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patients or employing any therapeutic products described in this educational activity.

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DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information

to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for

patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by

clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational

uses of agents that are not indicated by the FDA. Albert Einstein College of Medicine and IMER do not recommend the use of any agent outside of the labeled

indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Albert Einstein College of Medicine and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestKathy D. Miller, MDKathy D. Miller, MD

Reported a financial interest/relationship or affiliation in the form of: Contracted Research, Clovis Oncology, Inc., Geron Corporation, Merrimack Pharmaceuticals, Roche Pharmaceuticals, Inc.; Consultant, Clovis Oncology, Inc., Necktar Therapeutics, Roche Pharmaceuticals, Inc.

Future Directions in the Treatment Future Directions in the Treatment of Patients With HER2-Positive Breast of Patients With HER2-Positive Breast Cancer: What Community Oncologists Cancer: What Community Oncologists

Need to KnowNeed to Know

Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,

participants should be better able to:participants should be better able to:

Identify treatment options for patients with HER2+ breast cancer that have failed trastuzumab

Describe the significance of HER2 status in making clinical decisions

Assess the optimal combinations of HER2-targeted therapy for treating patients with HER2+ breast cancer

Identify proposed mechanisms of resistance to HER2-targeted therapies for treating HER2+ patients

Cite new data from clinical trials on novel and emerging agents for treating HER2+ breast cancer including mTOR inhibitors, antiangiogenic inhibitors, and HER2-targeted therapies

Activity AgendaActivity Agenda

Activity Overview (5 mins)

Anthracyclines or No Anthracyclines: Are Adjuvant Anthracyclines Necessary for the Treatment of HER2+ Breast Cancer? (10 mins)

Trastuzumab Progression: Which Treatment Options Provide the Best Outcomes for Patients With HER2+ Breast Cancer After Progression on Trastuzumab? (20 mins)

Combination Approaches: What Combination Approaches Are Options for Treating Patients With HER2+ Breast Cancer? (20 mins)

Questions & Answers (5 mins)

HER2/neu OverviewHER2/neu Overview

General Features of HER2/neu Located on chromosome17q

Amplified in approximately 20% of primary breast cancers

Encodes for tyrosine kinase transmembrane growth factor receptor

Both a prognostic and predictive factor in early stage and advanced breast cancer

HER2 overexpression seen in DCIS but not in earlier premalignant lesions

Characteristics of HER2 + Disease Increased tumor size

Positive nodal status

Decreased ER and PR expression

Ductal rather than lobular histology

– High S-phase fraction

– High nuclear grade

Higher risk of recurrence

More advanced stage at presentation

DCIS = ductal carcinoma in situ; ER = estrogen receptor; PR = progesterone receptor.Gutierrez et al, 2011.

Anthracyclines or No Anthracyclines: Anthracyclines or No Anthracyclines: Are Adjuvant Anthracyclines Necessary Are Adjuvant Anthracyclines Necessary

for the Treatment of HER2+ Breast Cancer? for the Treatment of HER2+ Breast Cancer?

Topics for DiscussionTopics for Discussion

Anthracyclines or nonanythracyclines combined with trastuzumab: Efficacy vs.risk factors?

What risk factors and preexisting conditions define which regimen to use?

Adjuvant Trastuzumab Trial DesignsAdjuvant Trastuzumab Trial Designs

Tripathy, 2011.

Trastuzumab AdjuvantTrastuzumab AdjuvantTrial DFS BenefitsTrial DFS Benefits

Study FU (yrs) N

HERA1 3,387

2 3,401

NSABP B-31/NCCTG 9831

2 3,351

4 3,968

BCIRG 006 3 3,222

FinHer 3 231

PACS 04 4 528

0 1 2In favor of T In favor of Obs.

HR

0.54

0.64

0.48

0.48

0.61

0.42

0.86

DFS = disease-free survival; FU = follow-up; HR = hazard ratio.Metcalfe, 2007.

BCIRG 006 – Final BCIRG 006 – Final AnalysisAnalysis

CI = confidence interval.Slamon et al, 2009.

