1 Building on the Success of Targeted Therapies in Metastatic Disease Harold J. Burstein, MD, PhD Assistant Professor of Medicine Department of Oncology

11

Building on the Success of Targeted Building on the Success of Targeted Therapies in Metastatic DiseaseTherapies in Metastatic Disease

Harold J. Burstein, MD, PhDHarold J. Burstein, MD, PhD

Assistant Professor of MedicineAssistant Professor of MedicineDepartment of OncologyDepartment of Oncology

Dana-Farber Cancer InstituteDana-Farber Cancer InstituteBoston, MassachusettsBoston, Massachusetts

22

TrastuzumabTrastuzumab

Monoclonal antibody binding to HER2/neu (erbB2) receptorMonoclonal antibody binding to HER2/neu (erbB2) receptor Standard treatment (in combination with chemotherapy) for Standard treatment (in combination with chemotherapy) for

HER2-positive metastatic breast cancer for past 7 yearsHER2-positive metastatic breast cancer for past 7 years Reduces the risk of recurrent HER2-positive disease by Reduces the risk of recurrent HER2-positive disease by

~50%~50% Cardiotoxicity the most important adverse eventCardiotoxicity the most important adverse event

– Trastuzumab + paclitaxel: 13% Trastuzumab + paclitaxel: 13% – Trastuzumab + anthracycline: 27%Trastuzumab + anthracycline: 27%

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

33

BevacizumabBevacizumab

Targets tumor angiogenesis—the formation of Targets tumor angiogenesis—the formation of new blood vessels necessary to support tumor new blood vessels necessary to support tumor growth and metastasis—by inhibiting vascular growth and metastasis—by inhibiting vascular endothelial growth factor, an important signaling endothelial growth factor, an important signaling molecule in regulating this processmolecule in regulating this process1,21,2

1. Cross MJ, Claesson-Welsh L. 1. Cross MJ, Claesson-Welsh L. Trends Pharmacol SciTrends Pharmacol Sci. 2001;22:201.. 2001;22:201.2. Brown JM, Giaccia AJ. 2. Brown JM, Giaccia AJ. Cancer Res.Cancer Res. 1998;58:1408. 1998;58:1408.

44

Bevacizumab + Paclitaxel Bevacizumab + Paclitaxel Phase III TrialPhase III Trial

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

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

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

Response rate (%)Response rate (%) 14.214.2 28.228.2Progression-free survival (mo)Progression-free survival (mo) 6.16.1 10.9710.97

55

Bevacizumab + PaclitaxelBevacizumab + PaclitaxelToxicitiesToxicities

13% of patients receiving bevacizumab developed 13% of patients receiving bevacizumab developed hypertension requiring treatmenthypertension requiring treatment

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

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

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

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

66

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

Trastuzumab + vinorelbineTrastuzumab + vinorelbine Trastuzumab + bevacizumabTrastuzumab + bevacizumab Trastuzumab + docetaxel +/- carboplatinTrastuzumab + docetaxel +/- carboplatin Trastuzumab + heat shock protein inhibitorTrastuzumab + heat shock protein inhibitor

77

Trastuzumab + Vinorelbine vs Trastuzumab + TaxaneTrastuzumab + Vinorelbine vs Trastuzumab + Taxane

HER2+ Metastatic Breast CancerHER2+ Metastatic Breast Cancer

Trastuzumab/Trastuzumab/ Trastuzumab/Trastuzumab/VinorelbineVinorelbine Taxane*Taxane*

n = 41n = 41 n = 40n = 40 P-P-ValueValue

Response rateResponse rate(strict criteria)(strict criteria) 51%51% 40%40% .37.37

Response rateResponse rate(unconfirmed)(unconfirmed) 66%66% 58%58% .50.50

Median time toMedian time to 8.58.5 6.06.0 .09.09Progression (mo) Progression (mo)

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

* * Paclitaxel (n=14), docetaxel (n=24), or paclitaxel/carboplatin (n=2) at discretion of treating oncologist.Paclitaxel (n=14), docetaxel (n=24), or paclitaxel/carboplatin (n=2) at discretion of treating oncologist.Burstein HJ, et al. 42Burstein HJ, et al. 42ndnd ASCO; June 2-6, 2006. Abstract 650. ASCO; June 2-6, 2006. Abstract 650.

