Management of HER2 Over- Expressed Breast Cancer in the Adjuvant, Neoadjuvant, and Metastatic settings Christy A Russell, MD Keck School of Medicine University.

Management of HER2 Over-Expressed Breast Cancer in the Adjuvant, Neoadjuvant, and

Metastatic settings

Christy A Russell, MDKeck School of Medicine

University of Southern California

Metastatic Breast Cancer

Chemotherapy Plus Trastuzumabin Metastatic Disease

Slamon et al

n = 469Marty et al

n = 186Treatment Arms AC or T*

vsAC or T→H†

Docetaxelvs

Docetaxel →H†

Time to Disease Progression (mos) 4.6 7.4

P value

6.1 11.7P value

< 0.001 0.0001

Response Rate 32% 50% < 0.001 34% 61% 0.0002Median Overall Survival (mos)

20 25 0.046 23 31 0.0325

*T = paclitaxel; †H = trastuzumab.

Hudis CA. N Engl J Med. 2007;357:36-51; Slamon DJ, et al. N Engl J Med. 2001;344:783-792 ; Marty M, et al. J Clin Oncol. 2005;23:4265-4267.

Anti-HER2 Targeted Therapy:Pertuzumab

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

Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and May Have Synergistic Activity

HER2Trastuzumab Pertuzumab

Subdomain IV of HER2

Trastuzumab does not inhibit HER2 dimerization, thus blocking HER2:HER3

Trastuzumab prevents HER2 receptor shedding Trastuzumab blocks HER2 signaling and flags cells for

destruction by the immune system

Pertuzumab inhibits HER2 from forming dimer pairs

Flags cells for destruction by the immune system

Pertuzumab does not prevent HER2 receptor shedding

Dimerization domain of HER2

HER3

Baselga J, et al. N Engl J Med. 2012;366:109-119.

Centrally confirmed HER2-positive locally recurrent, unresectable or MBC

≤ 1 hormonal regimen for MBC

Prior (neo)adjuvant systemic Rx, including trastuzumab and/or taxane allowed if followed by DFS ≥ 12 mos

Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after previous trastuzumab

Trastuzumab

Docetaxel (≥ 6 cycles recommended)

Trastuzumab

Docetaxel (≥ 6 cycles recommended)

Placebo

Pertuzumab

1:1

N = 406

N = 402

R

Primary endpoint: Independently assessed PFS

CLEOPATRA Study Design

CLEOPATRA: PFS Assessed at an IRF

Baselga J, et al. N Engl J Med. 2012;366:109-119

100

90

80

70

60

50

40

30

20

10

00 5 10 15 20 25 30 35 40

Mos

PF

S (

%)

Pertuzumab (median: 18.5 mos)Control (median: 12.4 mos)

HR: 0.62(95% CI: 0.51-0.75;

P < .001)

Pts at Risk, nPertuzumabControl

402406

345311

267209

13993

8342

3217

107

00

00

Adding Pertuzumab to Trastuzumab and Chemotherapy

Pertuzumab

Pertuzumab

CLEOPATRA: Safety

Baselga J, et al. N Engl J Med. 2012;366:109-119.

Adverse Events, %

Trastuzumab + Docetaxel + Pertuzumab(n = 407)

Trastuzumab + Docetaxel + Placebo (n = 397)

All Grades Grade 3/4 All Grades Grade 3/4

Diarrhea 66.8 7.9 46.3 5.0

Alopecia 60.9 NR 60.5 NR

Neutropenia 52.8 48.9 49.6 45.8

Nausea 42.3 NR 41.6 NR

Fatigue 37.6 2.2 36.8 3.3

Rash 33.7 NR 24.2 NR

Decreased appetite 29.2 NR 26.4 NR

Mucosal inflammation 27.8 NR 19.9 NR

Asthenia 26.0 2.5 30.2 1.5

Peripheral edema 23.1 NR 30.0 NR

Constipation 15.0 NR 24.9 NR

Febrile neutropenia 13.8 13.8 7.6 7.6

Dry skin 10.6 NR 4.3 NR

Leukopenia NR 12.3 NR 14.6

NCCN: First-line Treatment of HER2+ MBC With No Previous Trastuzumab Exposure

Preferred regimens

– Docetaxel + trastuzumab + pertuzumab (category 1)

