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Building on the Success of Targeted Therapies in Metastatic Disease Harold J. Burstein, MD, PhD Assistant Professor of Medicine Department of Oncology Dana-Farber Cancer Institute Boston, Massachusetts Trastuzumab Monoclonal antibody binding to HER2/neu (erbB2) receptor

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Building on the Success of Targeted Therapies in Metastatic Disease

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Building on the success of targeted therapies in metastatic disease l.jpg

Building on the Success of Targeted Therapies in Metastatic Disease

Harold J. Burstein, MD, PhD

Assistant Professor of Medicine

Department of Oncology

Dana-Farber Cancer Institute

Boston, Massachusetts


Trastuzumab l.jpg

Trastuzumab

  • Monoclonal antibody binding to HER2/neu (erbB2) receptor

  • Standard treatment (in combination with chemotherapy) for HER2-positive metastatic breast cancer for past 7 years

  • Reduces the risk of recurrent HER2-positive disease by ~50%

  • Cardiotoxicity the most important adverse event

    • Trastuzumab + paclitaxel: 13%

    • Trastuzumab + anthracycline: 27%

  • Piccart-Gebhart MJ. 42nd ASCO; June 2-6, 2006. Education Session.


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Bevacizumab

Targets tumor angiogenesis—the formation of new blood vessels necessary to support tumor growth and metastasis—by inhibiting vascular endothelial growth factor, an important signaling molecule in regulating this process1,2

1. Cross MJ, Claesson-Welsh L. Trends Pharmacol Sci. 2001;22:201.

2. Brown JM, Giaccia AJ. Cancer Res. 1998;58:1408.


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Bevacizumab + Paclitaxel Phase III Trial

The addition of bevacizumab (BEV) to paclitaxel (PAC) doubled the response rate and extended progression-free survival by almost 5 months, compared with paclitaxel alone

PAC AlonePAC/BEV(n = 316)(n = 330)

Response rate (%)14.228.2

Progression-free survival (mo)6.110.97

Miller KD, et al. 41st ASCO; May 13-17, 2005.


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Bevacizumab + PaclitaxelToxicities

  • 13% of patients receiving bevacizumab developed hypertension requiring treatment

  • Serious bleeding events were rare and not substantially increased with addition of bevacizumab

  • There was a significant increase in grade 3 neuropathy from 13.6% with paclitaxel alone to 19.9% in the combination arm

  • Chemotherapy-related toxicities were mild and did not interfere with therapy

Miller KD et al. 41st ASCO; May 13-17, 2005. Abstract.


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ASCO 2006—New Trastuzumab Combination Regimens in Metastatic/Recurrent Disease

  • Trastuzumab + vinorelbine

  • Trastuzumab + bevacizumab

  • Trastuzumab + docetaxel +/- carboplatin

  • Trastuzumab + heat shock protein inhibitor


Trastuzumab vinorelbine vs trastuzumab taxane her2 metastatic breast cancer l.jpg

Trastuzumab + Vinorelbine vs Trastuzumab + TaxaneHER2+ Metastatic Breast Cancer

Trastuzumab/Trastuzumab/

VinorelbineTaxane*

n = 41n = 40P-Value

Response rate

(strict criteria)51%40%.37

Response rate

(unconfirmed)66%58%.50

Median time to8.56.0.09

Progression (mo)

Weekly trastuzumab + vinorelbine is at least as effective as weekly trastuzumab/taxane

* Paclitaxel (n=14), docetaxel (n=24), or paclitaxel/carboplatin (n=2) at discretion of treating oncologist.

Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650.


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Trastuzumab + Vinorelbine vsTrastuzumab + Taxane

Time to Tumor Progression (TTP)

Courtesy of Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650. Poster Session.