88

Trastuzumab + Vinorelbine vsTrastuzumab + Vinorelbine vsTrastuzumab + TaxaneTrastuzumab + Taxane

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

Months

1.0 -

0.8 -

0.6 -

0.4 -

0.2 -

0.0 -0

Time to Tumor Progression (TTP)Time to Tumor Progression (TTP)

2 4 6 8 10 12 14 16 18

Pro

ba

bil

ity

Median TTP:

A (Trast + Vln)

B (Trast + Tax)

Log-rank P = .20

99

Trastuzumab + Vinorelbine vs Trastuzumab + TaxaneTrastuzumab + Vinorelbine vs Trastuzumab + TaxaneToxicitiesToxicities

Generally similarGenerally similar Trastuzumab + vinorelbineTrastuzumab + vinorelbine

– Greater myelosuppression Greater myelosuppression Trastuzumab + taxaneTrastuzumab + taxane

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

Cardiotoxicity <5% in all groups Cardiotoxicity <5% in all groups

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

1010

Trastuzumab + BevacizumabTrastuzumab + Bevacizumab Relapsed/Metastatic HER2+ DiseaseRelapsed/Metastatic HER2+ Disease

First report of 2 humanized monoclonal antibodies in First report of 2 humanized monoclonal antibodies in humanshumans

Phase 1 (9 patients)Phase 1 (9 patients)– 2 complete responses; 3 partial responses;2 complete responses; 3 partial responses; 2 stable disease (>6 mo)2 stable disease (>6 mo)

Phase II ongoing (16 patients with response)Phase II ongoing (16 patients with response)– 8 partial responses; 6 stable disease8 partial responses; 6 stable disease

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

1111

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

TDTD TDCTDCn = 131n = 131 n = 131n = 131 P-P-ValueValue

Median time to Median time to tumor progression (mo)*tumor progression (mo)* 11.111.1 10.410.4 .57.57

Objective response rateObjective response rate 73%73% 73%73%

Duration of response (mo)Duration of response (mo) 10.710.7 9.49.4

Median overall survival (mo)Median overall survival (mo) Not reachedNot reached 41.741.7

Clinical benefitClinical benefit 67%67% 67%67%

* Primary end point* Primary end point No increase in benefit with the addition of carboplatin to trastuzumab + docetaxelNo increase in benefit with the addition of carboplatin to trastuzumab + docetaxel

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

1212

Trastuzumab + Heat Shock Protein (HSP) Trastuzumab + Heat Shock Protein (HSP) InhibitorInhibitor

Chaperone protein is required for maturation and stabilization of Chaperone protein is required for maturation and stabilization of certain client proteins, including HER2certain client proteins, including HER2

Inhibition of HSP90 chaperone function induces degradation of Inhibition of HSP90 chaperone function induces degradation of client proteinclient protein

Phase I trial of KOS-953, an HSP90 inhibitor, plus trastuzumab: Phase I trial of KOS-953, an HSP90 inhibitor, plus trastuzumab: 17 HER2+ patients with trastuzumab-resistant metastatic breast 17 HER2+ patients with trastuzumab-resistant metastatic breast cancercancer– 1 partial response, 3 minimal response, 5 prolonged (1 partial response, 3 minimal response, 5 prolonged (>>4 mo) 4 mo)

stable disease stable disease Phase II trial under wayPhase II trial under way

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

1313

Trastuzumab ResistanceTrastuzumab Resistance

Virtually all HER2+ metastatic breast cancers Virtually all HER2+ metastatic breast cancers develop resistancedevelop resistance

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

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

1414

Possible Causes of Trastuzumab Possible Causes of Trastuzumab ResistanceResistance

Suboptimal drug deliverySuboptimal drug delivery Altered target expressionAltered target expression Altered targetAltered target Modified target-regulating proteinsModified target-regulating proteins Alternative pathway signalingAlternative pathway signaling


1515

Overcoming Trastuzumab ResistanceOvercoming Trastuzumab Resistance

Block the HER pathway(s) at other pointsBlock the HER pathway(s) at other points Block other growth factor receptor pathways Block other growth factor receptor pathways

(HER1, IGF-1R)(HER1, IGF-1R) Block angiogenesisBlock angiogenesis


1616

LapatinibLapatinib

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

1717

LapatinibLapatinibMechanism of ActionMechanism of Action

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

Phase I trial:Phase I trial:Storniolo, SABC 2005Storniolo, SABC 2005

Lapatinib and Trastuzumab:Lapatinib and Trastuzumab:Potential for SynergyPotential for Synergy

LapatinibLapatinib

TrastuzumabTrastuzumab

Maximum inactivation of Maximum inactivation of ErbB2 PathwayErbB2 Pathway

• • ErbB2 receptorErbB2 receptor

• • Truncated Erb2 receptorTruncated Erb2 receptor

• • ErbB1/ErbB2 heterodimesErbB1/ErbB2 heterodimes

Downstream signaling cascadeDownstream signaling cascade

Cell Division/Tumor GrowthCell Division/Tumor Growth

1818

Lapatinib+Capecitabine vs Capacitabine in Lapatinib+Capecitabine vs Capacitabine in Trastuzumab-Resistant DiseaseTrastuzumab-Resistant Disease

Time to Tumor ProgressionTime to Tumor ProgressionLapatinib/Lapatinib/CapecitabineCapecitabine CapecitabineCapecitabinen = 160n = 160 n = 161n = 161

Progressed or diedProgressed or died 45 (28%) 45 (28%) 69 (43%)69 (43%)

