New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Jointly sponsored by...

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC

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This program is supported by an educational grant from

clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer

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Faculty

Dennis J. Slamon, MD, PhDProfessor and Chief Division of Hematology/OncologyDepartment of Internal MedicineDavid Geffen School of Medicine at UCLALos Angeles, California

Sara Hurvitz, MDAssistant Professor of Medicine Director, Breast Oncology ProgramDivision of Hematology-Oncology Department of Internal Medicine David Geffen School of Medicine at UCLALos Angeles, California


Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

The faculty and CCO staff reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity.


Disclosures

Dennis J. Slamon, MD, PhD, has disclosed that he has served on advisory boards for GlaxoSmithKline and Roche/Genentech.

Sara Hurvitz, MD, has disclosed that she has received consulting fees from Abraxis, fees for non-CME services from Abraxis and Bristol-Myers Squibb, and contracted research from Roche/Genentech.


Disclosures

Jennifer Swanson; Edward King, MA; Andrew D. Bowser; Gordon Kelley; Jennifer M. Blanchette, PhD; and Jim Mortimer have no significant financial relationships to disclose.

The following planners and managers, Jan Hixon, RN, BSN, MA; Trace Hutchison, PharmD; Julia Kimball, RN, BSN; Samantha Mattiucci, PharmD; Jan Schultz, RN, MSN, CCMEP; and Patricia Staples, MSN, NP-C, CCRN, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.


Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Postgraduate Institute for Medicine (PIM) and Clinical Care Options, LLC 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 PIM and Clinical Care Options, LLC. Please refer to the official prescribing information for each product for discussion of approved indication, contraindications, and warnings.


GoalThe goal of this activity is to provide participants with practical approaches on managing patients with HER2-positive metastatic breast cancer.

Target AudienceThis program is intended for physicians and other healthcare providerswho care for patients with breast cancer.

Learning ObjectivesAt the conclusion of this activity, participants should be able to:

Distinguish between the mechanisms of action and rationale for HER2-targeting approaches that have demonstrated efficacy in patients with HER2-positive breast cancer

Select treatment plans for patients with HER2-positive metastatic breast cancer based on available data on best management approaches

Formulate treatment approaches for women with breast cancer that progresses after treatment with HER2-targeted therapy

Discuss with patients agents in development for the treatment of HER2-positive metastatic breast cancer for which clinical trials may be available

Case 1


Case 1: Woman With MBC and No Previous Trastuzumab Presentation: 58-yr-old woman was found to have

architectural distortion in the right breast, upper outer quadrant, on routine screening mammography

– Core needle biopsy confirmed invasive ductal carcinoma, estimated by imaging to be a T1 lesion

Treatment: She underwent lumpectomy/SLNB that revealed a 0.9-cm intermediate-grade invasive ductal carcinoma that was ER+/PgR+/HER2+ by FISH, with a Ki-67 value of 30%

– 2 sentinel nodes were removed and found to be uninvolved by cancer


Case 1: Woman With MBC and No Previous Trastuzumab Follow-up: She received adjuvant radiation therapy followed by

letrozole for 1 yr, at which time she was seen by her oncologist for new cough and mild shortness of breath

– CT scan of the chest revealed a mild right pleural effusion and several nodules up to 1 cm in size in the right, middle, and lower lobes

– Biopsy revealed adenocarcinoma that was ER+/PgR-/HER2 3+ by IHC, consistent with breast primary

– No other metastases were detected by CT or bone scan

There are no clinical trials available at your center for which she is eligible. You review multiple treatment options with her and she tells you she would like to take the treatment that has the highest chance of leading to a response and to a prolonged survival, as she recently found out her daughter is pregnant with her first grandchild


Case 1: Woman With MBC and No Previous TrastuzumabWhat treatment option would you recommend at this time?

A. Trastuzumab plus chemotherapy

B. Trastuzumab plus aromatase inhibitor

C. Lapatinib plus capecitabine

D. Single-agent aromatase inhibitor

E. Trastuzumab single agent


Case 1: Woman With MBC and No Previous TrastuzumabWhat treatment option would you recommend at this time?

A. Trastuzumab plus chemotherapy (preferred choice)

B. Trastuzumab plus aromatase inhibitor

C. Lapatinib plus capecitabine

D. Single-agent aromatase inhibitor

E. Trastuzumab single agent


Normal (1x)~ 25,000-50,000 HER2

receptors

Overexpressed HER2 (10-100x)

up to ~ 2,000,000 HER2 receptors

Excessive cellular division

HER2 Overexpression in Breast Cancer

Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Slamon DJ, et al. Science. 1987;235:177-182.