1.0 -

0.8 -

0.6 -

0.4 -

0.2 -

0.0 -

Median TTP:

A (Trast + Vln)

B (Trast + Tax)

Probability

Log-rank P = .20

0

2

18

4

6

8

14

10

16

12

Months


Trastuzumab vinorelbine vs trastuzumab taxane toxicities l.jpg

Trastuzumab + Vinorelbine vs Trastuzumab + TaxaneToxicities

  • Generally similar

  • Trastuzumab + vinorelbine

    • Greater myelosuppression

  • Trastuzumab + taxane

    • Greater hair loss, nail changes, rash, and fluid retention

  • Cardiotoxicity <5% in all groups

Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650. Poster Session.


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Trastuzumab + BevacizumabRelapsed/Metastatic HER2+ Disease

  • First report of 2 humanized monoclonal antibodies in humans

  • Phase 1 (9 patients)

    • 2 complete responses; 3 partial responses;

      2 stable disease (>6 mo)

  • Phase II ongoing (16 patients with response)

    • 8 partial responses; 6 stable disease

Rugo HS. 42nd ASCO; June 2-6, 2006. Education Session.


Trastuzumab t docetaxel d carboplatin c phase iii trial in her2 metastatic breast cancer l.jpg

Trastuzumab (T) + Docetaxel (D) +/- Carboplatin (C)Phase III Trial in HER2+ Metastatic Breast Cancer

TDTDC

n = 131n = 131P-Value

Median time to

tumor progression (mo)*11.110.4.57

Objective response rate73%73%

Duration of response (mo)10.79.4

Median overall survival (mo)Not reached41.7

Clinical benefit67%67%

* Primary end point

No increase in benefit with the addition of carboplatin to trastuzumab + docetaxel

Forbes JF, et al. 42nd ASCO; June 2-6, 2006. Abstract LBA516.


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Trastuzumab + Heat Shock Protein (HSP) Inhibitor

  • Chaperone protein is required for maturation and stabilization of certain client proteins, including HER2

  • Inhibition of HSP90 chaperone function induces degradation of client protein

  • Phase I trial of KOS-953, an HSP90 inhibitor, plus trastuzumab:

    17 HER2+ patients with trastuzumab-resistant metastatic breast cancer

    • 1 partial response, 3 minimal response, 5 prolonged (>4 mo) stable disease

  • Phase II trial under way

Modi S, et al. 42nd ASCO; June 2-6, 2006. Abstract 501.


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Trastuzumab Resistance

  • Virtually all HER2+ metastatic breast cancers develop resistance

  • Adjuvant trastuzumab reduces the annual hazard rate by 1/2, ie, 1/2 of recurrences are not prevented

Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.


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Possible Causes of Trastuzumab Resistance

  • Suboptimal drug delivery

  • Altered target expression

  • Altered target

  • Modified target-regulating proteins

  • Alternative pathway signaling

Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.


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Overcoming Trastuzumab Resistance

  • Block the HER pathway(s) at other points

  • Block other growth factor receptor pathways (HER1, IGF-1R)

  • Block angiogenesis

Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.


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Lapatinib

Dual inhibitor targeting both erbB1 (or epidermal growth factor) and erbB2 (or HER2/neu) receptors


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LapatinibMechanism of Action

Lapatinib and Trastuzumab:Potential for Synergy

Rugo HS. 42nd ASCO; June 2-6, 2006. Education Session.

Phase I trial:

Storniolo, SABC 2005

Trastuzumab

Lapatinib

Downstream signaling cascade

Cell Division/Tumor Growth

Maximum inactivation of ErbB2 Pathway

• ErbB2 receptor

• Truncated Erb2 receptor

• ErbB1/ErbB2 heterodimes


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Lapatinib+Capecitabine vs Capacitabine in Trastuzumab-Resistant DiseaseTime to Tumor Progression

Lapatinib/CapecitabineCapecitabinen = 160 n = 161

Progressed or died45 (28%) 69 (43%)

Median TTP (wk) 36.9 19.7

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

P-value (log rank, 1-sided) .00016

Geyer CE, et al. Presented at 42nd ASCO; June 2-6, 2006. Special Session.


