effective in preventing invasive disease Not as effective in preventing in situ disease

• And resulted in: Fewer thromboembolic events Fewer cataracts Fewer endometrial cancers

• Patient reported outcomes More musculoskeletal symptoms, weight gain, dyspareunia with

raloxifene More vasomotor symptoms, bladder problems, leg cramps, gynecologic

symptoms with tamoxifen• The future of prevention trials?

Comparison of aromatase inhibitors to placebo• Map 3 – exemestane vs placebo (4560 pts)• IBIS-2 – anastrozole vs placebo (6000 pts)

IES Trial Design

Tamoxifen

RANDOMIZE

Exemestane5162*

Tamoxifen5294*

Post Treatment Follow-up

10335*

Diagnosis

2-3 years2-3 years study

treatment

Total 5 years endocrine therapy

Start of study

* Total women years

47244724

Coombes, # LBA527

First Mature Survival Analysis of the IES Trial: Switching to Exemestane after 2-3 Years of

Adjuvant Tamoxifen Coombes, # LBA527

Hazard Ratio* P Value

DFS

Intent to Treat 0.76 .0001

ER+/Unknown 0.75 .0001

Overall Survival

Intent to Treat 0.85 .08

ER+/Unknown 0.83Adjusted .88

.05Adjusted .04

Median Follow-up: 55.7 months, 4.6 yrs

122 pts found to be ER- on central review, 2.4 vs 2.8%

End oftreatm

ent

End oftreatm

ent

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 1 2 3 4 5

Time since randomization (years)Cu

mul

ativ

e R

ate

Cumulative Hazard Rate - OS

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 1 2 3 4 5

Time since randomization (years)

Cum

ulat

ive

Rat

e

Exemestane Tamoxifen

Annual Hazard Rate, % (95% CI)

ITT 1 2 3 4 5

Exemestane 0.8 (0.5, 1.2) 1.8 (1.3, 2.5) 2.2 (1.6, 2.9) 3.6 (2.8, 4.5) 2.3 (1.6, 3.4)

Tamoxifen 1.0 (0.7, 1.5) 2.4 (1.8, 3.1) 2.5 (2.0, 3.3) 3.2 (2.5, 4.1) 2.9 (2.1, 4.1)

ITT ER+/Unknown

IES: Cardiovascular Safety

Coombes, # LBA527

Exe Tam P-Value

Ischemic Cardiac Events

9.9% 8.6% .12

Myocardial Infarction 1.3% 0.8% .08

Angina 7.1% 6.5% .44

Other cardiac events 11.3% 11.2% .96

CVA 2.5% 2.4% .89

Thromboembolic Thromboembolic eventsevents

1.9%1.9% 3.1%3.1% .01.01

IES: SafetyExe Tam P-Value

FractureFracture 7.0%7.0% 4.9%4.9% .003.003OsteoporosisOsteoporosis 9.2%9.2% 7.2%7.2% .01.01ArthritisArthritis 17.5%17.5% 14.6%14.6% .008.008Musculoskeletal painMusculoskeletal pain 25.7%25.7% 20.3%20.3% <.001<.001ArthralgiaArthralgia 20.8%20.8% 15.1%15.1% <.001<.001Cramp 2.5% 4.4% <.001Gastric Ulcer 1.2% 0.3% .001Serious gyn events 6.4% 9.8% <.001Vaginal Bleeding 4.8% 7.1% .001Endometrial hyperplasia

0.2% 1.0% <.001

Uterine fibroids/polyps 1.4% 4.0% <.001Uterine D&C 0.7% 1.5% .006Endometrial Cancer 0.4% 0.7% .17

ARNO 95: ARNO 95: Survival Benefit of Switching to Anastrozole after Survival Benefit of Switching to Anastrozole after

2 yrs Tamoxifen vs Continued Tamoxifen 2 yrs Tamoxifen vs Continued Tamoxifen Kaufmann, # 547

• Small trial, small number of events N = 979 No adjuvant chemotherapy given, 74% node negative Median follow-up 30 months

• Results Switching to anastrozole reduced risk of recurrence (HR 0.66;