HER2 is overexpressed in ~ 25% of breast cancers


HER2 Overexpression Shortens Survival

HER2 oncogeneamplification

HER2 oncoproteinoverexpression

Shortened survivalMedian Survival From First DiagnosisHER2 overexpressing

3 yrsHER2 normal

6-7 yrs

Slamon DJ, et al. Science. 1987;235:177-182. Slamon DJ, et al. Science. 1989;244:707-712.

HER2-Targeted Agents


Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.

Trastuzumab: Mechanism of Action

Copyright © 2005 Massachusetts Medical Society. All rights reserved.


Single-Agent Trastuzumab in First-line Treatment of HER2+ MBCPatients Response Rate, % Median Time to

Progression, Mos

HER2+ by IHC(N = 111)

26 3.5

HER2+ by FISH (n = 79)

34 4.9

Vogel CL, et al. J Clin Oncol. 2002; 20:719-726.


Trastuzumab Combinations as First-line Therapy for MBC: Pivotal Phase III Trial

Patients with HER2+ (IHC 2+/3+) MBC, no previous

chemotherapy, measurable

disease, KPS ≥ 60%

(N = 469)No previous

adjuvantAC

Paclitaxel(n = 96)

Trastuzumab+ Paclitaxel

(n = 92)

AC(n = 138)

Trastuzumab+ AC

(n = 143)

Previousadjuvant

AC

Slamon DJ, et al. N Engl J Med. 2001;344:783-792.


Trastuzumab in MBC: The Pivotal Trial

Treatment ObjectiveResponse Rate, %

Median TTP, Mos Median OS, Mos

Chemo 32 4.6 20.3

Chemo +Trastuzumab

50 7.4 25.1

Slamon DJ, et al. N Engl J Med. 2001;344:783-792.

P < .001 for all 3 comparisons.


Trastuzumab in Recommended First-line Combinations for HER2+ MBC HER2+ disease without previous trastuzumab: trastuzumab

plus

– Paclitaxel ± carboplatin

– Docetaxel

– Vinorelbine

– Capecitabine

HER2+ disease with previous trastuzumab: trastuzumab plus

– Other first-line agents

– Capecitabine

– Lapatinib (without cytotoxic therapy)

NCCN. Clinical practice guidelines in oncology: breast cancer. v2.2011.


Addition of Carboplatin to Docetaxel/Trastuzumab Does Not Improve Efficacy BCIRG 007 phase III study (N = 263 patients with HER2-amplified

MBC)

No significant differences seen in responses, survival, or TTP

– Differences in docetaxel dose between 2 groups

Valero V, et al. J Clin Oncol. 2011;29:149-156.

Outcome Docetaxel/Carboplatin/Trastuzumab (n = 132)

Docetaxel/Trastuzumab (n = 131)

ORR, % 72 72

PR 55 54

CR 17 18

Median TTP, mos 10.35 11.07

Median OS, mos 37.4 37.1


Trastuzumab in Triple-Combination Regimens: Response Rates

ORR (%)

H + Carbo + T

H + V + T

H + E90 + C

H + E60 + C

H + Carbo + T

H + V + X

H + G + P

H + G + Carbo

H + G + P

H + E + T

H + Carbo + P every 3 wks

H + Carbo + P every wk

H + TLC D-99 + P

H + Carbo + T

H + Carbo + T

H + Cisplatin + T

H + Carbo + P

H + X + T

Forbes et al, 2006 (N = 130)

Wardley et al, 2006 (N = 111)

Robert et al, 2006 (N = 92)

Pegram et al, 2004 (N = 62)

Pegram et al, 2004 (N = 59)

Yardley et al, 2002 (N = 61)

Cortes et al, 2004 (N = 54)

Perez et al, 2005 (N = 48)

Perez et al, 2005 (N = 43)

Venturini et al, 2006 (N = 45)

Miller et al, 2002 (N = 45)


Fountzilas et al, 2004 (N = 40)

Chan et al, 2007 (N = 34)

Dirix et al, 2006 (N = 34)

Untch et al, 2004 (N = 26)

Untch et al, 2004 (N = 25)


0 10 20 30 40 50 60 70 80 90 100


Hormonal Therapy in HER2+ MBC

Regimen ORR, % PFS, Mos

Trastuzumab (N = 79)[1] 26 3.5-3.8

Anastrozole + trastuzumab (N = 103)[2] 20 4.8

Anastrozole (N = 104)[2] 7 2.4

Lapatinib + letrozole (N = 642)[3] 28 8.2

Letrozole (N = 644)[3] 15 3.0

Lapatinib (N = 138)[4] 24 NA

1. Vogel C, et al. J Clin Oncol. 2002;20:719-726.2. Mackey JR, et al. SABCS 2006. Abstract 3.3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.4. Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.