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Lapatinib + Capecitabine vs Capecitabinein Trastuzumab-Resistant DiseaseBrain Metastasesas Site of Progression

Lapatinib/CapecitabineCapecitabinen = 160n = 161

Patients with CNS

metastases at baseline22

Patients with CNS relapse*411

Patients with CNS as

only site of relapse310

*P-value (Fisher’s exact, 2-sided) = .110

Geyer CE, et al. 42nd ASCO; June 2-6, 2006. Special Session.


Lapatinib capecitabine vs capacitabine in trastuzumab resistant disease adverse events aes l.jpg

Lapatinib + Capecitabine vs Capacitabinein Trastuzumab-Resistant DiseaseAdverse Events(AEs)

  • Similar rates for all AEs and serious AEs

  • Most common AEs: diarrhea, PPE, rash, and/or skin reactions

  • AEs leading to discontinuation of study medication

    • Lapatinib + capecitabine: 22 (14%)

    • Capecitabine: 16 (11%)

  • Cardiac events

    • 4 lapatinib + capecitabine; 1 capecitabine

    • All asymptomatic (grade 2)

    • No withdrawals due to decreased LVEF

  • 1 treatment-related death in capecitabine arm

PPE = palmar-plantar erythrodysesthesia; LVEF = left ventricular ejection fraction.

Geyer CE, et al. 42nd ASCO; June 2-6, 2006. Special Session.


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Lapatinib + Capecitabine vs Capecitabinein Trastuzumab-Resistant DiseaseSummary

Compared with capecitabine alone, lapatinib + capecitabine results in

  • Significantly longer time to tumor progression

  • Fewer CNS metastases

  • Comparable safety


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Lapatinib in Brain Metastases

  • Approximately 1/3 of women with HER2+ metastatic breast cancer develop CNS metastases

  • Apparently higher incidence of CNS metastases in women treated with trastuzumab

  • Trastuzumab is not thought to cross the blood-brain barrier

  • Phase II trial of lapatinib monotherapy in CNS metastases

    • 39 patients with CNS metastases that developed on trastuzumab (38 of whom progressed after prior radiation)

      • 2 partial responses by RECIST

      • 8 progression-free in CNS at 16 weeks

      • Volumetric declines >30% in 4 patients; declines of 10% to 30% in an additional 6 patients

  • RECIST = Response Evaluation Criteria in Solid Tumors.

  • Lin NU, et al. 42nd ASCO; June 2-6, 2006. Abstract 503.


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Lapatinib Monotherapyin Inflammatory Breast Cancer

Cohort A:Cohort B:

erbB2+erbB1+/erbB2-

(n = 24)(n = 12)

Partial response62%8.3%

erbB2 overexpression, but not erbB1 expression alone, predicts for sensitivity to lapatinib in inflammatory breast cancer

Spector NL, et al. 42nd ASCO; June 2-6, 2006. Abstract 502


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Conclusions

Targeted therapy has assumed a prominent role in the treatment of breast cancer

  • Three targeted agents—trastuzumab, bevacizumab, and lapatinib—have demonstrated impressive activity in metastatic breast cancer

  • Trastuzumab + vinorelbine has proven at least as efficacious as trastuzumab + taxane-based treatment

  • The combination of 2 targeted agents—trastuzumab and bevacizumab—shows promising early results


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Conclusions(cont’d)

New agents and approaches continue to expand the benefit of targeted therapy

  • Inhibition of heat shock protein (HSP) chaperone function by a HSP90 inhibitor induces degradation of HER2 and may increase efficacy of trastuzumab when used in a combination regimen

  • Lapatinib is effective in treating trastuzumab-resistant tumors; early results indicate that it may be beneficial in treating CNS metastases and inflammatory breast cancer, as well


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Getting the Most Out of Targeted Therapy