Median TTP (wk) Median TTP (wk) 36.9 36.9 19.719.7

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

PP-value (log rank, 1-sided) -value (log rank, 1-sided) .00016.00016

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

1919

Lapatinib + Capecitabine vs CapecitabineLapatinib + Capecitabine vs Capecitabinein Trastuzumab-Resistant Diseasein Trastuzumab-Resistant Disease

Brain MetastasesBrain Metastases as Site of Progressionas Site of ProgressionLapatinib/Lapatinib/

CapecitabineCapecitabine CapecitabineCapecitabinen = 160n = 160 n = 161n = 161

Patients with CNS Patients with CNS metastases at baselinemetastases at baseline 22 22

Patients with CNS relapse*Patients with CNS relapse* 44 1111

Patients with CNS as Patients with CNS as only site of relapseonly site of relapse 33 1010

**PP-value (Fisher’s exact, 2-sided) = .110-value (Fisher’s exact, 2-sided) = .110Geyer CE, et al. 42Geyer CE, et al. 42ndnd ASCO; June 2-6, 2006. Special Session. ASCO; June 2-6, 2006. Special Session.

2020

Lapatinib + Capecitabine vs CapacitabineLapatinib + Capecitabine vs Capacitabinein Trastuzumab-Resistant Diseasein Trastuzumab-Resistant Disease

Adverse EventsAdverse Events (AEs)(AEs)

Similar rates for all AEs and serious AEsSimilar rates for all AEs and serious AEs Most common AEs: diarrhea, PPE, rash, and/or skin reactions Most common AEs: diarrhea, PPE, rash, and/or skin reactions AEs leading to discontinuation of study medicationAEs leading to discontinuation of study medication

– Lapatinib + capecitabine: 22 (14%)Lapatinib + capecitabine: 22 (14%)– Capecitabine: 16 (11%)Capecitabine: 16 (11%)

Cardiac eventsCardiac events– 4 lapatinib + capecitabine; 1 capecitabine4 lapatinib + capecitabine; 1 capecitabine– All asymptomatic (All asymptomatic (grade 2)grade 2)– No withdrawals due to decreased LVEFNo withdrawals due to decreased LVEF

1 treatment-related death in capecitabine arm1 treatment-related death in capecitabine arm

PPE = palmar-plantar erythrodysesthesia; LVEF = left ventricular ejection fraction.PPE = palmar-plantar erythrodysesthesia; LVEF = left ventricular ejection fraction.Geyer CE, et al. 42Geyer CE, et al. 42ndnd ASCO; June 2-6, 2006. Special Session. ASCO; June 2-6, 2006. Special Session.

2121

Lapatinib + Capecitabine vs CapecitabineLapatinib + Capecitabine vs Capecitabinein Trastuzumab-Resistant Diseasein Trastuzumab-Resistant Disease

SummarySummary

Compared with capecitabine alone, lapatinib + Compared with capecitabine alone, lapatinib + capecitabine results incapecitabine results in– Significantly longer time to tumor progressionSignificantly longer time to tumor progression– Fewer CNS metastasesFewer CNS metastases– Comparable safetyComparable safety

2222

Lapatinib in Brain MetastasesLapatinib in Brain Metastases

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

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

Trastuzumab is not thought to cross the blood-brain barrierTrastuzumab is not thought to cross the blood-brain barrier Phase II trial of lapatinib monotherapy in CNS metastasesPhase II trial of lapatinib monotherapy in CNS metastases

– 39 patients with CNS metastases that developed on trastuzumab 39 patients with CNS metastases that developed on trastuzumab (38 of whom progressed after prior radiation) (38 of whom progressed after prior radiation) 2 partial responses by RECIST2 partial responses by RECIST 8 progression-free in CNS at 16 weeks8 progression-free in CNS at 16 weeks Volumetric declines >30% in 4 patients; declines of 10% to Volumetric declines >30% in 4 patients; declines of 10% to

30% in an additional 6 patients30% in an additional 6 patients

RECIST = Response Evaluation Criteria in Solid Tumors.RECIST = Response Evaluation Criteria in Solid Tumors.Lin NU, et al. 42Lin NU, et al. 42ndnd ASCO; June 2-6, 2006. Abstract 503. ASCO; June 2-6, 2006. Abstract 503.

2323

Lapatinib MonotherapyLapatinib Monotherapyin Inflammatory Breast Cancerin Inflammatory Breast Cancer

Cohort A:Cohort A: Cohort B: Cohort B: erbB2+erbB2+ erbB1+/erbB2- erbB1+/erbB2- (n = 24)(n = 24) (n = 12)(n = 12)

Partial responsePartial response 62%62% 8.3%8.3%

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

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

2424

ConclusionsConclusions

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

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

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

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

2525

ConclusionsConclusions(cont’d)(cont’d)

New agents and approaches continue to expand the New agents and approaches continue to expand the benefit of targeted therapybenefit of targeted therapy• Inhibition of heat shock protein (HSP) chaperone Inhibition of heat shock protein (HSP) chaperone

function by a HSP90 inhibitor induces degradation of function by a HSP90 inhibitor induces degradation of HER2 and may increase efficacy of trastuzumab when HER2 and may increase efficacy of trastuzumab when used in a combination regimenused in a combination regimen