P=.049)• 3-year DFS

• Absolute difference of 4.2% (93.5% vs 89.3%) Switching to anastrozole improved OS (HR 0.53; P=.045) Serious adverse events were reported less frequently with

anastrozole (22.7% vs 30.8%; P=.0065)• Vascular events 9.2% A vs 8.8% T• Musculoskeletal events 16.8% A vs 8.0% T • Endometrial events 4.5% A vs. 15.9% T

Pooled Analysis of Grocta 4 and ITA Trials:Pooled Analysis of Grocta 4 and ITA Trials:Mortality Benefit of Switching to an AI Mortality Benefit of Switching to an AI

Boccardo, # 548• Two consecutive small phase III trials

Tamoxifen for 2-3 yrs followed by either aminoglutethimide or anastrozole for a total of 5 yrs

• N=813 (pooled)• 415 tamoxifen for 5 years• 413 tam followed by either A

• Results All-cause mortality

HR 0.61 favoring switch, P = .007 Breast cancer mortality

HR 0.61 favoring switch, P =0.25 Breast cancer unrelated deaths HR = 0.62; P=.10

Small studies, hard to evaluate P values in pooled analyses, encouraging results!

Updated analysis of NCIC CTG MA.17 (letrozole vs. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblindingplacebo to letrozole vs placebo) post unblinding

Robert, # 550

TamoxifenN = 5187

Placebo n= 25945 years Letrozole (PLAC-LET) n = 1655

Median F/U (mo) 30 54

Letrozole n= 2593

Unblinding

Letrozole n = 2457

Placebo (PLAC) n = 613

• Purpose: compare PLAC-LET vs PLAC to determine benefits/safety of starting letrozole after prolonged periods (1-5 y) off tamoxifen

• Patients: those who switched (PLAC-LET) were younger, had more advanced disease, and were more likely to have had adjuvant chemotherapy than PLAC patients

0-3 mo

R

0.310.28

0.53

0.23

0

0.1

0.2

0.3

0.4

0.5

0.6

DFS Distant DFS OS CBC

P<0.0001 P=0.002

P=0.05

P=0.012

PLA

C-L

ET to

PLA

C

Haz

ard

Rat

io

• Safety

PLAC-LET vs PLAC: no significant increase in fractures (P=0.60); more new osteoporosis (P=0.007); no difference in cardiovascular disease (P=0.84)

OS = overall survival; CBC = contralateral breast cancer.

Robert, ASCO 2006 # 550

Updated analysis of NCIC CTG MA.17 (letrozole vs. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblindingplacebo to letrozole vs placebo) post unblinding

NCIC CTG MA.17: Intent to treat analysis NCIC CTG MA.17: Intent to treat analysis (ITT) of randomized patients after a median (ITT) of randomized patients after a median

follow-up of 54 monthsfollow-up of 54 monthsIngle, # 549

Univariate Multivariate4 yr % HR P Value HR P Value

DFS L 94.3%

P 91.4%

0.64 .00002 .64 .00003

DDFS L 96.2%

P 94.9%

.76 .041 .76 .045

OS L 95.0%

P 95.1%

1.00 .99 1.00 0.97

CL BC - .061 .037 - -

•Advantage of letrozole for DFS, DDFS and contralateral breast Advantage of letrozole for DFS, DDFS and contralateral breast cancer reduction maintained despite 73% of patients on placebo cancer reduction maintained despite 73% of patients on placebo opting to receive letrozole after study unblindingopting to receive letrozole after study unblinding

• Bone subprotocol: Anastrozole N=81, Tamoxifen N=86• More bone loss reported with anastrozole in lumbar spine

(P<.0001) and hip (P<.0001)• No patients with normal bone at baseline became No patients with normal bone at baseline became

osteoporotic while on treatmentosteoporotic while on treatment 17% on anastrozole became osteopenic versus 3% on tamoxifen

• Of patients osteopenic at baseline 5% became osteoporotic on anastrozole versus 1% on tamoxifen

• On the ATAC trial, a total of 11% of patients on anastrozole experienced bone fracture, versus 7.7% on tamoxifen (HR 1.49; P<.0001)

Effect of Anastrozole on Bone Mineral Effect of Anastrozole on Bone Mineral Density: 5-year Results from the ATAC Trial Density: 5-year Results from the ATAC Trial