Francisco J. Esteva, MD, PhD

Associate Professor of MedicineBreast Medical OncologyThe University of TexasM.D. Anderson Cancer CenterHouston, Texas


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Trastuzumab in Early-Stage Disease


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HERA Trial Design

Women with locally determined HER2 + invasive early breast cancer

Surgery + (neo)adjuvant CT ± RT

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

Randomization

Observation

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

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

X

After ASCO 2005,option of switchto trastuzumab

HERA Trial2-Year Follow-Up

CT = chemotherapy; RT = radiotherapy; IHC = immunohisochemistry; FISH = fluorescence in situ hybridization; LVEF = left ventricular ejection fraction.

Smith IE. Presented at 42nd ASCO; June 2-6, 2006.


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HERA TrialDisease-Free Survival (ITT)

Median Follow-Up 2 years

ITT = intent to treat; DFS = disease-free survival; HR = hazard ratio; CI = confidence interval.

Smith IE. 42nd ASCO; June 2-6, 2006.

100806040200

1 year trastuzumab

6.3%

Observation

Patients (%)

3-yearDFS

HR

P-Value

Events

95% Cl

80.6

218

0.64

0.54, 0.76

<.0001

74.3

321

24

12

18

30

0

6

36

Months from Randomization

1703 1591 1434 1127 742 383 140

No.at risk

1698 1535 1330 984 639 334 127


Hera trial overall survival itt l.jpg

HERA TrialOverall Survival (ITT)

Median Follow-Up 2 Years

ITT = intent to treat; OS = overall survival; HR = hazard ratio; CI = confidence interval.

Smith IE. 42nd ASCO; June 2-6, 2006.

100806040200

1 year trastuzumab

2.7%

Observation

Patients (%)

3-yearOS

HR

P-Value

Events

95% Cl

92.4

59

0.66

0.47, 0.91

.0115

89.7

90

24

12

18

30

0

6

36

Months from Randomization

1703 1627 1498 1190 794 407 146

No.at risk

1698 1608 1453 1097 711 366 139


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HERA TrialCardiac Safety

Number Patients (%)

Observation Trastuzumab: 1 y

n = 1708 n = 1678

Cardiac death 1 (0.1) 0 (0.0)

Severe CHF

(NYHA III and IV) 0 (0.0) 10 (0.6)

Symptomatic CHF 3 (0.2) 36 (2.1)

Confirmed significant

LVEF drop 9 (0.5) 51 (3.0)

CHF = congestive heart failure; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction.

Smith IE. 42nd ASCO; June 2-6, 2006.


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HERA TrialSummary

  • Trastuzumab following adjuvant chemotherapy significantly improves overall survival (HR 0.66) in women with early-stage HER2+ breast cancer

  • Gain in disease-free survival after 1 year median follow-up is maintained after 2 years median follow-up

  • Risk of cardiac toxicity remains low

HR=hazard ratio

Smith IE. 42nd ASCO; June 2-6, 2006.


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Identification of Patients Likely to Benefit

  • Balancing risk and benefit

  • Using biomarkers to predict response

    • Trastuzumab

    • Anti epidermal growth factor receptor therapy


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Trastuzumab for All HER2+ Patients?

  • Adjuvant trastuzumab results in significant reduction of recurrence in high-risk HER2+ breast cancer patients

  • However, trastuzumab is associated with significant cardiac toxicity

  • What is the risk of adverse effects vs survival benefit of trastuzumab in patients with low risk of recurrence and/or high risk of cardiac toxicity?

Gupta AK, et al. 42nd ASCO; June 2-6, 2006. Abstract 6022.