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

2626

Getting the Most Out Getting the Most Out of Targeted Therapyof Targeted Therapy

Francisco J. Esteva, MD, PhDFrancisco J. Esteva, MD, PhD

Associate Professor of MedicineAssociate Professor of MedicineBreast Medical OncologyBreast Medical OncologyThe University of TexasThe University of Texas

M.D. Anderson Cancer CenterM.D. Anderson Cancer CenterHouston, TexasHouston, Texas

2727

Trastuzumab in Early-Stage DiseaseTrastuzumab in Early-Stage Disease

2828

HERA TrialHERA Trial2-Year Follow-Up2-Year Follow-Up

CT = chemotherapy; RT = radiotherapy; IHC = immunohisochemistry; FISH = fluorescence CT = chemotherapy; RT = radiotherapy; IHC = immunohisochemistry; FISH = fluorescence in situ hybridization; LVEF = left ventricular ejection fraction.in situ hybridization; LVEF = left ventricular ejection fraction.Smith IE. Presented at 42Smith IE. Presented at 42ndnd ASCO; June 2-6, 2006. ASCO; June 2-6, 2006.

HERA Trial DesignHERA Trial Design

Women with locally determined HER2 + invasive early breast cancer

Women with locally determined HER2 + invasive early breast cancer

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

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

Surgery + (neo)adjuvant CT ± RT

RandomizationRandomization

ObservationObservation1 year trastuzumab8 mg/kg 6 mg/kg3 weekly schedule

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

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

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

After ASCO 2005,option of switchto trastuzumab

After ASCO 2005,option of switchto trastuzumab

2929

HERA TrialHERA TrialDisease-Free Survival (ITT)Disease-Free Survival (ITT)

ITT = intent to treat; DFS = disease-free survival; HR = hazard ratio; CI = confidence interval.ITT = intent to treat; DFS = disease-free survival; HR = hazard ratio; CI = confidence interval.Smith IE. 42Smith IE. 42ndnd ASCO; June 2-6, 2006. ASCO; June 2-6, 2006.

Median Follow-Up 2 yearsMedian Follow-Up 2 yearsP

ati

en

ts (

%)

100

80

60

40

20

00 6 12 18 24 30 36

1 year trastuzumab

Observation 6.3%

Events3-yearDFS HR 95% Cl P-Value

218 0.64 0.54, 0.76 <.000180.6

321 74.3

No.at risk

Months from Randomization

1703 1591 1434 1127 742 383 140 1698 1535 1330 984 639 334 127

3030

HERA TrialHERA TrialOverall Survival (ITT)Overall Survival (ITT)

ITT = intent to treat; OS = overall survival; HR = hazard ratio; CI = confidence interval.ITT = intent to treat; OS = overall survival; HR = hazard ratio; CI = confidence interval.Smith IE. 42Smith IE. 42ndnd ASCO; June 2-6, 2006. ASCO; June 2-6, 2006.

100

80

60

40

20

00 6 12 18 24 30 36

1 year trastuzumab

Observation

2.7%

Events3-year

OS HR 95% Cl P-Value

59 0.66 0.47, 0.91 .011592.4

90 89.7

No.at risk

Months from Randomization

1703 1627 1498 1190 794 407 146 1698 1608 1453 1097 711 366 139

Median Follow-Up 2 YearsMedian Follow-Up 2 YearsP

ati

en

ts (

%)

3131

HERA TrialHERA TrialCardiac SafetyCardiac Safety

Number Patients (%)Number Patients (%)

Observation Trastuzumab: 1 yObservation Trastuzumab: 1 y n = 1708 n = 1678n = 1708 n = 1678

Cardiac deathCardiac death 1 (0.1) 1 (0.1) 0 (0.0) 0 (0.0)

Severe CHFSevere CHF(NYHA III and IV) 0 (0.0) 10 (0.6)(NYHA III and IV) 0 (0.0) 10 (0.6) Symptomatic CHF 3 (0.2) 36 (2.1)Symptomatic CHF 3 (0.2) 36 (2.1)

Confirmed significantConfirmed significantLVEF drop 9 (0.5) 51 (3.0)LVEF drop 9 (0.5) 51 (3.0)

CHF = congestive heart failure; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction.CHF = congestive heart failure; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction.Smith IE. 42Smith IE. 42ndnd ASCO; June 2-6, 2006. ASCO; June 2-6, 2006.

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HERA TrialHERA TrialSummarySummary

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

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

Risk of cardiac toxicity remains lowRisk of cardiac toxicity remains low

HR=hazard ratioHR=hazard ratioSmith IE. 42Smith IE. 42ndnd ASCO; June 2-6, 2006. ASCO; June 2-6, 2006.