Lapatinib Blocks Signaling Through Multiple Receptor Combinations

Downstream signaling cascade

Downstream signaling cascade

1 + 11 + 1 2 + 22 + 2 1 + 21 + 2 Blocks signaling throughErbB1 and ErbB2 homodimers and heterodimers

Might also prevent signaling through heterodimers between these receptors and other ErbB family members

Potentially blocks multiple ErbB signaling pathways

Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment

Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment


Patients (N = 138) randomized to 2 schedules of lapatinib monotherapy

Median time to response (all patients): 7.9 wks; median duration of response (all patients): 28.4 wks

Safety: only grade 1/2 asymptomatic cardiac adverse events (4 patients)

Lapatinib as First-line Treatment for HER2-Amplified LABC or MBC

Endpoint Lapatinib1500 mg/day

(n = 69)

Lapatinib500 mg BID

(n = 69)

All Patients(N = 138)

Response rate, n (%) 15 (22) 18 (26) 33 (24)

Clinical benefit rate, n (%) 20 (29) 23 (33) 43 (31)

6-mo PFS, % 41 45 43

Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.


Recap Case 1: Woman With MBC and No Previous TrastuzumabWhat treatment option would you recommend as first-line therapy for the 58-year-old woman with MBC?

A.Trastuzumab plus chemotherapy (preferred choice)

B.Trastuzumab plus aromatase inhibitor

C.Lapatinib plus capecitabine

D.Single-agent aromatase inhibitor

E.Trastuzumab single agent

Case 2


Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab Background: 39-yr-old woman diagnosed with stage IIA, breast cancer

in 2004

– 2.6-cm tumor

– ER+/PgR-/HER2+

Treatment: TAC for 6 cycles plus radiation therapy and tamoxifen

Follow-up: 1 yr after end of chemotherapy, she is found to have bone and lymph node metastases

– Lymph node biopsy reveals the tumor is negative for hormone receptors (ER/PgR) and continues to overexpress HER2

Treatment: she receives 6 cycles of TCH and achieves CR

– She continues on maintenance single-agent trastuzumab without progression for almost 2 yrs


Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabScans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones.

What treatment option would you recommend at this time?

A.Switch to lapatinib/capecitabine

B.Switch to lapatinib/trastuzumab

C.Switch to trastuzumab and new chemotherapy

D.Start chemotherapy without HER2-targeted therapy

E.Switch to lapatinib alone


Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabScans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones.

What treatment option would you recommend at this time?

A.Switch to lapatinib/capecitabine (preferred choice)

B.Switch to lapatinib/trastuzumab (reasonable)





1 2

Downstream signaling pathways

Cell proliferation Cell survival

21 1 2

TrastuzumabT

LapatinibL L L L L L

Erb receptors

Mechanism of Action of LapatinibCompared to Trastuzumab


Patients with HER2+ progressive MBC or stage IIIB/IIIC LABC with

T4 lesion and unlimited previous therapies*

Primary endpoint: TTP

Secondary endpoints: OS, PFS, ORR


Secondary endpoints: OS, PFS, ORR

Lapatinib1250 mg/day PO +

Capecitabine 2000 mg/m2/day on

Days 1-14 every 21 days

Lapatinib1250 mg/day PO +

Capecitabine 2000 mg/m2/day on


Capecitabine2500 mg/m2/day on




*No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or adjuvant).

Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer


Lapatinib + Capecitabine in HER2+ MBC:TTP

Cameron D, et al. Oncologist. 2010;15:924-934.

TTP With 1 Previous Trastuzumab Regimen TTP With > 1 Previous Trastuzumab Regimen

CapecitabineLapatinib + capecitabine

Cu

mu

lati

ve P

rog

ress

ion

Fre

e (%

)

100

80

60

40

20

00 20 40 60 80

Wks

100

80

60

40

20

00 20 40 60 80

WksC

um

ula

tive

Pro

gre

ssio

n F

ree

(%)

CapecitabineLapatinib + capecitabine

Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed through Copyright Clearance Center, Inc.


Result Capecitabine(n = 201)

Capecitabine + Lapatinib(n = 207†)

HR P Value

Median TTP, wks[1] 18.6 31.3 0.50 < .001

OS, wks[1] 56.6 71.4 0.79 .077

ORR, %[2] 13.9 23.7 -- .017

Brain mets as site of first progression,* n (%)[2]

13 (6) 4 (2) -- .045

† n=198 in 2008 study.*Exploratory analysis.

1. Cameron D, et al. Oncologist. 2010;15:924-9342. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.

Lapatinib + Capecitabine in HER2+ MBC: Efficacy


Combining Lapatinib and Trastuzumab Increases Antitumor Activity

Scaltriti M, et al. Oncogene. 2009;28:803-814. Konecny GE, et al. Cancer Res. 2006;66:1630-1639. Xia W, et al. Oncogene. 2004;23:646-653.

Tu

mo

r V

olu

me

(m

m3)

1600

1400

1200

1000

800

600

400

200

013 16 19 21 23

Days After Injection*P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab; §P < .01 vs both lapatinib and trastuzumab.