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Low Risk of Recurrence and/or High Risk of Toxicity

Cumulative

Cardiac 10-y 10-y

Patient Treatment Toxicity (%) QALYs DFS (%) Cardiac Deaths (%)

50 y CT 0.8 20.61 70.2 0.06

2 cm

node+ CT+T 6 25.34 81.9 0.68

ER/PR-

EF 60%

70 y CT 0.8 13.58 62.1 0.06

2 cm

node- CT+T 20 14.18 66.8 2.03

ER/PR-

EF 50%

QALYs = quality adjusted life years; DFS = disease-free survival; CT = chemotherapy; T= trastuzumab; ER = estrogen receptor; PR = progesterone receptor; EF = ejection fraction.

Gupta AK, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 6022. Reprinted with permission from the American Society of Clinical Oncology.


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Conclusions

  • The addition of trastuzumab to standard chemotherapy is more beneficial than standard chemotherapy alone in most cases, including elderly patients with node-negative disease and those at increased risk of cardiac toxicity

  • However, incremental benefit decreases with increasing age, higher risk of cardiac toxicity, and lower risk of recurrence

Gupta AK, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 6022. Reprinted with permission from the American Society of Clinical Oncology.


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Change in Serum HER2 and Outcome

Change in HER2

Serum Levels DR TTP OS

from Baseline ORR (median/d) (median/d) (median/d)

<20% decrease 28.4% 230 182 593

>20% decrease 56.5% 369 320 898

P value <.001 .008 <.001 .018

Patients with <20% decrease in serum HER2 have decreased benefit from

trastuzumab and should be considered for additional HER2-targeted therapies

ORR = objective response rate; DR = duration of response; TTP = time to tumor progression; OS = overall survival.

Ali SM, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 500. Reprinted with permission from the American Society of Clinical Oncology.


Er pr status l.jpg

ER+/PR- Status

  • Compared with ER+/PR+ disease, ER+/PR- breast cancer has

    • Lower response rate to estrogen deprivation

    • Worse prognosis

    • May be dependent on other signaling pathways

ER = estrogen receptor; PR = progesterone receptor.

Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.


Er pr breast cancer and egfr inhibition l.jpg

ER+/PR- Breast Cancer and EGFR Inhibition

  • Presurgical exposure to short-term gefitinib, an EGFR inhibitor, in 43 patients with operable breast cancer

  • Tissue obtained at surgery

    • ER+/PR- tumors more likely to show molecular growth inhibition

    • ER+/PR+ tumors more likely to show molecular growth proliferation

  • Conclusions

    • ER+/PR- breast cancer is growth factor dependent

    • ER+/PR- patients may be more likely to benefit from EGFR inhibition

ER = estrogen receptor; PR = progesterone receptor; EGFR = epidermal growth factor receptor.

Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.


Egfr expression and tumor characteristics l.jpg

EGFR Expression and Tumor Characteristics

  • Comparision of EGFR+ and EGFR- tumors in 2567 patients

  • EGFR+ tumors were more common in patients who were

    • Younger (<50 y)1

    • Premenopausal1

    • Black2

  • EGFR expression was associated with

    • Larger tumors1

    • Aneuploidy1

    • High S-phase fraction1

    • Nodal involvement3

  • EGFR+ tumors were more likely to be HER2+1, but less likely to be ER+1 and PR+1

1P <.0001

2P = .005

3P = .009

EGFR = epidermal growth factor receptor; ER = estrogen receptor; PR = progesterone receptor.

Rimawi MF, et al. 42nd ASCO; June 2-6, 2006. Abstract 513.


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EGFR Expression and Prognosis

  • 1256 treated patients;1 1068 untreated patients2

  • In treated patients, EGFR expression was negatively correlated with

    • DFS (P = .001)

    • 0S (P = .001)

  • No relationship was found between EGFR status and DFS or OS in untreated patients

    EFGR expression is associated with significant resistance to adjuvant hormonal therapy and chemotherapy. Blocking EFGR activity may help to overcome this resistance in selected patients

1 Systemic chemotherapy and/or hormonal therapy

2 No systemic therapy

EGFR = epidermal growth factor receptor; DFS = disease-free survival; OS = overall survival.

Rimawi MF, et al. 42nd ASCO; June 2-6, 2006. Abstract 513.