3333

Identification of Patients Likely to BenefitIdentification of Patients Likely to Benefit

Balancing risk and benefitBalancing risk and benefit Using biomarkers to predict responseUsing biomarkers to predict response

– TrastuzumabTrastuzumab– Anti epidermal growth factor receptor therapyAnti epidermal growth factor receptor therapy

3434

Trastuzumab for All HER2+ Patients?Trastuzumab for All HER2+ Patients?

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

However, trastuzumab is associated with significant cardiac However, trastuzumab is associated with significant cardiac toxicitytoxicity

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

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

3535

Low Risk of Recurrence and/or High Risk of ToxicityLow Risk of Recurrence and/or High Risk of Toxicity CumulativeCumulative Cardiac 10-y 10-yCardiac 10-y 10-yPatient Treatment Toxicity (%) QALYs DFS (%) Cardiac Deaths (%)Patient Treatment Toxicity (%) QALYs DFS (%) Cardiac Deaths (%)

50 y CT 0.8 20.61 70.2 0.0650 y CT 0.8 20.61 70.2 0.062 cm 2 cm node+ CT+T 6 25.34 81.9 0.68node+ CT+T 6 25.34 81.9 0.68ER/PR-ER/PR-EF 60%EF 60%

70 y CT 0.8 13.58 62.1 0.0670 y CT 0.8 13.58 62.1 0.062 cm2 cmnode- CT+T 20 14.18 66.8 2.03node- CT+T 20 14.18 66.8 2.03ER/PR-ER/PR-EF 50%EF 50%

QALYs = quality adjusted life years; DFS = disease-free survival; CT = chemotherapy; QALYs = quality adjusted life years; DFS = disease-free survival; CT = chemotherapy; T= trastuzumab; ER = estrogen receptor; PR = progesterone receptor; EF = ejection fraction.T= trastuzumab; ER = estrogen receptor; PR = progesterone receptor; EF = ejection fraction.Gupta AK, et al. 42Gupta AK, et al. 42ndnd ASCO Abstracts. ASCO Abstracts. J Clin OncolJ Clin Oncol. 2006;24:Abstract 6022. Reprinted with . 2006;24:Abstract 6022. Reprinted with permission from the American Society of Clinical Oncology.permission from the American Society of Clinical Oncology.

3636


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

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

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

3737

Change in Serum HER2 and OutcomeChange in Serum HER2 and Outcome

Change in HER2 Change in HER2 Serum Levels DR TTP OS Serum Levels DR TTP OS

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

<20% decrease 28.4% 230 182 593<20% decrease 28.4% 230 182 593

>20% decrease 56.5% 369 320 898>20% decrease 56.5% 369 320 898

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

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

trastuzumab and should be considered for additional HER2-targeted therapiestrastuzumab and should be considered for additional HER2-targeted therapies

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

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

3838

ER+/PR- StatusER+/PR- Status

Compared with ER+/PR+ disease, ER+/PR- Compared with ER+/PR+ disease, ER+/PR- breast cancer hasbreast cancer has– Lower response rate to estrogen deprivationLower response rate to estrogen deprivation– Worse prognosisWorse prognosis– May be dependent on other signaling May be dependent on other signaling

pathwayspathways

ER = estrogen receptor; PR = progesterone receptor.ER = estrogen receptor; PR = progesterone receptor.Finn RS, et al. 42Finn RS, et al. 42ndnd ASCO; June 2-6, 2006. Abstract 514. ASCO; June 2-6, 2006. Abstract 514.

3939

ER+/PR- Breast Cancer and EGFR InhibitionER+/PR- Breast Cancer and EGFR Inhibition

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

Tissue obtained at surgeryTissue obtained at surgery– ER+/PR- tumors more likely to show molecular growth inhibitionER+/PR- tumors more likely to show molecular growth inhibition– ER+/PR+ tumors more likely to show molecular growth ER+/PR+ tumors more likely to show molecular growth

proliferation proliferation ConclusionsConclusions

– ER+/PR- breast cancer is growth factor dependentER+/PR- breast cancer is growth factor dependent– ER+/PR- patients may be more likely to benefit from EGFR ER+/PR- patients may be more likely to benefit from EGFR

inhibitioninhibition

ER = estrogen receptor; PR = progesterone receptor; EGFR = epidermal growth factor receptor.ER = estrogen receptor; PR = progesterone receptor; EGFR = epidermal growth factor receptor.Finn RS, et al. 42Finn RS, et al. 42ndnd ASCO; June 2-6, 2006. Abstract 514. ASCO; June 2-6, 2006. Abstract 514.