ControlTrastuzumabLapatinibTrastuzumab + lapatinib*

*†‡ †

†

§

Reprinted by permission from Macmillan Publishers Ltd: Oncogene; Scaltriti, et al. 28:803-814, copyright 2009.

Treatment with lapatinib plus trastuzumab resulted in complete tumor remission in mouse model

– Effect was durable: no tumor relapse observed at 8 mos after treatment

Lapatinib induced accumulation of inactive HER2 at plasma membrane

– Trastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cells

In vivo activity was consistent with in vitro data demonstrating the combination as synergistic

http://www.nature.com/onc/index.html

http://www.nature.com/onc/index.html


Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.

• Staging occurred at 4, 8, 12, 16 weeks, and then every 8 weeks

• Steady state of single-agent lapatinib occurs at approximately 7 days

Crossover allowed to lapatinib + trastuzumab if progression after at

least 4 weeks on therapy

Patients with HER2+ (FISH/IHC3+) MBC and

progression on anthracycline, taxane, and

trastuzumab

Lapatinib 1500 mg/day PO(n = 148)

Lapatinib 1000 mg/day PO + Trastuzumab 4 mg/kg → 2 mg/kg IV weekly

(n = 148)

Primary endpoint: PFS

Secondary endpoints: OS, ORR, clinical benefit

Patients with progression after ≥ 4 wks of lapatinib monotherapy allowed to cross over to receive trastuzumab

EGF104900 Phase III Study: Dual HER2 Blockade in MBC

jswanson

Production: please check--when I printed this slide, there was extra text floating over bullets, but I cannot see it on the slide.


Lapatinib ± Trastuzumab in MBC: Efficacy

Outcome Lapatinib, % (95% CI)(n = 145)

Lapatinib/Trastuzumab, %

(95% CI)(n = 146)

OR(95% CI)

P Value

ORR* 6.9(3.4-12.3)

10.3(5.9-16.4)

1.5 (0.6-3.9)

.46

Clinical benefit rate† 12.4(7.5-18.9)

24.7(17.9-32.5)

2.2(1.2-4.5)

.01

*Confirmed CR + PR.†Confirmed CR + PR + stable disease ≥ 6 mos.



Lapatinib ± Trastuzumab in MBC: PFS

Outcome Lapatinib(n = 145)

Lapatinib/Trastuzumab

(n = 146)

HR(95% CI)

P Value

6-mos PFS, % 13 28 0.73 (0.57-0.93)

.008

Progressed or died, n 128 127 -- --

Median PFS, wks 8.1 12.0 -- --



EGF104900: OS With Lapatinib ± Trastuzumab in MBC (ITT Population)

OS Outcome L (n = 145)

L + T (n = 146)

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

Median, mos 9.5 14

HR (95% CI) 0.74 (0.57-0.97)

Log-rank P value .026

6 Month OS

80%

70%

12 Month OS

56%

41%

Blackwell KL, et al. SABCS 2009. Abstract 61.

Ali

ve w

ith

ou

t P

rog

ress

ion

(C

um

ula

tive

%)

Patients at Risk, n148148

LL + T

121102

8865

6447

4328

2513

0

20

40

60

80

100

0 5 10 15 20 25 35Mos From Randomization

1

30

LL + T


Adverse Event (All Grades), % Lapatinib + Trastuzumab (n = 149)

Lapatinib (n = 146)

P Value

Nausea 28 28 NS

Fatigue 21 19 NS

Diarrhea* 60 48 .03

Rash 22 29 NS

*7% grade 3/4 events on each treatment arm.

Cardiac Events† Lapatinib + Trastuzumab (n = 149)

Lapatinib (n = 146)

Total no. patients with events‡

Symptomatic83

32

Therapy related 8 3

Deaths 1§ 0†Defined by ≥ 20% LVEF drop relative to baseline and below institution’s lower limits of normal.‡2 patients had > 1 occurrence.§Cause of death: pulmonary thromboembolism.


Lapatinib ± Trastuzumab in Heavily Pretreated MBC: Selected Adverse Events


Trastuzumab Beyond Progression in HER2+ MBC: BIG 03-05 Phase III Trial

Patients with progressive MBC orLABC, HER2 overexpression, previous

trastuzumab within 6 wks, and LVEF ≥ 50

(N = 156*)


Secondary endpoints: OS, ORR, safety


Secondary endpoints: OS, ORR, safety

Trastuzumab6 mg/kg every 3 wks +


Days 1-14 every 21 days(n = 78)

Trastuzumab6 mg/kg every 3 wks +







*Study closed at 156 patients due to slow accrual following FDA approval of lapatinib for this indication.

von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.


BIG 03-05: Trastuzumab Beyond Progression in HER2+ MBC

Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.