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Cost-Effectiveness of Trastuzumab—Model 1

  • Cost-effectiveness of adding trastuzumab to standard adjuvant therapy (doxorubicin, cyclophosphamide, and paclitaxel)

  • Based on Markov model with 3 disease states

    • Disease-free survival

    • Recurrence

    • Death

  • Costs included

    • Testing for HER2 status

    • Drug and administration costs for trastuzumab

    • Cardiac monitoring

    • Treatment of cardiac toxicity

    • Treatment following recurrence

    • End-of-life costs for dying patients

Garrison LP Jr, et al. 42nd ASCO; June 2-6, 2006. Abstract 6023.


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Cost-Effectiveness of Trastuzumab—Model 1(cont’d)

  • Patient: 50 year-old woman

  • Efficacy based on NCCTG N9831 and NSABP B-31 trials; projections to recurrence and death based on literature (Lancet, 2005)

  • With trastuzumab

    • Lifetime cost per QALY gained: $27,800 (range: $17,900 to $39,100)

    • Projected life expectancy 3 years longer (trastuzumab: 19.4 years; without trastuzumab: 16.4 years)

    • Additional cost of adding trastuzumab: $46,300

    • Expected gain of 1.28 QALY

    • Cost/QALY = $36,100

      Utility/cost ratio of adding trastuzumab is below that of many treatments used for oncology patients.

Garrison LP Jr, et al. 42nd ASCO; June 2-6, 2006. Abstract 6023.


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Cost-Effectiveness of Trastuzumab in Early-Stage and Metastatic Breast Cancer—Model 2

Comparison of

  • Cost per relapse prevented by adjuvant chemotherapy (docetaxel, paclitaxel, filgrastim) vs

  • Cost per relapse prevented by adjuvant trastuzumab

Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.


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Cost-Effectiveness of Trastuzumab in Early-Stage and Metastatic Breast Cancer—Model 2(cont’d)

Trastuzumab Docetaxel Paclitaxel Filgrastim

Reduction

in relapse 50% 7%1 5%2 4%3

Cost per relapse

prevented € 147,000 € 126,000 € 148,000 € 231,000

Adjuvant trastuzumab is more cost-effective than adjuvant paclitaxelor filgrastim

1 BCIRG 001

2 CALGB 9344

3 CALGB 9741

Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.


Slide46 l.jpg

Cost-Effectiveness of Trastuzumab in Early-Stage and Metastatic Breast Cancer—Model 2(cont’d)

Conclusions

  • Assuming no retreatment with trastuzumab, adjuvant trastuzumab appears to be a relatively cost-effective means of reducing relapses

  • Possibility of a shorter treatment regimen (FinnHER study) should result in even greater cost-effectiveness

Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.


Conclusions47 l.jpg

Conclusions

  • Initial gains in disease-free survival and overall survival observed with trastuzumab in early-stage breast cancer continue to be sustained after median follow-up of 2 years

  • Trastuzumab is cost-effective in reducing relapse and compares favorably with many treatments used for oncology patients

  • Clinical benefit and cost-effectiveness can be increased with the use of biomarkers to identify patients most likely to benefit from targeted therapies


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Adverse Events andTargeted Therapy

Maureen Major, RN, MS

Clinical Nurse Specialist

Department of Nursing

Memorial Sloan-Kettering Cancer Center

New York, New York


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Adverse Events

  • Cardiac toxicity

  • Osteoporosis


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= Doxorubicin/cyclophosphamide 60/600 mg/m2 q3wk x 4

= Paclitaxel 175 mg/m2 q3wk x 4

= Paclitaxel 80 mg/m2 qwk x 12

= Trastuzumab 4 mg/kg loading  2 mg/kg qwk x 51

NCCTG N9831 Trial Designs

NCCTG N9831

Arm A

Arm B

Arm C

NCCTG = North Central Cancer Treatment Group.

N9831 PI. EA Perez.