– Paclitaxel + trastuzumab + pertuzumab

Other regimens

– Trastuzumab with:

– Paclitaxel ± carboplatin

– Docetaxel

– Vinorelbine

– Capecitabine

NCCN. Clinical practice guidelines in oncology: breast cancer. V.1.2014.

NCCN: Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure

Preferred agents

– Ado-trastuzumab emtansine (T-DM1)

Other agents

– Lapatinib + capecitabine

– Trastuzumab + capecitabine

– Trastuzumab + lapatinib (without cytotoxic therapy)

– Trastuzumab + other agents

NCCN. Clinical practice guidelines in oncology: breast cancer. V.1.2014.

Second-line and Further TherapyTDM-1

Highly potent cytotoxic agent

Cytotoxic agent: emtansine (DM1)

Monoclonal antibody: trastuzumab

Target expression: HER2

Systemically stable

Linker: SMCCT-DM1

Average drug:antibody ratio ≅ 3.5:1

Trastuzumab/Emtansine: Novel Antibody–Drug Conjugate

Trastuzumab

MCCDM1

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

Primary endpoint: PFS by IRF, OS, safety Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment

Verma S, et al. NEJM 2012;367:1783-91.

T-DM1 3.6 mg/kg by IV every 3 wks(n = 495)

Capecitabine 1000 mg/m2 orally twice dailyon Days 1-14, every 3 wks +

Lapatinib 1250 mg/day orally continuously(n = 496)

Patients withHER2-positive

locally advancedor MBC*(N = 980)

PD

Stratified by world region, number of previous chemotherapy regimens for MBC or unresectable

locally advanced breast cancer, presence of visceral disease

*All pts received previoustaxane and trastuzumab

T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): PFS

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n P

rog

ress

ion

Fre

e

Mos0 302 4 6 8 10 12 14 16 18 20 22 24 26 28

Median, Mos Events, n

Capecitabine/lapatinibT-DM1

6.49.6

304265

Stratified HR: 0.650 (95% CI: 0.55-0.77;P < .0001)

T-DM1

Capecitabine/lapatinib

Verma S, et al. NEJM 2012;367:1783-91.

OS: Second Interim Analysis

Data cutoff July 31, 2012; median follow-up: 18.6 mos.

Verma S, et al. N Engl J Med. 2012;367:1783-1791.

100

80

60

40

20

00

OS

(%

)

2 4 8 10 12 14 16 30

Mos

6 18 20 22 24 26 28

T-DM1

Lapatinib-capecitabine

Lapatinib-capecitabineT-DM1

Median No.of Mos

25.130.9

No. of Events

182149

Stratified HR: 0.68(95% CI: 0.55-0.85;

P < .001)

Pts at Risk, nLapatinib-capecitabineT-DM1

496

495

471

485

453

474

435

457

403

439

368

418

297

349

240

293

204

242

159

197

133

164

86

111

63

86

17

28

7

13

4

5

3632 34

Efficacy stopping boundary

P = .0037 or HR: 0.73

110

136

27

38

45

62

51.8% (95% CI: 45.9-57.7)

78.4% (95% CI: 74.6-82.3)

85.2% (95% CI: 82.0-88.5)

64.7% (95% CI: 59.3-70.2)

T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): Adverse Events

Adverse Event, % T-DM1(n = 490)

Capecitabine + Lapatinib(n = 488)