Therapeutic Index for Critical Therapeutic Index for Critical Clinical EventsClinical Events

Clinical Event Number of Events

AC-T AC-T plus Trastuzumab

TCH

Total Events 201 146 149

Distant breast-cancer recurrence 188 124 144

Grade 3 or 4 congestive heart failure

7 21 4

Acute Leukemia 6 1 1

This is a compilation of the distant breast-cancer recurrences, cases of CHF, and cases of acute leukemia.

CI = confidence interval, AC-T = doxorubicin and cyclophosphamide followed by docetaxel, TCH = docetaxel, carboplatin, and trastuzumab..Slamon et al, 2011.

Smith et al, 2007; Perez et al, 2008; Slamon et al, 2011; Rastogi et al, 2007.

H = trastuzumab; A = doxorubicin; C = cyclophosphamide; P = paclitaxel; T = docetaxel;LVEF = left ventricular ejection fraction; CHF = congestive heart failure.

Clinical Cardiomyopathy inClinical Cardiomyopathy inTrastuzumabTrastuzumab Adjuvant Trials Adjuvant Trials

N9831: Schema and Cardiac TestingN9831: Schema and Cardiac Testing

R

Arm A: AC(q3wks x 4)

Paclitaxel(qwk x 12)

Arm B: AC(q3wks x 4)

Paclitaxel H(qwk x 12) (qwk x 52)

Arm C: AC(q3wks x 4)

Paclitaxel + H(qwk x 12)

H(qwk x 40)

Time (mos)0

LVEF Measurement3 6 9 18–21

RT/Hormone as Indicated

Pre-AC Post-AC Post T or TH

RT = radiation therapy. Perez et al, 2008.

* Repeat LVEF assessment after 4 wks – If criteria for continuation met – resume trastuzumab

– If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab

Relationship of LVEF to LLN

Absolute Decrease

< 10%

Absolute Decrease of 10%–15%

Absolute Decrease ≥ 16%

WNL Continue Continue *Hold

1%–5% below LLN Continue *Hold *Hold

≥ 6% below LLN *Continue *Hold *Hold

WNL = within normal limits; LLM = lower limit of normal.

Asymptomatic PatientsAsymptomatic PatientsRules for Trastuzumab Continuation Based on Rules for Trastuzumab Continuation Based on

Serial LVEF Used in TrialsSerial LVEF Used in Trials

Post-AC LVEF Results forPost-AC LVEF Results for2,999 Patients2,999 Patients

Perez et al, 2005.

Arm A(n = 1,012;

%)Arm B

(n = 1,065; %)Arm C

(n = 922; %)Total

(N = 2,999; %)

LVEF decrease ≥ 15% 3.8 1.7 2.3 2.6

LVEF decrease ≤ 15% to below LLN 3.1 2.5 1.6 2.4

Prohibited from receiving trastuzumab

6.9

(5.3–8.6)

4.2

(3.1–5.6)

3.9

(2.8–5.4)

5.0

(4.3–5.8)

Cumulative Incidence Rate of Cumulative Incidence Rate of Cardiac Events (Arms B and C)*Cardiac Events (Arms B and C)*

*Among patients who enrolled prior to April 25, 2004 and had a satisfactory post-AC cardiac evaluation.

Arm B Arm C

n 1 yr 2 yrs n 1 yr 2 yrs

Post-AC LVEF ≤ 55%

Age ≤ 60 yrs 62 1.6% 3.6% 60 1.7% 1.7%

Age ≥ 60 yrs 13 0% 0% 6 1.7% 1.7%

Post-AC LVEF ≥ 55%

Age ≤ 60 yrs 541 1.5% 2.1% 414 2.4% 2.4%

Age ≥ 60 yrs 94 2.2% 4.5% 94 8.5% 8.5%

Perez et al, 2005.