With permission from Romond E. ASCO 2005; May 13–17, 2005. Oral Presentation.


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Incidence of Trastuzumab-Related Cardiac Toxicity in NSABP B31

6

Arm 2: AC P+T (N = 850)31 CHFsNo cardiac deaths

NSABP = National Surgical Breast and Bowel Project; AC = doxorubicin/cyclophosphamide; P = paclitaxel;T = trastuzumab; CHF = congestive heart failure; HR = hazard ratio.

Tan-Chiu E, et al. J Clin Oncol. 2005;23:7811-7819.

4.1%

4

Percent

HR = 5.9

Arm 1: AC P (N = 814) 4 CHFs1 cardiac death

2

0.8%

0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Years Post Day 1 Cyc 5

Cohort

Arm 1 Evaluable CohortArm 2 Evaluable Cohort


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Assessing Cardiotoxicitywith Trastuzumab Therapy

  • Goal—to discover dysfunction early

  • Diastolic dysfunction may be better predictor

  • Diagnostic testing

    • Echocardiography and doppler flow study

    • Multiple gated acquisition Scan (MUGA)

  • Blood testing

    • Troponin = measurement of heart injury

    • Brain natriuretic peptide (BNP) = strain

  • Monitor every 3 months

Swain SM. 42nd ASCO; June 2-6, 2006.


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Radiotherapy + TrastuzumabDoes Concomitant Administration Increase Risk?

NCCTG N9831

  • Preclinical studies suggest that trastuzumab may enhance radiotherapy

  • Trastuzumab, doxorubicin, and radiotherapy are potentially cardiotoxic

  • The NCCTG N9831 study examined adverse effects of concomitant radiotherapy + trastuzumab following chemotherapy in patients with stage I–IIA breast cancer:

ARM

A

B

C

NCCTG = North Central Cancer Treatment Group.

Halyard MY, et al. 42nd ASCO; June 2-6, 2006. Abstract 523.

N9831 PI. EA Perez.

With permission from Romond E. ASCO 2005; May 13–17, 2005. Oral Presentation.


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Radiotherapy + TrastuzumabDoes Concomitant Administration Increase Risk?

  • Timing: radiotherapy (RT) given concurrently with trastuzumab and within 5 weeks of completing paclitaxel

  • Patient characteristic

    • Lumpectomy: whole breast RT with optional tumor bed boost

    • Mastectomy: ≥ 4+ nodes received nodal and chest wall RT

  • Internal mammary nodal (IMN) RT not permitted

    • However, 41/1433 (3%) of patients received IMN

    • Dosimetry review showed that all 41 had cardiac sparing

  • Halyard MY, et al. 42nd ASCO; June 2-6, 2006. Abstract 523.


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Radiotherapy + TrastuzumabCardiac Events

Cardiac Events (% Pts)*

+RT –RT

2.2 2.9

1.5 6.3

NCCTG 9831

B

C

*Median follow-up of 1.5 years

NCCTG = North Central Cancer Treatment Group; RT = radiotherapy.

Halyard MY, et al. 42nd ASCO; June 2-6, 2006. Abstract 523.

With permission from Romond E. ASCO 2005; May 13–17, 2005. Oral Presentation.


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Lapatinib Dual Tyrosine Kinase Inhibitor

  • Lapatinib is an epidermal growth factor receptor and ErbB2 (Her2/neu) inhibitor

  • Studies under way in treatment of solid tumors, such as breast and lung cancer

  • ErbB2 signaling is important for cardiac function

  • Trastuzumab is known to be associated with cardiac toxicity

  • Is lapatinib associated with cardiac toxicity?