4040

EGFR Expression and Tumor CharacteristicsEGFR Expression and Tumor Characteristics Comparision of EGFR+ and EGFR- tumors in 2567 patientsComparision of EGFR+ and EGFR- tumors in 2567 patients EGFR+ tumors were more common in patients who were EGFR+ tumors were more common in patients who were

– Younger (<50 y)Younger (<50 y)11

– PremenopausalPremenopausal11– BlackBlack22

EGFR expression was associated withEGFR expression was associated with– Larger tumorsLarger tumors11

– AneuploidyAneuploidy11

– High S-phase fractionHigh S-phase fraction11

– Nodal involvementNodal involvement33

EGFR+ tumors were more likely to be HER2+EGFR+ tumors were more likely to be HER2+11, but less likely to be ER+, but less likely to be ER+11 and and PR+PR+11

11 P P <.0001<.000122 P P = .005= .00533 P P = .009= .009EGFR = epidermal growth factor receptor; ER = estrogen receptor; PR = progesterone receptor.EGFR = epidermal growth factor receptor; ER = estrogen receptor; PR = progesterone receptor.Rimawi MF, et al. 42Rimawi MF, et al. 42ndnd ASCO; June 2-6, 2006. Abstract 513. ASCO; June 2-6, 2006. Abstract 513.

4141

EGFR Expression and PrognosisEGFR Expression and Prognosis

1 1 Systemic chemotherapy and/or hormonal therapySystemic chemotherapy and/or hormonal therapy22 No systemic therapy No systemic therapyEGFR = epidermal growth factor receptor; DFS = disease-free survival; OS = overall survival.EGFR = epidermal growth factor receptor; DFS = disease-free survival; OS = overall survival.Rimawi MF, et al. 42Rimawi MF, et al. 42ndnd ASCO; June 2-6, 2006. Abstract 513. ASCO; June 2-6, 2006. Abstract 513.

1256 treated patients;1256 treated patients;11 1068 untreated patients 1068 untreated patients22

In treated patients, EGFR expression was negatively correlated In treated patients, EGFR expression was negatively correlated withwith

– DFS (DFS (P = P = .001).001)– 0S (0S (PP = .001) = .001)

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

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

4242

Cost-Effectiveness of Trastuzumab—Model 1Cost-Effectiveness of Trastuzumab—Model 1

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

Based on Markov model with 3 disease statesBased on Markov model with 3 disease states– Disease-free survivalDisease-free survival– RecurrenceRecurrence– DeathDeath

Costs includedCosts included– Testing for HER2 statusTesting for HER2 status– Drug and administration costs for trastuzumabDrug and administration costs for trastuzumab– Cardiac monitoringCardiac monitoring– Treatment of cardiac toxicityTreatment of cardiac toxicity– Treatment following recurrenceTreatment following recurrence– End-of-life costs for dying patientsEnd-of-life costs for dying patients

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

4343

Patient: 50 year-old womanPatient: 50 year-old woman Efficacy based on NCCTG N9831 and NSABP B-31 trials; projections to Efficacy based on NCCTG N9831 and NSABP B-31 trials; projections to

recurrence and death based on literature (recurrence and death based on literature (LancetLancet, 2005), 2005) With trastuzumabWith trastuzumab

– Lifetime cost per QALY gained: $27,800 (range: $17,900 to $39,100)Lifetime cost per QALY gained: $27,800 (range: $17,900 to $39,100)– Projected life expectancy 3 years longer (trastuzumab: 19.4 years; Projected life expectancy 3 years longer (trastuzumab: 19.4 years;

without trastuzumab: 16.4 years) without trastuzumab: 16.4 years) – Additional cost of adding trastuzumab: $46,300Additional cost of adding trastuzumab: $46,300– Expected gain of 1.28 QALYExpected gain of 1.28 QALY– Cost/QALY = $36,100Cost/QALY = $36,100

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

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

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

4444

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

Comparison ofComparison of Cost per relapse prevented by adjuvant Cost per relapse prevented by adjuvant

chemotherapy (docetaxel, paclitaxel, filgrastim) chemotherapy (docetaxel, paclitaxel, filgrastim) vsvs

Cost per relapse prevented by adjuvant Cost per relapse prevented by adjuvant trastuzumab trastuzumab

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

4545

Trastuzumab Docetaxel Paclitaxel FilgrastimTrastuzumab Docetaxel Paclitaxel Filgrastim

ReductionReductionin relapse 50% 7%in relapse 50% 7%11 5% 5%22 4% 4%33

Cost per relapseCost per relapseprevented € 147,000 € 126,000 € 148,000 € 231,000prevented € 147,000 € 126,000 € 148,000 € 231,000

Adjuvant trastuzumab is more cost-effective than adjuvant paclitaxelAdjuvant trastuzumab is more cost-effective than adjuvant paclitaxelor filgrastimor filgrastim

11 BCIRG 001 BCIRG 001 22 CALGB 9344 CALGB 93443 3 CALGB 9741CALGB 9741Wilson E, et al. 42Wilson E, et al. 42ndnd ASCO; June 2-6, 2006. Abstract 6081. ASCO; June 2-6, 2006. Abstract 6081.