PFS1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y o

f P

FS

0 10 20 30 40Mos

XXHCensoredLog-rank P = .0338

Pts at Risk, nX

XH7477

4055

1529

812

54

33

21

11

11

OS1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y o

f O

S

0 10 20 30 40Mos

XXHCensoredLog-rank P = .2570

Pts at Risk, nX

XH7477

6668

5059

3347

2127

1015

36

31

21


Trastuzumab Beyond Progression in HER2+ MBC: Effect of Previous Treatment

Outcome Capecitabine Capecitabine +Trastuzumab

HR P Value

Median TTP, mos 5.6 8.2 0.69 .034

Median OS, mos 20.4 25.5 0.76 .26

ORR, % 27.0 48.1 -- .012

CBR,* % 54.1 75.3 -- .0068

*CBR: CR + PR + SD > 24 wks.

Previous treatments (N = 156)

First-line taxane + trastuzumab (n = 111)

Trastuzumab alone or with other first-line chemotherapy (n = 42)

Taxane + trastuzumab as adjuvant therapy (n = 3)

von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.


Recap Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabWhat treatment option would you recommend for the 39-year-old woman who has progressed following trastuzumab?

A.Switch to lapatinib/capecitabine (preferred choice)

B.Switch to lapatinib/trastuzumab (reasonable)




Case 3


Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib Presentation: 56-yr-old woman was diagnosed with stage III ER+/

PgR-/HER2+ breast cancer

– Treatment: doxorubicin/cyclophosphamide and docetaxel/trastuzumab

Follow-up: 3 yrs after completing maintenance trastuzumab, she was diagnosed with bone and lung metastases

– Treatment: docetaxel/trastuzumab

Follow-up: after achieving PR that lasted for 9 mos, she developed liver metastases

– Treatment: lapatinib/capecitabine

Follow-up: she achieved SD for 6 mos, after which she developed lung and lymph node metastases


Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/LapatinibWhat treatment options do you feel are appropriate to consider for this patient at this time?

A.Lapatinib/trastuzumab

B.Enrollment in a trial evaluating a new agent for HER2+ breast cancer

C.Trastuzumab plus bevacizumab

D.Lapatinib/trastuzumab/chemotherapy

E.Trastuzumab plus chemotherapy


Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/LapatinibWhat treatment options do you feel are appropriate to consider for this patient at this time?

A.Lapatinib/trastuzumab (reasonable)

B.Enrollment in a trial evaluating a new agent for HER2+ breast cancer (preferred choice)



E.Trastuzumab plus chemotherapy (reasonable)


Highly potent cytotoxic agent

Cytotoxic agent: DM1

Monoclonal antibody: Trastuzumab

Target expression: HER2

Systemically stable

Linker: SMCCT-DM1

Average drug:antibody ratio ≅ 3.5:1

Trastuzumab-DM1: Novel Antibody-Drug Conjugate

Trastuzumab

MCCDM1


T-DM1 Safety in MBC: Every-3-Wk and Weekly Schedules (Phase I Studies) Safety profile was similar between every-3-wk and weekly schedules

MTD: determined for each schedule tested

– Every-3-wk schedule: 3.6 mg/kg

– Weekly schedule: 2.4 mg/kg

Efficacy: similar between every-3-wk and weekly schedules

– 15 patients treated at every-3-wk MTD (3.6 mg/kg)

– Median PFS: 10.4 mos

– Clinical benefit rate with every-3-wk schedule: (ORR + SD at 6 mos): 73%

– Measurable disease: 9 patients; confirmed response rate in these patients was 44%

Krop IE, et al. J Clin Oncol. 2010;28:2698-2704. Holden SN, et al. ASCO 2008. Abstract 1029.


T-DM1: Phase II Results in Previously Treated HER2+ MBC Treatment: single-agent T-DM1 3.6 mg/kg every 3 wks

1. Burris HA, et al. J Clin Oncol. 2011;29:398-405. 2. Krop I, et al. SABCS 2009. Abstract 5090.

Outcome TDM4258[1]

(N = 112)TDM4374[2]

(N = 110)

ORR, % 25.9 32.7

CBR, % 34.8 44.5

Median PFS, mos 5.3 7.3

Confirmed HER2+ 8.2 --

Grade 3/4 AEs, %

Thrombocytopenia 8.0 5.4

Fatigue 4.5 2.7

Hypokalemia 8.9 --


Phase II Study of First-line T-DM1 vs Trastuzumab/Docetaxel in HER2+ MBC

No statistically significant differences between study groups


Secondary endpoints: ORR, CBR, OS, QoL, symptom control

Patients in trastuzumab/docetaxel arm allowed to cross over to T-DM1 on progression

PD

Perez EA, et al. ESMO 2010. Abstract LBA3.