All Grades Grades ≥ 3 All Grades Grades ≥ 3

Nonhematologic

Diarrhea 23.3 1.6 79.7 20.7

Hand-foot syndrome 1.2 0 58.0 16.4

Vomiting 19.0 0.8 29.3 4.5

Hypokalemia 8.6 2.2 8.6 4.1

Fatigue 35.1 2.4 27.9 3.5

Nausea 39.2 0.8 44.7 2.5

Mucosal inflammation 6.7 0.2 19.1 2.3

Increased AST 22.4 4.3 9.4 0.8

Increased ALT 16.9 2.9 8.8 1.4

Hematologic

Neutropenia 5.9 2.0 8.6 4.3

Febrile neutropenia 0 0 1.0 1.0

Anemia 10.4 2.7 8.0 1.6

Thrombocytopenia 28.0 12.8 2.5 0.2

Verma S, et al. NEJM 2012;367:1783-91.

Ongoing Clinical Trialsfor Metastatic Breast Cancer

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, DOR

ClinicalTrials.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)

Phase III Trial of Everolimus in Combination With Trastuzumab and Paclitaxel as Frontline Therapy for

HER2+ MBC (BOLERO-1)

HER+ MBC No prior

anthracycline/taxane-based chemotherapy in the metastatic setting

(N = 719)

Everolimus 10 mg PO + Paclitaxel 80 mg/m2 qwk d 1, 8, 15

+ Trastuzumab 2 mg/kg d 1, 8, 15, 22

Placebo + Paclitaxel 80 mg/m2 qwk d 1, 8, 15

+ Trastuzumab 2 mg/kg d 1, 8, 15, 22

RANDOMIZATI

ON

Primary Endpoint: PFS

Available at: www.clinicaltrials.gov/NCT 00876395.

Other Trials With Completed or Ongoing Accrual in MBC

• T-DM1 vs investigator’s choice (TH3RESA)

• Addition of pertuzumab to vinorelbine and trastuzumab (VELVET)

Neoadjuvant Therapy

Trastuzumab + Lapatinib Trials

pCR Rates (breast and LN) with Trastuzumab (H) and/or Lapatinib (L)

Study/Neoadjuvant Regimen

Total pCRTrastuzumab

Total pCRLapatinib

Total pCRH + L

NeoALTTO1

(6 week H and/or L (WP) x 12 plus H and/or L)N=455

27.6% 20.0% 46.8%

NSABP B-412

(AC x 4 WP x 12 plus H and/or L)N=519

49.4% 47.4% 60.2%

CALGB 406013

(WP x 16 plus H and/or L)N=299

43% 29% 52%

CHER-LOB4

(WP x 12 FEC x 4 plus H and or L throughoutN=121

25% 26.3% 46.7%

WP=weekly paclitaxel; AC=doxorubicin/cyclophosphamide; FEC=5-FU, epirubicin, cyclophosphamide1. Baselga J, et al. Lancet 2012;18:633-640. 2. Robidoux, et al Lancet Oncol; pub online Oct 4, 20133. Carey, et al. ASCO 2013, abst 500. 4. Guarneri, et al. JCO 2012;31.

CALGB 40601 Schema

Carey L, et al ASCO 2013 Abstr # 500

Breast pCR Rate by HR Status

Carey L, et al ASCO 2013 Abstr # 500

HR+ (N=173) HR- (N=123)

Basal-like(N=11)

pCR Rate by Arm and Subtype

Carey L, et al ASCO 2013 Abstr # 500

HER2-E(N=52)

Lum-A(N=51)

Lum-B(N=35)

Neoadjuvant Trastuzumab + Pertuzumab Trials

NeoSphere: study design

THP (n=107)docetaxel + trastuzumab +pertuzumab

HP (n=107)trastuzumab + pertuzumab

TP (n=96)docetaxel + pertuzumab

S

U

R

G

E

R

Ydocetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17

FEC q3w x 3trastuzumab q3w cycles 5–17

FEC q3w x 3trastuzumab q3w cycles 5–17

FEC q3w x 3trastuzumab q3w cycles 5–21

Study dosing: q3w x 4

TH (n=107)docetaxel + trastuzumab

Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417)

BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide*Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0H, trastuzumab; P, pertuzumab; T, docetaxel

3

H, trastuzumab; P, pertuzumab; T, docetaxel

NeoSphere pCR rates: ITT population summary

p = 0.014150

40

30

20

10

0TH THP HP TP

pCR,

%

95%

CI

p = 0.0198

p = 0.003

29.0

45.8

16.824.0

NeoSphere: pCR and Hormone Receptors Status

Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].