(cont’d)(cont’d)

4646

ConclusionsConclusions Assuming no retreatment with trastuzumab, Assuming no retreatment with trastuzumab,

adjuvant trastuzumab appears to be a relatively adjuvant trastuzumab appears to be a relatively cost-effective means of reducing relapsescost-effective means of reducing relapses

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

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


(cont’d)(cont’d)

4747


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

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

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

4848

Adverse Events andAdverse Events andTargeted TherapyTargeted Therapy

Maureen Major, RN, MSMaureen Major, RN, MSClinical Nurse SpecialistClinical Nurse SpecialistDepartment of NursingDepartment of Nursing

Memorial Sloan-Kettering Cancer CenterMemorial Sloan-Kettering Cancer CenterNew York, New YorkNew York, New York

4949

Adverse EventsAdverse Events

Cardiac toxicityCardiac toxicity OsteoporosisOsteoporosis

5050

NCCTG N9831

Arm A

Arm B

Arm C

= 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 DesignsNCCTG N9831 Trial Designs

NCCTG = North Central Cancer Treatment Group.N9831 PI. EA Perez.With permission from Romond E. ASCO 2005; May 13–17, 2005. Oral Presentation.

5151

Incidence of Trastuzumab-Related Cardiac Toxicity Incidence of Trastuzumab-Related Cardiac Toxicity in NSABP B31in NSABP B31

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.

0

2

4

6

0.0Years Post Day 1 Cyc 5

Arm 1 Evaluable CohortArm 2 Evaluable Cohort

0.5 1.0 1.5 2.0 2.5 3.0

Cohort

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

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

4.1%

0.8%

HR = 5.9

Perc

ent

5252

Assessing CardiotoxicityAssessing Cardiotoxicitywith Trastuzumab Therapywith Trastuzumab Therapy

Goal—to discover dysfunction earlyGoal—to discover dysfunction early Diastolic dysfunction may be better predictorDiastolic dysfunction may be better predictor Diagnostic testingDiagnostic testing

– Echocardiography and doppler flow studyEchocardiography and doppler flow study– Multiple gated acquisition Scan (MUGA) Multiple gated acquisition Scan (MUGA)

Blood testingBlood testing– Troponin = measurement of heart injuryTroponin = measurement of heart injury– Brain natriuretic peptide (BNP) = strainBrain natriuretic peptide (BNP) = strain

Monitor every 3 monthsMonitor every 3 months

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

5353

Radiotherapy + TrastuzumabRadiotherapy + TrastuzumabDoes Does ConcomitantConcomitant Administration Administration

Increase Risk?Increase Risk?

Preclinical studies suggest that Preclinical studies suggest that trastuzumab may enhance radiotherapytrastuzumab may enhance radiotherapy

Trastuzumab, doxorubicin, and Trastuzumab, doxorubicin, and radiotherapy are potentially cardiotoxicradiotherapy are potentially cardiotoxic

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

NCCTG N9831

ARMA

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.

5454

Radiotherapy + TrastuzumabRadiotherapy + TrastuzumabDoes Does ConcomitantConcomitant Administration Administration

Increase Risk?Increase Risk?

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

Patient characteristicPatient characteristic– Lumpectomy: whole breast RT with optional tumor bed Lumpectomy: whole breast RT with optional tumor bed

boost boost – Mastectomy: ≥ 4+ nodes received nodal and chest wall RTMastectomy: ≥ 4+ nodes received nodal and chest wall RT

Internal mammary nodal (IMN) RT not permittedInternal mammary nodal (IMN) RT not permitted– However, 41/1433 (3%) of patients received IMNHowever, 41/1433 (3%) of patients received IMN– Dosimetry review showed that all 41 had cardiac sparingDosimetry review showed that all 41 had cardiac sparing

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

5555

Radiotherapy + TrastuzumabRadiotherapy + TrastuzumabCardiac EventsCardiac Events

+RT –RT+RT –RT

2.2 2.92.2 2.9

1.5 6.31.5 6.3

B

C

NCCTG 9831

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.

Cardiac Events (% Pts)*Cardiac Events (% Pts)*

*Median follow-up of 1.5 years*Median follow-up of 1.5 years

5656

Lapatinib Lapatinib Dual Tyrosine Kinase InhibitorDual Tyrosine Kinase Inhibitor

Lapatinib is an epidermal growth factor receptor and Lapatinib is an epidermal growth factor receptor and ErbB2 (Her2/neu) inhibitorErbB2 (Her2/neu) inhibitor

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

ErbB2 signaling is important for cardiac functionErbB2 signaling is important for cardiac function Trastuzumab is known to be associated with cardiac Trastuzumab is known to be associated with cardiac

toxicitytoxicity Is lapatinib associated with cardiac toxicity?Is lapatinib associated with cardiac toxicity?