Stratified by region (US vs ROW), previous adjuvant trastuzumab, disease-free interval (≤ 24 mos vs > 24 mos)

T-DM1 3.6 mg/kg q3w(n = 67)

Trastuzumab 8 mg/kg dose → 6 mg/kg q3w

followed by Docetaxel

75 or 100 mg/m2 (n = 70)

Patients with HER2+ MBC or recurrent

LABC and no previous chemo for metastatic disease

(N = 137)


First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Prior TreatmentPrevious Treatment, n (%) Trastuzumab +

Docetaxel(n = 70)

T-DM1(n = 67)

Trastuzumab Yes No

18 (25.7)52 (74.3)

13 (19.4)54 (80.6)

Taxane Yes No

28 (40.0)42 (60.0)

22 (32.8)45 (67.2)

Trastuzumab and/or taxane Yes No

31 (44.3)39 (55.7)

24 (35.8)43 (64.2)



First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Adverse EventsAdverse Event, n (%) Trastuzumab +

Docetaxel(n = 68)

T-DM1(n = 67)

Any AE 68 (100) 63 (94.0)

Grade ≥ 3 AE 51 (75.0) 25 (37.3)

Serious AE* 15 (22.1) 13 (19.4)

Most common AEs (any grade) on trastuzumab + docetaxel arm Alopecia Neutropenia Diarrhea

45 (66.2)39 (57.4)31 (45.6)

1 (1.5)5 (7.5)

7 (10.4)

Most common AEs (any grade) on T-DM1 arm Nausea Fatigue Pyrexia

27 (39.7)29 (46.2)14 (20.6)

32 (47.8)31 (46.3)24 (35.8)


*Resulting in death, life threatening situation, in-patient hospitalization, prolongation of existing hospitalization, persistent or significant disability/incapacity, or birth defects.


First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Grade ≥ 3 AEsGrade ≥ 3 AEs, n (%) NCI CTCAE

GradeTrastuzumab + Docetaxel

(n = 68)T-DM1(n = 67)

Neutropenia 3 4

6 (8.8)30 (44.1)

(0)(0)

Leukopenia 3 4

12 (17.6)5 (7.4)

(0)(0)

Febrile neutropenia3 4

6 (8.8)1 (1.5)

(0)(0)

Pneumonia3 4

1 (1.5)0 (0)

3 (4.5)0 (0)

Hypercalcemia3 4

(0)(0)

1 (1.5)1 (1.5)

Thrombocytopenia 3 1 (1.5) 5 (7.5)



Objective Response Rate, n/N (%; range)

Trastuzumab + Docetaxel

T-DM1

Overall population 29/70 (41.4; 30.2-53.8) 32/67 (47.8; 35.4- 60.3)

Previous trastuzumab and/or taxane therapy

11/31 (35.5; 20.0-53.4) 13/24 (54.2; 33.9-74.5)

No previous trastuzumab and/or taxane therapy

18/39 (46.2; 30.1-61.7) 19/43 (44.2; 29.5-60.1)


First-line T-DM1 vs Trastuzumab/Docetaxel in HER2+ MBC: Efficacy Summary


Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC

Primary endpoints: PFS as assessed by IRF, AEs

– Superiority design with a noninferiority analyses

– Interim futility analysis: option to drop experimental arm

Secondary endpoints: OS, TTF by IRF, ORR, CBR, DORClinicalTrials.gov. NCT01120184.

PD

Trastuzumab + Taxane(n = 364)

T-DM1 + Pertuzumab(n = 364)

T-DM1 + Placebo(n = 364)

Patients with HER2+, previously untreated MBC

(N = 1092)


EMILIA (TDM4370g) Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC

Patients with HER2+ locally advanced or metastatic breast cancer following treatment with a taxane

and trastuzumab

(N = 980)

T-DM1 q3w(n = 490)

Lapatinib + Capecitabine q3w(n = 490)

Primary endpoint: PFS by IRF, OS, safety

Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment

PD or unacceptable toxicity

ClinicalTrials.gov. NCT00829166.


Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopes

Hubbard SR. Cancer Cell. 2005;7:287-288.

Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex

PertuzumabDimerization domain

TrastuzumabIII

II

I

Inhibits HER2 dimerization with other HER family receptors (particularly HER3)

Activates ADCC

Inhibits multiple HER-mediated signaling pathways

Activates ADCC

Inhibits HER-mediated signaling pathways

Prevents HER2 domain cleavage

III

II

I

IV IV


Phase II Trial of Pertuzumab + Trastuzumab in HER2+ MBC: Efficacy

Responses were durable:

Median duration of response: 5.8 mos

Median PFS (all patients): 5.5 mos

Baselga J, et al. J Clin Oncol. 2010;28:1138-1144.Baselga J, et al. J Clin Oncol. 2010;28:1138-1144.