NeoSphere Trial: pCR in Breast and Nodes

HR+ HR-

n %pCR n %pCR

Trastuzumab + docetaxel

50 12% 57 29.8%

Trastuzumab + docetaxel + pertuzumab

50 22% 57 54.4%

Trastuzumab + pertuzumab

51 2% 55 20%

Docetaxel + pertuzumab

46 8.7% 50 26%

TRYPHAENA Study: TCH + pertuzumab

• 225 patients with locally advanced, operable, or inflammatory breast cancer (T2-T4d)

• Trial was designed to assess cardiac safety

Schneeweiss, et al. Ann Oncol 2013;24

TRYPHAENA pCR

Neoadjuvant Regimen HR+ HR-

%pCR %pCR

TCH + Pertuzumab (76)47.5% 81.1%

FEC (75) P + T + Docetaxel 45.7% 62.5%

Pertuzumab + Trastuzumab41.0% 73.5%

FEC (72) Docetaxel

Schneeweiss, et al. Ann Oncol 2013;24

FDA Approval in Neoadjuvant Setting

• Pertuzumab is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2+, locally advanced, inflammatory, or early stage breast cancer (either >2 cm or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pCR rate. No data are available demonstrating improvement in EFS or OS.

• Limitations of Use:– The safety of pertuzumab as part of a doxorubicin-containing regimen

has not been established.– The safety of pertuzumab administered for > 6 cycles for early breast

cancer has not been established.

Adjuvant HER-2 Targeted Therapy

NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy

CP1270832-44

RANDOMIZE

HER2 positive (FISH+ or IHC 3+)

Group A

Group C

Group B

ACT

ACT

H

H

ACT

= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4) = T (paclitaxel 80 mg/m2/wk × 12) = H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)

n=3,505

NSABP B-31 Trial Incorporating Trastuzumab in Adjuvant Therapy

CP1270832-45

RANDOMIZE

Node positiveHER2 positive (FISH+ or IHC 3+)

Group 1

Group 2

ACTH

ACT

= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4) = T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12) = H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)

N=2,006

Joint Analysis of HER2+ Adjuvant Trials2 Arms of N9831 + B-31

CP1270832-46

Control Group (n=1,979): AC T

N9831 Group A

B-31 Group 1

Trastuzumab Group (n=1,989): AC T+H

N9831 Group C

B-31 Group 2

= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4) = T (paclitaxel 80 mg/m2/wk × 12) = T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12) = H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)

ACTH

ACT

ACTH

ACT

Kaplan-Meier estimates of (A) event-free survival and (B) overall survival.

Perez E A et al. JCO 2011;29:3366-3373©2011 by American Society of Clinical Oncology

P < .001HR 0.52

P < .001HR 0.61

Events Per Year From Randomization

Perez E A et al. JCO 2011;29:3366-3373

©2011 by American Society of Clinical Oncology

Breast Cancer International Research Group (BCIRG) 006 Trial: Treatment Schema

Slamon et al. NEJM 2011;365.

Endpoints1°: Disease-free survival (DFS)2°: Overall survival, toxicity, pathologic and molecular markers

= H = Trastuzumab 4 mg/kg loading dose = H = Trastuzumab 2 mg/kg qw = H = Trastuzumab 6 mg/kg q3w

HER2-positive tumor (FISH+); node-positive or high-risk

node-negative disease

RANDOMIZE

SURGERY

AC T (n=1073)

TCH (n=1075)

AC TH (n=1074)