SubStudySubStudy Coleman, # 511

SWOG 0012SWOG 0012Standard AC vs Weekly A and Daily C, followed by Standard AC vs Weekly A and Daily C, followed by Weekly T, a Randomized Phase III Comparison as Weekly T, a Randomized Phase III Comparison as Neoadjuvant Therapy of Inflammatory and Locally Neoadjuvant Therapy of Inflammatory and Locally

Advanced Breast CancerAdvanced Breast CancerEllis, # LBA537

RANDOMIZE

A (60 mg/m2) withC(600 mg/m2) q 3 wks x 5→ Paclitaxel 80 mg/m2 wkly x 12

A (24/m2/wk) withC (60/m2/day) + G-CSF wkly x 15→ Paclitaxel 80 mg/m2 wkly x 12

Inflammatory or Locally

Advanced BC

N=265(IBC 31%)

SURGERY

Primary endpoint: Pathologic CR

SWOG 0012Results

Standard AC Continuous AC + G

P

pCR (% at breast)pCR (% at breast) 19%19% 31%31% .03.03pCR and node-negative

15% 26% -

Grade 3/4 AE Standard AC Continuous AC + G

Hand-foot Hand-foot syndromesyndrome

00 13%13%

Neutropenia 47% 16%Febrile Neutropenia

1.8% 0.6%

StomatitisStomatitis 2%2% 11%11%Nausea/Vomiting 11% 5%

Ellis, ASCO 2006 # LBA537

S0221 (Intergroup Trial)

AC + pegfilgrastim q2 wk x 6A = 60 mg/m2, C = 600 mg/m2

Node (+) Node (+) and High and High

Risk Node Risk Node ((--))

AC + filgrastim wkly x 15A = 24 mg/m2, C = 60 mg qd

RRaannddoommi i z z ee

AC + pegfilgrastim q2 wk x 6A = 60 mg/m2, C = 600 mg/m2

AC + filgrastim wkly x 15A = 24 mg/m2, C = 60 mg qd

P + pegfilgrastim q2 wk x 6P = 175 mg/m2

P + pegfilgrastim q2 wk x 6P = 175 mg/m2

P wkly x 12P = 80 mg/m2

P wkly x 12P = 80 mg/m2

Cumulative Doses:A = 360 mg/m2C = 3,600 mg/m2(q2) vs. 900 mg(wkly)P = 1,050 mg/m2(q2) vs. 960 mg/m2(wkly)

Conclusions• We need to carefully select patients for adjuvant clinical

trials testing different chemotherapy regimens Differences in regimens will be magnified in specific

patient groups• Topoisomerase II gene amplifications and deletions

associated with response to anthracyclines• Genes associated with cellular proliferation correlate

with response to chemotherapy• Aromatase inhibitors should be part of adjuvant hormonal

therapy for postmenopausal women and are beneficial even late after diagnosis Careful attention should be paid not only to side effects,

but risk factors that predispose women to adverse events

Surgery + (neo)adjuvant CT ± RT

Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%

Randomization

2 years trastuzumab8 mg/kg 6 mg/kg3 weekly schedule

1 year trastuzumab8 mg/kg 6 mg/kg3 weekly schedule

Observation

Women with locally determined HER2-positive invasive early breast cancer

HERA Trial: Median F/U 2 yrs

XAfter ASCO 2005, option of switch to trastuzumab

Smith et al, ASCO 2005

861 observation patients are known to have

switched to trastuzumab

Patient Characteristics

Prior (neo)adjuvant CTNo anthracyclines 5.9 5.9Anthracyclines, no taxanes 68.1 67.8

Anthracyclines + taxanes 26.0 26.3Hormone receptor status

Negative 50.4 50.5Positive 49.6 49.5

Nodal statusNeoadjuvant CT 10.5 11.4Negative 32.7 31.91-3 28.9 28.5 >4 27.9 28.1

539 events observed in the 2 arms (347 at ASCO 2005)

Observation(n=1698)

1 year trastuzumab(n=1703)

% patients

1703 1591 1434 1127 742 383 1401698 1535 1330 984 639 334 127

100

80

60

40

20

0

Patients(%)