60

50

30

20

10

0

Pat

ien

ts (

%)

All Patients (N = 66)

40

SDPRCR


CLEOPATRA Phase III Trial: Trastuzumab + Docetaxel ± Pertuzumab in HER2+ MBC

Primary endpoint: PFS (IRF evaluation)

Secondary endpoints: OS, incidence of CHF and LVEF events, safety

Patients with HER2+ MBC and no previous treatment

for metastatic disease

(N = 808)

Docetaxel 75 mg/m2 + Trastuzumab 8 mg/kg → 6 mg/kg

+ Placebo q3w

Docetaxel 75 mg/m2 + Trastuzumab 8 mg/kg → 6 mg/kg + Pertuzumab 840 mg → 420 mg

q3w


mTOR Inhibitors


Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496.Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.

mTOR

AKT

AMPKTSC1 TSC2

PTENLKB1

PI3K

RHEB

IGF-1R EGFR/HER2Increased signaling through IGF-1R

Constitutive PI3K/AKT activation

Elevated AKT or pAKT

Absent or low PTEN

Truncated HER2

Nutrients

mTOR inhibitorGrowth &

proliferation

Angiogenesis Cellmetabolism

Downstream inhibition with mTOR inhibitor counters these resistance mechanisms

Synergy of mTOR inhibition and trastuzumab in vitro and in vivo

mTOR Inhibition May Overcome Trastuzumab Resistance


Andre F, et al. J Clin Oncol. 2010;28:5110-5115.

Women with HER2-overexpressing MBC and progression after trastuzumab, WHO PS 0-1

– Previous exposure to lapatinib allowed

– Unrestricted number of previous antineoplastic therapy lines

(N = 33)

Endpoints: safety, tumor

response, cardiac toxicity

Everolimus: 5 mg → 2.5 or 10 mg/day, or 30 mg → 20, 50, or

70 mg/wk

Trastuzumab: 4 mg/kg → 2 mg/kg/wk

Paclitaxel: 80 mg/m2

on Days 1, 8, 15, every 4 wks

Everolimus, Trastuzumab, and Paclitaxelin HER2+ MBC (J2101 Phase I Study)


Characteristic, % Patients(N = 33)

Visceral disease 73

Trastuzumab resistant 97

Taxane pretreated Taxane resistant

94

39

Resistant to lapatinib 48

Pretreated with anthracyclines 73

Prior endocrine treatment 70


Everolimus, Trastuzumab, and Paclitaxelin HER2+ MBC: Baseline Characteristics


Response/Outcome, n (%) Everolimus Dose

5 mg/day(n = 5)

10 mg/day(n = 13)

30 mg/wk(n = 9)

All (N = 27)

Objective response 5 (100) 4 (31) 3 (33) 12 (44)

CR 1 (20) 1 (8) 0 (0) 2 (7)

PR 4 (80) 3 (23) 3 (33) 10 (37)

Clinical benefit rate(CR + PR + SD ≥ 24 wks)

5 (100) 8 (61) 7 (78) 20 (74)

Worse patient characteristics in 10-mg arm vs 5-mg arm

More visceral disease (82% vs 50%)

Median number of previous treatments (3 vs 2 [range: 1-6 vs 0-4])

More patients ongoing (7 vs 1)


Everolimus, Trastuzumab, and Paclitaxelin HER2+ MBC (J2101): Antitumor Activity


Everolimus, Trastuzumab, and Paclitaxelin HER2+ MBC (J2101): PFSRegimen Median PFS, Wks 95% CI

Daily 33.0 23.7-NA

Weekly 40.7 30.0-NA

Overall 34.0 29.1-40.7



BOLERO-1 Phase III Study: Paclitaxel + Trastuzumab Everolimus in HER2+ MBC

Patients with HER2-overexpressing, unresectable locally advanced or metastatic

breast cancer, no previous trastuzumab or chemotherapy

within 12 mos for advanced disease

(N = 717)

Everolimus 10 mg/day PO +Paclitaxel 80 mg/m2 on Days 1, 8, 15 +

Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22

Paclitaxel 80 mg/m2 on Days 1, 8, 15 +Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22

+ Placebo PO daily


Secondary endpoints: OS, ORR, CBR, safety, PK, biomarkers

Stratification by previous adjuvant or neoadjuvant trastuzumab

and presence of visceral metastases


2:1

28-day cycle

Targeting Angiogenesis


Angiogenesis in MCF-7 Spheroids: Day 14

MCF-7 Neo:3.5 x mag.

Mature vasculature No vessel buds

Development stopped

MCF-7 Neo:3.5 x mag.

Mature vasculature No vessel buds

Development stopped

MCF-7 HER-2/neu:10 x mag.

High number mature vessels Vessel buds in center of tumor

Vasculature still growing

MCF-7 HER-2/neu:10 x mag.

High number mature vessels Vessel buds in center of tumor

Vasculature still growing


Pegram MD, et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124.