Most Recent LVEF Levels for Patients Most Recent LVEF Levels for Patients Who Experienced CHF in Arms B and CWho Experienced CHF in Arms B and C

Arm B (n = 16) Arm C (n = 18)

LVEF (n) LVEF (n)

< 50% 50%–59% ≥ 60% < 50% 50%–59% ≥ 60%

Time since CHF diagnosis

1.0–0.59 mos 4 0 0 3 1 0

6.0–11.9 mos 2 2 2 1 2 1

≥ 12 mos 2 1 3 3 4 3

Perez et al, 2005.

Key TakeawaysKey Takeaways

Adjuvant trastuzumab after anthracycline-based chemotherapy leads to an approximate 3-yr cumulative incidence rate of 2.5%–3.5% of significant clinical cardiac events

– The cardiac function in the majority of patients improved following medical treatment

Trend towards increased risk of cardiac toxicity with increased patient age

No correlation between radiation therapy cardiac toxicity

No correlation between post-AC LVEF and subsequent cardiac toxicity

– Differs from analysis of NSABP B-31

Perez et al, 2005.

Case Study 1Case Study 1 65-yr-old, postmenopausal woman presented with a palpable left

axillary mass

Mammogram and ultrasound demonstrated a 1.8-cm left breast mass and 3.1-cm axillary mass

PATHOLOGY: Core biopsy: Poorly diff. IDC, ER+ (20%), PR-, HER2 “3+” on IHC, FISH 9.2

– CT of chest/abdomen and bone scan: No evidence of metastasis

COMORBIDITIES: Obesity, HTN, osteoarthritis, 3 yrs ago treated with thrombolytics and stent placement

– LVEF normal (52%) by ECHO

PRIMARY SURGERY: Left modified radical mastectomy

– Primary tumor 2.2 cm, margins negative

– 1/15 LN involved, 3.2 cm with no extracapsular extension

IDC = invasive ductal carcinoma; ER = estrogen receptor; PR = progesterone receptor;IHC = immunohistochemistry; FISH = fluorescence in situ hybridization; CT = computed tomography; HTN = hypertension; ECHO = echocardiogram; LN = lymph node.

Case Study 1: Question 1Case Study 1: Question 1

What adjuvant therapy would you recommend?

1) AC > TH as in N9831

2) TCH as in BCIRG 006

3) Dose-dense AC > wkly paclitaxel + trastuzumab

4) Taxane > FEC with concurrent trastuzumab

5) Other trastuzumab-based regimen

Case Study 1 (cont.)Case Study 1 (cont.)

She was treated with the TCH regimen. Docetaxel and carboplatin were dose reduced for neuropathy after Cycle 4 but she otherwise did well.

– LVEF after TCH Cycle 6 was 50%

She continued trastuzumab and proceed with chest wall and regional node RT

– 3 mos later (2 wks after completing RT) she complains of fatigue but otherwise feels well(LVEF was 42%)

Case Study 1: Question 2Case Study 1: Question 2

At this point you would:

1) Continue trastuzumab and refer to cardiology

2) Discontinue trastuzumab

3) Hold trastuzumab and repeat LVEF in 4–6 wks

4) Discontinue trastuzumab, complete planned adjuvant therapy with lapatinib

Key TakeawaysKey Takeaways Both anthracycline and non-anthracycline regimens

are supported by phase III data

Risk of CHF is 2%–4% with anthracycline regimens

– Higher risk in older patients

Only 1 trial evaluated a non-anthracycline regimen (TCH)

– Risk of CHF ~ 0.5%

– Lower risk for leukemia

– Numerically higher risk of recurrence

Trastuzumab Progression: Trastuzumab Progression: Which Treatment Options Provide the Best Which Treatment Options Provide the Best Outcomes for Patients With HER2+ Breast Outcomes for Patients With HER2+ Breast

Cancer After Progression on Trastuzumab? Cancer After Progression on Trastuzumab?

Topics for DiscussionTopics for Discussion

Is continuation of HER2-targeted therapy with either trastuzumab or lapatinib recommended following progression on a trastuzumab-based regimen?

When should you switch to lapatinib?