Months from randomisation12 36

1 year trastuzumab

Observation

0 186

No. at risk

Disease-free survival (ITT)Median FU 2 yrs

24 30

Events HR 95% CI p value

0.64 0.54, 0.76 <0.0001

3-yearDFS

80.674.3

218321

6.3%

1703 1627 1498 1190 794 407 146

100

80

60

40

20

0

Patients(%)

Months from randomisation

Observation

No. at risk 1698 1608 1453 1097 711 366 139

Overall survival (ITT)

1 year trastuzumab

Events HR 95% CI p value

0.66 0.47, 0.91 0.0115

3-yearOS

92.489.7

12 360 186 24 30

5990

Median FU 2 yrs

2.7%

Secondary efficacy end points(ITT analysis)

95% CIp value (log rank)3-year percent, %

0.52, 0.74<0.0001

75.4 vs 82.1

0.49, 0.73<0.0001

79.4 vs 85.7

0.47, 0.910.0115

89.7 vs 92.4

TTR TTDR OS

No. events

Observation 1 year trastuzumab

HR 1.0

0

TTR, time to recurrence; TTDR, time to distant recurrence; OS, overall survival

305 198 255 160 90 59

0.620.62 0.600.60 0.660.66

Annualized DFS hazards - ITTobservation and 1 year trastuzumab

groups

0

0.05

0.1

0.15

0.2

1 to 6 7 to 12 13 to 18 19 to 24 25 to 30 31 to 36

Months

Haz

ard

Rat

es

Observation 1 Year Trastuzumab

Months since randomisation

ADJUVANT TRASTUZUMAB TRIALSADJUVANT TRASTUZUMAB TRIALSTotal randomized : 13,365Total randomized : 13,365

Total analyzed : 10,192Total analyzed : 10,192

0

2000

4000

6000

ChemoChemo NilNil

ChemoChemo T 1 yearT 1 year

ChemoChemo T 2 yearT 2 year

AC x 4AC x 4 D x 4D x 4

AC x 4AC x 4 D x 4 + T 1yD x 4 + T 1y

C +D x 6C +D x 6+ T 1y+ T 1y

ACx4ACx4P P wk x 12wk x 12

ACx4ACx4Pwk x 12 Pwk x 12

+ T 1y+ T 1y

ACx4ACx4P P wk x 12 wk x 12 + T 1y+ T 1y

ACx4ACx4Px4 Px4 + T 1y+ T 1y

ACx4 ACx4 Px4 Px4

D or VD or VFECFEC

D or V+T 9wksD or V+T 9wksFECx3FECx3

HERAHERAN=5102N=5102

Analyzed=3387Analyzed=3387

BCRIG006BCRIG006N=3222N=3222

Analyzed=3222Analyzed=3222N9831N9831N=2766N=2766

Analyzed=1736Analyzed=1736 NSABP-B31NSABP-B31N=2046N=2046

Analyzed=1615Analyzed=1615FINHERFINHER

N=232N=232Analyzed=232Analyzed=232

F-up (months)F-up (months) 12 m12 m 24 m24 m 24 m24 m 24 m24 m 39 m39 m

T=trastuzumabT=trastuzumabD=DocetaxelD=DocetaxelP=paclitaxelP=paclitaxelV=VinorelbineV=VinorelbineAC=adriamycin+AC=adriamycin+cyclophosphamidecyclophosphamide

Control arms w/o trastuzumab (T)Control arms w/o trastuzumab (T)Trastuzumab single agent following anthracycline Trastuzumab single agent following anthracycline taxane taxaneTrastuzumab with taxane following anthracycline regimenTrastuzumab with taxane following anthracycline regimenTrastuzumab with chemo, avoiding or preceding anthracycline regimenTrastuzumab with chemo, avoiding or preceding anthracycline regimen

Lapatanib Mechanism of Action

• Binds to intracellular ATP binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation

• Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB-1) and HER2 (ErbB-2)

• Dual blockade of signaling may be more effective than the single-target inhibition provided by agents such as trastuzumab

1+1 2+2 1+2

Lapatinib

Downstream signaling cascade

Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263;Konecny et al. Cancer Res. 2006;66:1630-1639