Phase I/II Trial of Trastuzumab + Bevacizumab in Relapsed/MBC

Investigator-initiated, investigator held IND

First report of 2 humanized MAbs in human subjects

Primary endpoints: PK and safety

Phase ICohort 1 (n = 3)

Trastuzumab qw +Bevacizumab 3 mg/kg on Day 7, then q2w

Cohort 2 (n = 3)Trastuzumab qw +

Bevacizumab 5 mg/kg on Day 7, then q2w

Cohort 3 (n = 3)Trastuzumab qw +

Bevacizumab 10 mg/kg on Day 7, then q2w**RP2D

HER2+ (FISH+)

(N = 9)


PK/Toxicity/Efficacy Data in 9 Patients

No change in PK of either antibody when used as combination

No untoward toxicity induced by combination

– 1 patient with mild increased blood pressure

– 1 patient with decreased LVEF

Response

– 1 CR

– 4 PRs

– 2 SDs > 11 mos

– 2 PDs

Pegram MD, et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124.


Trastuzumab 4 mg/kg 2 mg/kg qw+

Bevacizumab q14d


Bevacizumab q14d


Bevacizumab dose escalation (n = 24) 3 mg/kg 5 mg/kg 10 mg/kg IV on Day 7,

then q14d


Bevacizumab dose escalation (n = 24) 3 mg/kg 5 mg/kg 10 mg/kg IV on Day 7,

then q14d

Phase I/II Trial of Trastuzumab and Bevacizumab in Relapsed/MBC (TORI B03)

Inclusion Criteria: LABC or MBC HER2+ by FISH ECOG 0-1 > 18 yrs of age LVEF WNL

Hypothesis: Upregulation of VEGF in HER2+ MBC contributes to the aggressive phenotype of HER2+ MBC. The “angiogenic switch” modulated by trastuzumab can be exploited in the clinic by combined blockade of these 2 “linked” pathways

Study endpoints

1. Clinical safety

2. Pharmacokinetics

3. Efficacy

Pegram MD, et al. SABCS 2006. Abstract 301.


Phase II Trial of Trastuzumab and Bevacizumab in Relapsed/MBC (TORI B03) No change in PK of either antibody when used as combination in phase I;

currently being tested in phase II

Toxicity

– 1 patient with grade IV decreased LVEF and CHF

– 1 patient with gastric perforation

Response: ORR 48%

– 2 CR

– 22 PRs (many with continued response → ? CR)

– 15 SDs (out to minimum of 24 wks)

– 5 PDs

Median TTP: 7.1 mos (95% CI: 5.5-12.9)

Median OS: 43.8 mos (95% CI: 40.6-not reached)

Clinical benefit: 86%Hurvitz, S, et al. SABS 2009. Poster 6094.


Locally recurrent or MBC, HER2+

No previous chemotherapy for MBC

RT for metastatic bone pain relief only

(N = 407)


Secondary outcomes: OS, OR, DR, TTF, QoL, safety/tolerability

Trastuzumab 8 mg/kg IV loading dose, 6 mg/kg IV q3w +

Docetaxel 100 mg/m2 IV q3w

Trastuzumab 8 mg/kg IV loading dose, 6 mg/kg IV q3w +

Bevacizumab 15 mg/kg IV q3w +Docetaxel 100 mg/m2 IV q3w


AVEREL Phase III Study: Trastuzumab ± Bevacizumab in 1st-line HER2+ MBC


6 x docetaxel and carboplatin

1 yr of trastuzumab

TCHB(Group 1B)

1 yr of bevacizumab

RT

6 x docetaxel and carboplatin

1 yr of trastuzumab

TCH(Group 1A) RT

BETH Phase III Study: Chemotherapy + Trastuzumab ± Bevacizumab

Primary endpoint: IDFS

Secondary endpoints: DFS, OS, RFI, DRFI, toxicity

HER2+, N+ or high-risk N-

Stratified by Ns and HRS

(N ~ 3500)



P

P

P

P

Cell growth, proliferation, survival, metastasis, angiogenesis

Akt/PKB

mTOR

S6K1

PI3-K

Lapatinibphase III

Gefitinibphase II

Everolimusphase III

EGFR HER2

4E-BP1

elF-4E

Protein synthesis

Neratinibphase III

Pertuzumabphase III

Trastuzumab

T-DM1 phase III

P

P

P

P

PTEN

VEGFRSunitinibphase II

Bevacizumabphase III VEGF

Targeted Agents for HER2+ Breast Cancer


Recap Case 3: Woman With HER2+ MBC, Relapse Following Trastuzumab/LapatinibWhat treatment options do you feel are appropriate to consider for this 56-year-old woman who has relapsed?

A.Lapatinib/trastuzumab (reasonable)

B.Enrollment in a trial evaluating a new agent for HER2+ breast cancer (preferred choice)



E.Trastuzumab plus chemotherapy (reasonable)


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