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Prospective Evaluation of LapatinibCardiac Safety

  • 1674 breast cancer patients treated with lapatinib

  • Decreased LVEF: 22 (1.3%)

    • Symptomatic: 2 (0.1%)

    • Asymptomatic: 20 (1.2%)

  • Average LVEF decrease relative to baseline: 29% (range 22%–42.3%)

  • Average duration: 40 days (9–113)

  • 41% (9/22) recovered while continuing to receive lapatinib

Perez EA, Byrne JA. 42nd ASCO: June 2-6, 2006. Updated abstract 583.


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22 Patientswith Decreased LVEF

Characteristics of 22 Patients with Breast Cancer and Decreased LVEF

13

Symptomatic Patients

45

Symptomatic Patients

12

40

11

35

10

9

30

8

% LVEF Decrease Relative to Baseline

25

7

Patient

6

20

5

15

4

3

10

2

5

1

0

0

20

40

60

80

100

120

1

2

3

4

5

6

7

8

9

11

12

13

14

15

16

17

18

19

20

21

22

10

LVEF Event Duration (D)

Patient

Perez EA, Byrne JA. 42nd ASCO: June 2-6, 2006. Updated abstract 583.


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Osteoporosis

  • Breast cancer patients with bone metastases are at an increased risk for skeletal-related events

    • Fractures

    • Hypercalcemia of malignancy

    • Spinal cord compression

    • Pain

  • Goals of treatment

    • Treat underlying disease

    • Stabilize the bone

    • Prevent further bone breakdown

    • Relieve pain

    • Improve quality of life

  • Measurement of bone loss

    • Urinary N-telopeptide levels (uNTx): biomarker for bone turnover

Peterson MC, et al. 42nd ASCO; June 2-6, 2006. Abstract 3086.


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Bone Turnover

Bone remodeling is characterized by 2 activities

  • Resorption of old bone by osteoclasts

  • Formation of new bone by osteoblasts


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OsteoporosisCurrent and Emerging Treatment Options

  • Bisphosphonate therapy

    • Oral

    • Intravenous

      • Zoledronic acid

      • Pamidronate disodium

  • Emerging therapies

    • Denosumab

Peterson MC, et al. 42nd ASCO; June 2-6, 2006. Abstract 3086.


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Denosumab—Mechanism of Action

  • RANKL

    • A key mediator of osteoclast formation, function, and survival, thus, a pivotal factor in much of the pathologic bone destruction associated with bone metastases

  • Denosumab

    • Binds to and inhibits RANKL, potentially reducing bone destruction in patients with breast cancer

RANKL = receptor activator of NFKappa B ligand.

Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.


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Effects of Denosumab on Bone Resorption in Breast Cancer Patientswith Bone Metastases

  • 5 cohorts of ~40 patients each

  • Dosages

    • Denosumab 30 mg Q4W

    • Denosumab 120 mg Q4W

    • Denosumab 180 mg Q4W

    • Denosumab 60 mg Q12W

    • Denosumab 180 mg Q12W

  • Rapid and sustained suppression of uNTx from baseline in all 5 cohorts

Peterson MC, et al. 42nd ASCO; June 2-6, 2006. Abstract 3086.


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Effect of Denosumab on Bone Resorption and Skeletal-Related Events

% Change in uNTx No. (%) of pts with

from baseline to week 13 >1 SRE on study

IV bisphosphonates-797 (16)

Denosumab

30 mg Q4wk SC-714 (10)

120 mg Q4wk SC-825 (12)

180 mg Q4wk SC-715 (12)

60 mg Q12wk SC-633 (5)

180 mg Q12wk SC -713 (7)

Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.


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Denosumab Adverse Events

  • Commonly reported adverse events

    • Nausea

    • Vomiting

    • Asthenia

    • Diarrhea

    • Bone pain

Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.


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DenosumabSummary

  • Resulted in a rapid suppression of bone turnover among advanced cancer patients with bone metastases; these results were also sustained at all time points measured in the study

  • Appears to be at least as effective as intravenous bisphosphonates in preventing skeletal-related events

  • No dose-dependent increase in adverse events

  • No serious or fatal adverse events

Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.


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Cancer …………Touches One and All


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