Phase I Trial of Lapatanib and Capecitabine vs Cabecitabine in Advanced or Metastatic Breast

Cancer• Progressive, HER2+

MBC or LABC • Previously treated

with anthracycline, taxane and trastuzumab*

• No prior capecitabine

Lapatinib 1250 mg po qd continuously +

Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk

Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk

Patients on treatment until progression or unacceptable toxicity, then followed for survival

Stratification:• Disease sites• Stage of disease

RANDOMIZE

*Trastuzumab must have been administered for metastatic diseaseN=528

Geyer et al, ASCO 2006

Protocol Specified Interim

Analysis Plan

Per Protocol IRC IRC TTP Events

Number of Investigator Defined TTP

Events Required for IA:

133 + 10% = 144

321 Patients Accrued by Time

of Data Lock

Imaging &photograph

assessments sent to IRC

N=321

Number of Events: 114

103 Progressive BC

11 BC Related Deaths

IDMC Recommendations March 20th, 2006 • Agreed with superiority and futility boundaries

• Unanimous recommendation for termination of study enrollment based on :

“clinically meaningful, statistically significant advantage in primary endpoint (TTP) in the capecitabine + lapatinib arm vs capecitabine alone arm”

• No safety or tolerability concerns

• Accrual as of 3/20/06: 392 of 528

Disease Characteristics and Prior Treatment

• Patients must have relapsed w/in 6 mo of adjuvant therapy or have progression of metastatic disease

• Tumor 35-38% hormone receptor positive 96% stage IV disease, 50% > 3 metastatic sites

• Prior treatment 98% prior anthracylines, 98% prior taxanes 97% prior trastuzumab

• 91-93% metastatic• 4-6% adjuvant• 97-99% progressed on prior trastuzumab• Median duration of prior trastuzumab 43 wks• No difference in interval from last dose of T to randomization

(66-70% > 4 weeks)

Time to Progession – ITT Population

70

1020

30405060708090

0

100

* Censors 4 patients who died due to causes other than breast cancer

10 20 30 40 50 600Time (weeks)

CapecitabineLapatinib +

Capecitabine

0.00016P-value (log-rank, 1-sided)

69 (43%)45 (28%)Progressed or died*19.736.9Median TTP, wk

161160No. of pts

0.51 (0.35, 0.74)Hazard ratio (95% CI)

% o

f pat

ient

s fr

ee fr

om p

rogr

essi

on*

Time (weeks)0 10 20 30 40 50 60 70

Cum

ulat

ive

Prog

ress

ion-

Free

Sur

viva

l, %

0102030

405060

708090

100

Progression-Free Survival - ITT Population

0.000045P-value (log-rank, 1-sided)

73 (45%)45 (28%)Progressed or died

0.48 (0.33, 0.70)Hazard ratio (95% CI)

17.936.9Median PFS, wk

161160No. of ptsCapecitabine

Lapatinib + capecitabine

Response Rate - ITT Population

Lapatinib + Capecitabine(n=160)

Capecitabine(n=161)

Complete response 1 (< 1%) 0 (0%)

Partial response 35 (22%) 23 (14%)

Overall response rate* (95% CI)

22.5% (16.3 - 29.8)

14.3%(9.3 - 20.7)

*P-value (Fisher’s exact, 2-sided) = 0.113

Brain Metastases as Site of Progression

Lapatinib + Capecitabine

(n=160)

Capecitabine(n=161)

Patients with CNS metastases at baseline

2 2

Patients with CNS relapse* 4 11

Patients with CNS as only site of relapse

3 10

*P-value (Fisher’s exact, 2-sided) = 0.110

Investigator Assessed Endpoints ITT Population

Lapatinib + Capecitabine

(n=160)

Capecitabine

(n=161)No. of pts progressed or died 60 (38%) 78 (48%)

Median TTP, wk 25.3 18.9

Hazard ratio for TTP (95% CI) P-value (log-rank, 2-sided)

0.63 (0.44 – 0.89)

0.007Overall response rate* (95% CI)P-value (Fisher’s exact, 2-sided)

28.8% (21.9 – 36.4)

16.1%(10.8 – 22.8)

0.017

Most Frequent Adverse Events All Grades

Gr 3Gr 2

SeverityGr 4

Gr 1

Diarrhea Rash and/or Skin Reaction

% o

f Pat

ient

s

PPE

L+C

L+CL+CC

CC

10

20

30

40

50

60

70

80

90

100

0

26

19

121

13

15

11

9

28

6

9

20

5

19

13

2.5

12

11

7

L = lapatinib; C = capecitabine.