5757

Prospective Evaluation of LapatinibProspective Evaluation of LapatinibCardiac SafetyCardiac Safety

1674 breast cancer patients treated with lapatinib1674 breast cancer patients treated with lapatinib Decreased LVEF: 22 (1.3%)Decreased LVEF: 22 (1.3%)

– Symptomatic: 2 (0.1%)Symptomatic: 2 (0.1%)– Asymptomatic: 20 (1.2%)Asymptomatic: 20 (1.2%)

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

Average duration: 40 days (9–113)Average duration: 40 days (9–113) 41% (9/22) recovered while continuing to receive 41% (9/22) recovered while continuing to receive

lapatiniblapatinib

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

5858

22 Patients22 Patientswith Decreased LVEFwith Decreased LVEF

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

45

40

35

30

25

20

15

10

5

0

% L

VEF

Dec

reas

e R

elat

ive

to B

asel

ine

Patient

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 20 22211917

Symptomatic Patients Symptomatic Patients

LVEF Event Duration (D)

Patie

nt

13

12

11

10

987

6

54

3

21

0 20 40 60 80 100 120

Characteristics of 22 Patients with Breast Cancer and Decreased LVEFCharacteristics of 22 Patients with Breast Cancer and Decreased LVEF

5959

OsteoporosisOsteoporosis Breast cancer patients with bone metastases are at an increased risk Breast cancer patients with bone metastases are at an increased risk

for skeletal-related eventsfor skeletal-related events– FracturesFractures– Hypercalcemia of malignancyHypercalcemia of malignancy– Spinal cord compressionSpinal cord compression– PainPain

Goals of treatmentGoals of treatment– Treat underlying diseaseTreat underlying disease– Stabilize the boneStabilize the bone– Prevent further bone breakdownPrevent further bone breakdown– Relieve painRelieve pain– Improve quality of lifeImprove quality of life

Measurement of bone lossMeasurement of bone loss– Urinary N-telopeptide levels (uNTx): biomarker for bone turnover Urinary N-telopeptide levels (uNTx): biomarker for bone turnover

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

6060

Bone TurnoverBone Turnover

Bone remodeling is characterized by 2 activitiesBone remodeling is characterized by 2 activities Resorption of old bone by osteoclastsResorption of old bone by osteoclasts Formation of new bone by osteoblasts Formation of new bone by osteoblasts

6161

OsteoporosisOsteoporosisCurrent and Emerging Treatment OptionsCurrent and Emerging Treatment Options

Bisphosphonate therapyBisphosphonate therapy– OralOral– IntravenousIntravenous

Zoledronic acidZoledronic acid Pamidronate disodiumPamidronate disodium

Emerging therapiesEmerging therapies– DenosumabDenosumab


6262

Denosumab—Mechanism of ActionDenosumab—Mechanism of Action

RANKL RANKL – A key mediator of osteoclast formation, function, A key mediator of osteoclast formation, function,

and survival, thus, a pivotal factor in much of the and survival, thus, a pivotal factor in much of the pathologic bone destruction associated with bone pathologic bone destruction associated with bone metastasesmetastases

Denosumab Denosumab – Binds to and inhibits RANKL, potentially reducing Binds to and inhibits RANKL, potentially reducing

bone destruction in patients with breast cancerbone destruction in patients with breast cancer

RANKL = receptor activator of NFKappa B ligand.RANKL = receptor activator of NFKappa B ligand.Lipton A. 42nd ASCO; June 2-6, 2006. Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.

6363

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

5 cohorts of ~40 patients each 5 cohorts of ~40 patients each DosagesDosages

– Denosumab 30 mg Q4WDenosumab 30 mg Q4W– Denosumab 120 mg Q4WDenosumab 120 mg Q4W– Denosumab 180 mg Q4WDenosumab 180 mg Q4W– Denosumab 60 mg Q12WDenosumab 60 mg Q12W– Denosumab 180 mg Q12WDenosumab 180 mg Q12W

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


6464

Effect of Denosumab on Bone Resorption and Effect of Denosumab on Bone Resorption and Skeletal-Related EventsSkeletal-Related Events

% Change in uNTx % Change in uNTx No. (%) of pts with No. (%) of pts with from baseline to week 13from baseline to week 13 >>1 SRE on study 1 SRE on study

IV bisphosphonatesIV bisphosphonates -79-79 7 (16)7 (16)DenosumabDenosumab 30 mg Q4wk SC30 mg Q4wk SC -71-71 4 (10)4 (10) 120 mg Q4wk SC120 mg Q4wk SC -82-82 5 (12)5 (12) 180 mg Q4wk SC180 mg Q4wk SC -71-71 5 (12)5 (12) 60 mg Q12wk SC60 mg Q12wk SC -63-63 3 (5)3 (5) 180 mg Q12wk SC 180 mg Q12wk SC -71-71 3 (7)3 (7)

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

6565

Denosumab Adverse EventsDenosumab Adverse Events

Commonly reported adverse events Commonly reported adverse events – NauseaNausea– VomitingVomiting– AstheniaAsthenia– DiarrheaDiarrhea– Bone painBone pain


6666

DenosumabDenosumabSummarySummary

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

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

No dose-dependent increase in adverse eventsNo dose-dependent increase in adverse events No serious or fatal adverse events No serious or fatal adverse events


Cancer ………… Cancer ………… Touches One and AllTouches One and All

Documents

1 Building on the Success of Targeted Therapies in Metastatic Disease Harold J. Burstein, MD, PhD Assistant Professor of Medicine Department of Oncology