52 weeks

52 weeks

= AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w = T = docetaxel 100 mg/m2 q3w = TC = docetaxel 75 mg/m2/carboplatin target AUC 6 mg/mL· min Radiation therapy and/or hormonal therapy may be given after completion of chemotherapy if indicated

Disease-Free Survival Among all Study Patients

AC-TH vs AC-THR .64 p<0.001

TCH vs AC-THR .75 p=0.04

DFS

OSAC-TH vs AC-THR .63 p<0.001

TCH vs AC-THR .77 p=0.04

Overall SurvivalOverall Survival

Trials to be Reported

Women with centrally

determined HER2-

positive invasive breast cancer

(N = 8381 accrued)

Trastuzumab 8 mg/kg IV (loading dose)* 6 mg/kg every 3 wks for 1 yr

Paclitaxel 80 mg/m2 IV once wkly x 12

Trastuzumab 8 mg/kg (loading dose) 6 mg/kg every 3 wks for 1 yr

Lapatinib 1000 mg orally once daily x 51 wks Paclitaxel 80 mg/m2 IV once wkly x 12

Lapatinib1500 mg orally once daily x

34 wks

Lapatinib 1500 mg/kg orally once daily x 51 wks Paclitaxel 80 mg/m2 IV once wkly x 12

(This arm closed in 9/2011 due to inferiority)

Trastuzumab 4 mg/kg IV (loading dose) 2 mg/kg

once wkly x 11 Paclitaxel 80 mg/m2 IV

once wkly x 12

Surgery, adjuvant

anthracycline-based

therapy for 4 cycles;

LVEF ≥ 50

6-week wash-out

ALTTO Trial Design

*For concomitant dosing with paclitaxel, trastuzumab will be given on a weekly schedule (4 mg/kg IV loading dose followed by 2 mg/kg IV weekly). Trastuzumab will revert to the 3-weekly schedule (6 mg/kg without loading dose).

N = 3806

SURGERY

Central confirmation

of HER2 status

Randomizationwithin 7 wksof surgery

Starttreatment

within1 wk

FOLLOW

UP

10

YRS

RANDOMIZATION

Chemotherapy + trastuzumab and pertuzumab

Anthracycline or non-anthracycline–based chemotherapy allowed

Chemotherapy + trastuzumab and placebo

Anthracycline or non-anthracycline–based chemotherapy allowed

Anti-HER2 therapy for a total of 1 yr (52 wks)

Radiotherapy and/or endocrine therapy may be startedat the end of adjuvant chemotherapy

APHINITY

N = 3806

ClinicalTrials.gov Identifier: NCT01358877

Conclusions

• Trastuzumab in addition to chemotherapy remains the standard for all “high-risk” HER-2+ early breast cancer.

• Controversies exist regarding the following:– Use of anthracyclines– Definition of “high-risk”– Role of additional biologic agents to trastuzumab

“Low-Risk” HER2+ Breast Cancer

Background

• The three randomized adjuvant trials of HER2+ early breast cancer included limited patients with stage I disease, and virtually no patients with tumors < 1 cm.

• Many patients with stage I, HER2+ EBC will have a sufficiently high risk of recurrence to justify administration of adjuvant therapy, but they will likely derive a smaller absolute benefit.

• The development of regimens with lower degrees of toxicity is important for this population.

Tolaney SM, et al. Cancer Res 2013;73:Abst S1-04.

[TITLE]

Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

[TITLE]

Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

Treatment of T1a/b N0 Tumors: NCCN

Luis IV, et al ASCO 2013 Abstr # 1006

[TITLE]

Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

APT Trial

Tolaney SM, et. Cancer Res 2013;73:Abst S1-04.

Conclusions

• Metastatic breast cancer: The landscape of drug choices has changed with the addition of pertuzumab in the front-line and TDM-1 in the second-line.

• Neoadjuvant therapy: The landscape has changed with the approval of pertuzumab in the neoadjuvant setting.

• Adjuvant therapy: – We await adjuvant trial data on anti-HER2 doublets– Identify “low-risk” patients for alternative trastuzumab +

chemotherapy regimens.