Mean LVEF at Scheduled Assessments

Week 12 Week 18 Week 24 Week 36 Week 48Week 6Screening

Assessment

Lapatinib + CapecitabineCapecitabine

Mea

n LV

EF (%

)

80

75

70

65

60

55

50

n=160 n=160

n=108

n=92

n=84 n=67

n=63n=37

n=37 n=26

n=15n=9

n=7n=1

Conclusions

• The planned interim analysis crossed pre-specified reporting boundary and demonstrated a clinically meaningful and statistically significant improvement in median TTP

Lapatinib + capecitabine 8.5 mo vs capecitabine 4.5 mo

• Lapatinib + capecitabine well tolerated; declines in LVEF were infrequent, asymptomatic, reversible

• Fewer patients developed brain metastases as first site of progression in the group receiving lapatinib

• Trials evaluating lapatinib in earlier stages of HER2+ breast cancer are warranted

Phase II Trial of Lapatanib in Patients with Relapse/Refractory Inflammatory Breast Cancer

Cohort AErbB2+

Cohort BErbB1+/ErbB2-

Two Stage Green-Dahlberg Design

Pre-treatment tumor biopsy

Administer lapatinib (1500 mg/d)

Clinical Evaluation: according to RECIST criteria and *chest wall/skin response documented by Canfield digital photography

*(CR: complete resolution of disease; PR >50% reduction; SD 20-49% reduction

Spector et al. ASCO 2006;Abstract 502

Baseline Characteristics/ Demographics

Median age, years (range) 53 (32-79)Stage of disease 79% Stage IV

21% Stage IIIBMedian prior chemotherapy regimens (range) 4.5 (0-21)

–Prior anthracycline 98% (48/49)–Prior anthracycline/taxane 78% (38/49)–Prior anthracycline + taxane/navelbine 86% (42/49)–Patients in Cohort A treated with trastuzumab (in countries where trastuzumab is available)

75% (15/20)

Evidence of dermal lymphatic invasion 75%HER2+ Cohort A

19% HER2 2+ 81% HER2 3+

Sites of enrollment 71% N.America/EU/Israel29% Tunisia

Spector et al. ASCO 2006;Abstract 502

0%

50%

100%

Cohort AErbB2+

24 patients

5 enrolled patients were not evaluable (did not express target or died prior to Day 28)

Cohort BErbB1+/ErbB2-

12 patients

8.3%

17%SD

58%PD

17%pending

Preliminary Results: Treatment Response

62%PR

21%SD

17%PD

62% clinical responders

100% of responders are ErbB2 (IHC

3+/FISH+)p-ErbB2 positive

100%

PTEN deficient

69%

Spector et al. ASCO 2006;Abstract 502

Site Skin RECIST

USPRPRPR

NANASD

UK PRPR

SDNA

CanadaPRPRPR

SDPRPR

Israel SD CR

Tunisia

PRCRCRPRPRPR

PRPRPRSDPRPR

Responses (RECIST and Skin)

Spector et al. ASCO 2006;Abstract 502

SummarySummaryLapatinib monotherapy is clinically active

in heavily pre-treated IBC patients

Lapatinib is well tolerated

• Generally grade 1/2 GI and skin toxicity

• Correlation of ErbB2 (IHC3+ or FISH+) with response• Responders are more likely to be p-ErbB2 positive (which appears to correlate with FISH +)• Co-expression of IGF-IR does not appear to preclude response• PTEN deficiency does not appear to preclude response

• 62% response rate in ErbB2 overexpressors

Preliminary biomarker analysis suggests

Spector et al. ASCO 2006;Abstract 502

Phase 2 Trial of Lapatanib for Brain Metastases in Patients with HER2+ Breast Cancer

Lapatinib given in four week cycles– 750 mg PO BID– response assessed every 2 cycles