What emerging options are available after relapse following trastuzumab/lapatinib treatment?

TKI After Trastuzumab?TKI After Trastuzumab?

HER2+ LABC or MBC with prior exposure to an anthracycline, a taxane, and trastuzumab*N = 324

Lapatinib 1,250 mg po qd continuously + Capecitabine 2,000 mg/m2/d

po Days 1–14 q3wks

(n = 163)

Capecitabine 2,500 mg/m2/dpo Days 1–14 q3wks

(n = 161)

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 disease.

TKI = tyrosine kinase inhibitor; LABC = locally advanced breast cancer; MBC = metastatic breast cancer.Geyer et al, 2006.

Lapatinib Increases TTPLapatinib Increases TTPAfter TrastuzumabAfter Trastuzumab

TTP = time to progression.Geyer et al, 2006.

Why Not Continue Trastuzumab?Why Not Continue Trastuzumab?GBG 26/BIG 3-05 GBG 26/BIG 3-05

Women with HER2+ Advanced Breast Cancer or MBC That Progressed

on Trastuzumab (N = 156)

Capecitabine 2,500 mg/m2/d on Days 1–14 q3wks

Capecitabine 2,500 mg/m2/d on Days 1–14 q3wks +

Trastuzumab 6 mg/kg q3wks

(Closed Early With Poor Accrual)

von Minckwitz et al, 2009.

Trastuzumab Remains Effective Trastuzumab Remains Effective After Disease ProgressionAfter Disease Progression

Capecitabine Capecitabine + Trastuzumab

von Minckwitz et al, 2009.

Longer PFS With Lapatinib + Trastuzumab Vs. Longer PFS With Lapatinib + Trastuzumab Vs. Lapatinib Alone in Trastuzumab-Refractory MBCLapatinib Alone in Trastuzumab-Refractory MBC

PFS = progression-free survival; ORR = overall response rate; CBR = clinical benefit rate.Blackwell et al, 2010.

PFS Outcome

Lapatinib

(n = 145)

Lapatinib + Trastuzum

ab (n = 146)

Progressed or died, n 128 127

Median, wks 8.1 12.0

HR (95% CI) 0.73 (0.57–0.93)

p Value .008

Response (%)Lapatini

bLapatinib +

TrastuzumabOdds Ratio

p Value

ORR 6.9 10.3 1.5 .46

CBR 12.4 24.7 2.2 .01

Blackwell et al, 2009.

Updated Overall Survival in ITTUpdated Overall Survival in ITTL

N = 145L+T

N = 146

Died, N (%) 113 (78) 105 (72)

Median, mos 9.5 10

HR (95% Cl) 0.74 (0.57, 0.97)

Log-Rank p Value 0.26

Patients at Risk

L+T148 121 88 64 43 25 1

L148 102 65 47 28 13 –

HER1/2 TKI Neratinib (HKI-272), Afatinib (BIBW 2992), PKI-166, EKB-569

Pan HER TKI Canertinib, BMS-599626

HER1/2/VEGFR TKI XL647, AEE788

HER2 dimerization inhibitor

Pertuzumab (FDA Approved 06/2012 – first-line HER2+ MBC)

Bispecific antibody Ertumaxomab, MM111

Conjugated antibodies Trastuzumab-MCC-DM1, Trastuzumab-A-Z-CINN 310-paclitaxel

Targeted nanoparticles MM302

HSP90 inhibitors Tanespimycin, alvespimycin, CNF2024, IPI-504, AUY922, SNX5422

IGF-1R inhibitors (mAb, TKI)CP-751871, EM164, IMC-A12, NVP-ADW742, INSM-18

HDAC inhibitors Vorinostat, LBH589, Belinostat (PXD101), NVP-LAQ824, depsipeptide, CI-994, MS-275

PI3K inhibitors SF1126, BEZ235, XL147, XL765, GDC-0941

Akt inhibitors Perifosine, XL418

mTOR inhibitors Sirolimus, temsirolimus, everolimus, ridaforolimus

HER2 vaccines E75 vaccine

Novel Agents: HER2Novel Agents: HER2

T-DM1T-DM1

Multicenter phase II (N = 110)

– Prior anthracycline, taxane, capecitabine, trastuzumab, lapatinib

ORR (by independent review) 34.4%

CBR (by independent review) 48.2%

Median PFS 6.9 mos

– 7.3 mos in centrally confirmed HER2+

Krop et al, 2009.