Dose modifications– grade 3 or 4 hold until grade 0 or 1 and

reduce one level– grade 3 or 4 LVEF dysfunction or interstitial

pneumonitis off study

Lin et al, ASCO 2006, #503

Patients and Toxicity

39 patients enrolled, all off study by 5/06 Prior CNS radiation in 95% (37)

– 51% WBRT, 15% SRS, 28% both Toxicity

– No grade 4– 21% grade 3 diarrhea, 22% grade 2– Other common toxicities

Fatigue Headache Mild rash

Best CNS Response (RECIST)(N=39)

Complete Response (CR) 0

Partial Response (PR) 2 (5.1%) [95% CI 1% to 17%]

Lin et al. ASCO 2006;Abstract 503

*Both received prior WBRT and SRSTTP 49 and 23 weeks

16 measurable disease, 4PR

Best CNS Response (RECIST)(N=39)

Complete Response (CR) 0Partial Response (PR) 2 (5.1%)

Baseline Week 8Lin et al. ASCO 2006;Abstract 503

Conclusions• Volumetric and PET changes also evaluated

Significance still unclear but both volume and PET changes noted

Volumetric declines greater than 30% in 4 pts, 6 pts 10-30%

• Quality of life generally stable at 8 weeks• Some evidence of clinical activity

2PR by RECIST 8 progression free in CNS at 16 weeks

• What do we know about Lapatanib? Crosses the blood brain barrier Has activity against HER2+ brain metastases Is generally well tolerated May have activity in prevention of brain metastases?

Cardiac Function in 3127 Patients Treated with Lapatanib

• Pooled analysis of 10 monotherapy trials and 8 trials of lapatanib in combination with chemotherapy or anti-hormonal agents

• All studies required EF within institutional range of normal Monitoring at baseline, q8 weeks on treatment

• Length of exposure (3535 including placebo) > 6 months in 1090

Perez E., ASCO 2006, #583

Results and Conclusion• Symptomatic LVEF decrease

Breast cancer: 2 (0.1%) Non breast cancer: 2 (0.1%)

• Asymptomatic LVEF decrease 37 (1.2%)

• Average duration of LVEF decrease was 40 days 41% (9/22) with breast cancer recovered while continuing to

receive lapatanib• Avereage decrease relative to baseline was 29%• Potential risk factors

Mediastinal/left sided radiation LVEF on trastuzumab (only 2 pts) Prior anthracyclines Past significant cardiac history

• Overall risk appears to be very low 1.3% across breast and other malignancies Further followup is ongoing

Sponsored and Cooperative Group Trials with Lapatanib

• First line metastatic Paclitaxel with trastuzumab with or without lapatanib Aromatase inhibitors with lapatanib Other chemotherapy combinations

• Trastuzumb resistant Lapatanib alone vs lapatanib combined with trastuzumab Lapatanib with bevacizumab (MSKCC and UCSF collaboration)

• Brain metastases Progression after radiation with lapatanib alone

• Cooperative group (pending, will open in 2008) Neoadjuvant chemotherapy with trastuzumab vs lapatanib vs the combination (3 arm study) Adjuvant trial (Perez et al)

• Chemotherapy with:• Lapatanib• Trastuzumab• The combination

• Other interesting research directions for HER2+ disease 17AAG (HSP inhibitor) IGFR inhibitors MTOR inhibitors (inhibition of the downstream pathway)

Node Neg, ER (+), Breast Cancer

RS RS << 10 10HormoneHormoneTherapyTherapyRegistryRegistry

RS 11 – 25RS 11 – 25RandomizeRandomize

Hormone RxHormone Rxvs.vs.

Chemotherapy Chemotherapy + Hormone + Hormone

RxRx

RS RS >> 25 25ChemotherapChemotherap

yy++

Hormone RxHormone Rx

Oncotype DX Assay

RegisterSpecimen banking

Primary study groupTarget Accrual: >10,000

Trial Assigning IndividuaLized Options for Treatment (Rx): TAILORx TrialTAILORx Trial

The Changing Paradigm of Clinical Trials in Breast Cancer

Non Selected Adjuvant Trials in

Breast Cancer