Phase III T-DM1 Vs. Capecitabine + Phase III T-DM1 Vs. Capecitabine + Lapatinib in HER2+ MBC (EMILIA)Lapatinib in HER2+ MBC (EMILIA)

Key inclusion criteria– Prior treatment to include a taxane and trastuzumab in adjuvant, locally advanced or metastatic setting– Documented progression of disease during or after treatment for advanced/metastatic disease or

within 6 mos of completing adjuvant therapy

Primary end points: OS, PFS, SafetySecondary end point: QOL

HER2+ (centrally confirmed)

LABC or MBC Previously Received Trastuzumab-Based Therapy (n = 980)

HER2+ (centrally confirmed)

LABC or MBC Previously Received Trastuzumab-Based Therapy (n = 980)

T-DM1(3.6 mg/kg) q3wks IV

T-DM1(3.6 mg/kg) q3wks IV

Lapatinib(1,250 mg/day) Days 1–21 po bid

+Capecitabine

(1,000 mg/m2) Days 1–14 q3wks po qd

Lapatinib(1,250 mg/day) Days 1–21 po bid

+Capecitabine

(1,000 mg/m2) Days 1–14 q3wks po qd

QOL = quality of life.

Blackwell et al. 2012

Case Study 2Case Study 2

38-yr-old patient presented with inflammatory breast cancer

– ER- and PgR-

– HER2+ by FISH (ratio 8.9)

– Imaging with PET/CT found regional nodal involvement but was otherwise negative

She was treated with neoadjuvant AC > TH followed by mastectomy (2 cm residual disease, LN-) and RT. She completed 1 yr of trastuzumab.

PgR = progesterone receptor; PET = positron emission tomography.

Case Study 2 (cont.)Case Study 2 (cont.)

3 yrs later she reports a persistent cough and increased fatigue

– Imaging finds several lung lesions with mediastinal and hilar adenopathy

– Biopsy confirms metastatic disease that remains ER-/PgR-/HER2+

– CBC, total bilirubin, AST, ALT, calcium, albumin: All normal

– LVEF 62% by MUGA

CBC = complete blood count; AST = aspartate aminotransferase; ALT = alanine aminotransferase; MUGA = multi-gated acquisition scan.

Case Study 2: Question 1Case Study 2: Question 1

Which of the following treatment options would you recommend for this patient?

1) Taxane-based chemotherapy + trastuzumab

2) Capecitabine + lapatinib

3) Docetaxel + carboplatin + trastuzumab

4) Vinorelbine + trastuzumab

5) Trastuzumab + lapatinib

Case Study 2 (cont.)Case Study 2 (cont.)

She was treated with vinorelbine + trastuzumab

– She had an excellent partial response with resolution of symptoms

– Vinorelbine discontinued after 9 cycles due to increased neuropathy (continued trastuzumab)

10 mos later, she develops headache and diplopia

– Imaging finds a large cavernous sinus met with several other small cerebral lesions

Case Study 2 (cont.)Case Study 2 (cont.)

She is started on steroids and completes whole brain radiation therapy

– CNS symptoms resolve

– Additional imaging finds asymptomatic progression of her systemic disease with increased lung nodules

CNS = central nervous system.

Case Study 2: Question 2Case Study 2: Question 2

Which of the following strategies would you recommend for this patient at this point?

1) Resume vinorelbine with continued trastuzumab

2) Capecitabine + lapatinib

3) Trastuzumab + lapatinib

4) Capecitabine + trastuzumab

5) Alternate chemotherapy + trastuzumab

Key TakeawaysKey Takeaways

Continued HER2 blockade through multiple lines of therapy is important for patients with HER2+ disease

Optimal sequence not defined

Lapatinib may have unique role in patients with CNS disease

Several new agents have activity and are likely to be available soon

Combination Approaches: Combination Approaches: What Combination Approaches What Combination Approaches

Are Options for Treating Are Options for Treating HER2+ Breast Cancer? HER2+ Breast Cancer?

Topics for DiscussionTopics for Discussion

Lessons from the neoadjuvant setting

Dual regimens of HER2-targeted therapies

Combined VEGF and HER2-targeted therapies

Lessons Neoadjuvant TrialsLessons Neoadjuvant Trials

Trast Trast + Paclitaxel

Lapatinib Lapatinib + Paclitaxel

Trast/Lap Trast/Lap + Paclitaxel

R

NEO-ALTTOn ~ 450

Trast + Docetaxel

Pertuz + Docetaxel

Pertuz + Trast + Docetaxel

Pertuz + Trast

NEO-SPHEREn ~ 400

R

Pathologic Response in Neo-ALTTOPathologic Response in Neo-ALTTO

No Difference in Proportion of Patients Undergoing Breast Conservation

Baselga et al, 2010.

Pertuzumab and Trastuzumab: Pertuzumab and Trastuzumab: Complementary Mechanisms of ActionComplementary Mechanisms of Action

Trastuzumab Inhibits ligand-independent

HER2 signaling Activates ADCC Prevents HER2 ECD shedding

Pertuzumab Inhibits ligand-dependent HER2

dimerization and signaling Activates ADCC

Baselga et al, 2012.

HER 1/3/4

HER2

Trastuzumab Pertuzumab

Dimerization domain

Subdomain IV

Pathologic CR Rates in NeoSpherePathologic CR Rates in NeoSphere

ITT = intent-to-treat.Gianni et al, 2010.

CLEOPATRA: Study DesignCLEOPATRA: Study Design

Primary end point: PFS (independently assessed)

Secondary end points: PFS (investigator assessment), ORR, OS, Safety

Women with previously

untreated, HER2+ locally recurrent or

MBC(N = 808)

Trastuzumab 6 mg/kg q3wks* +Docetaxel 75–100 mg/m2 q3wks† +

Pertuzumab 420 mg q3wks‡(n = 402)

Trastuzumab 6 mg/kg q3wks* +Docetaxel 75–100 mg/m2 q3wks† +

Placebo q3wks (n = 406)

Treatment until disease

progression or unacceptable

toxicity

Stratified by geographic regionand previous (neo)adjuvant

chemotherapy

*Trastuzumab 8 mg/kg loading dose given. †Minimum of 6 docetaxel cycles recommended; < 6 cycles permitted for unacceptable toxicity or disease progression.‡Pertuzumab 840 mg loading dose given.

Baselga et al, 2012; Perjeta™ prescribing information, 2012.

Pertuzumab was FDA Approved June 2012 based on the result of the CLEOPATRA trial for first-line treatment of HER2+ MBC in combination with trastuzumab and docetaxel.

CLEOPATRA: Independently Assessed PFSCLEOPATRA: Independently Assessed PFS

Baselga et al, 2012.

CLEOPATRA: Response DataCLEOPATRA: Response Data

1.5 1.53.8 8.314.6

20.8

74.665.2

5.5 4.2

0

10

20

30

40

50

60

70

80

90

100

Trastuzumab + Docetaxel + Pertuzumab

(n = 343)

Trastuzumab + Docetaxel + Placebo

(n = 336)

CR

PR

SD

PD

Not evaluable

Pat

ien

ts (

%) ORR

80.2%

ORR 69.3%

CR = complete response; PR = partial response; Sde = stable disease; PD = progressive disease.Baselga et al, 2012.

CLEOPATRA: SafetyCLEOPATRA: Safety

NR = not reported.Baselga et al, 2012.

Women with previously

untreated HER2+ locally recurrent or

MBC (N = 424)

Trastuzumab 6 mg/kg† +Docetaxel 100 mg/m2 +Bevacizumab 15 mg/kg,

all given q3wks(n = 216)

Trastuzumab 6 mg/kg† +Docetaxel 100 mg/m2,

both given q3wks(n = 208)

Treatment until disease progression

or unacceptable toxicity*

Stratified by previous (neo)adjuvant taxane,adjuvant trastuzumab, hormone receptor

status, measurable disease

*Planned minimum of 6 docetaxel cycles administered. †Trastuzumab 8 mg/kg loading dose given.OS = overall survival; DOR = duration of response; TTF = time to treatment failure. Gianni et al, 2011.

AVEREL: Study DesignAVEREL: Study Design Primary end point: PFS (investigator assessed)

Secondary end points: OS, ORR, DOR, TTF, Safety

AVEREL: PFS, Interim OS Analysis, AVEREL: PFS, Interim OS Analysis, and Responseand Response

ORR similar between T + Doc + Bev and T + Doc in investigator assessment (74.3% vs. 69.9, respectfully; p = .3492)

ORR significantly higher for with addition of Bev in IRC assessment (76.5% vs. 65.9, respectfully; p = .0265)

Gianni et al, 2011.

AVEREL TakeawaysAVEREL Takeaways

Addition of bevacizumab to first-line treatment with trastuzumab and docetaxel may prolong PFS

– Findings not significant according to investigator-assessed PFS (p = .0775)

– Findings significant according to independent review of PFS (p = .0162)

Bevacizumab-associated AEs led to higher incidence of discontinuation of any study drug

AE = adverse events.Gianni et al, 2011.

Case Study 3Case Study 3 52-yr-old postmenopausal woman presented with a 3-cm

mass in the right breast, clinically LN Negative

Biopsy found a grade III invasive ductal cancer, HER2 3+ by IHC, ER 0, PR 0

At surgery sentinel node was positive leading to completion axillary dissection

– Total 11/15 LNs involved

Post-operative imaging found 5 liver lesions (biopsy confirmed diagnosis of metastatic disease, ER 0, PR 0, HER2 + by FISH with ratio 13.5)

– Liver enzymes and Bili normal, ECOG PS = 0

ECOG = Eastern Cooperative Oncology Group; PS = performance status.

Case Study 3: Question 1Case Study 3: Question 1

Assuming all of these options were available,what systemic therapy would you recommend?

1) AC > TH

2) TCH

3) Docetaxel + trastuzumab + pertuzumab

4) Trastuzumab + lapatinib

5) Vinorelbine + trastuzumab

Case Study 3 (cont.)Case Study 3 (cont.)

She is treated with docetaxel + trastuzumab + pertuzumab on the Cleopatra trial

– She has a complete response

– Docetaxel discontinued after 6 cycles, continued trastuzumab + pertuzumab

Key TakeawaysKey Takeaways

Neoadjuvant trials suggested combined HER2 inhibition was beneficial. Similar results seen in the metastatic setting.

– Improved survival with trastuzumab + lapatinib in heavily pretreated patients

– Improved ORR, DFS with addition of pertuzumab in the first-line setting

Combined HER2 and VEGF inhibition had less activity than was hoped

Key Takeaways (cont.)Key Takeaways (cont.) T-DM1 demonstrated a CBR of 48% in heavily pre-treated patients with

HER2+ metastatic disease

In the reported adjuvant trials, the risk of CHF with sequential anthracycline chemotherapy followed by trastuzumab ranged from 2%–3.8%

Older age has been consistently associated with cardiac toxicity in patients receiving adjuvant trastuzumab

In the GBG trial, ORR and PFS were improved for patients continuing trastuzumab after progressing on trastuzumab

In the neoadjuvant setting, combined pertuzumab and trastuzumab increased pCR rate with chemotherapy compared to trastuzumab + chemotherapy

Toxicities increased with the triple-drug combination pertuzumab, docetaxel, and trastuzumab. These included febrile neutropenia, diarrhea, mucosal inflammation, and skin rash.

CBR = clinical benefit rate