Updates from the San Antonio Breast Cancer Symposium 2013 HER2+ Breast Cancer

Updates from the San Antonio Breast Updates from the San Antonio Breast Cancer Symposium 2013Cancer Symposium 2013

HER2+ Breast CancerHER2+ Breast Cancer

Julie R. Gralow, M.D.Julie R. Gralow, M.D.

Director and Jill Bennett Professor of Breast Medical Director and Jill Bennett Professor of Breast Medical OncologyOncology

Professor of Global HealthProfessor of Global Health

University of Washington School of MedicineUniversity of Washington School of Medicine

Fred Hutchinson Cancer Research CenterFred Hutchinson Cancer Research Center

Seattle Cancer Care AllianceSeattle Cancer Care Alliance

2

HER-2 Over-Expressing Breast CancerHER-2 Over-Expressing Breast Cancer

cell division

HER-2

nucleus

cancer cell

Trastuzumab Anti-HER-2 Antibody

HER-2 Oncogene: amplified and overexpressed in 20-HER-2 Oncogene: amplified and overexpressed in 20-25% of breast cancer25% of breast cancer

LapatinibDual HER-1/HER-2

Tyrosine Kinase Inhibitor

Pertuzumab Anti-HER-2 Antibody

T-DM1T-DM1Antibody-Drug

Conjugate

APT Study: Phase II Study of Paclitaxel + APT Study: Phase II Study of Paclitaxel + Trastuzumab as Adjuvant Therapy for Trastuzumab as Adjuvant Therapy for

Small, Node-negative HER2+ Breast CancerSmall, Node-negative HER2+ Breast CancerTolaney SM et al, SABCS 2013, abstract #S1-04Tolaney SM et al, SABCS 2013, abstract #S1-04

• Randomized adjuvant HER2+ trials included few small, lymph node negative breast cancers

• Patients: 406 pts with node-negative, HER2+ breast cancer, < 3 cm

– 2/3 ER+, 20% < 0.5 cm

• Treatment: Paclitaxel and trastuzumab weekly x 12, followed by 9 months of single agent trastuzumab

• Results: 3.6 years median follow-up

– 10 recurrences/deaths (2.5%): 2 distant, 4 locoregional, 3 ): 2 distant, 4 locoregional, 3 contralateral breast cancers, 1 non-breast cancer death contralateral breast cancers, 1 non-breast cancer death (ovarian ca)(ovarian ca)

– 3 year DFS 98.7%3 year DFS 98.7%

APT Study: Phase II Study of Paclitaxel + APT Study: Phase II Study of Paclitaxel + Trastuzumab as Adjuvant Therapy for Trastuzumab as Adjuvant Therapy for

Small, Node-negative HER2+ Breast CancerSmall, Node-negative HER2+ Breast CancerTolaney SM et al, SABCS 2013, abstract #S1-04Tolaney SM et al, SABCS 2013, abstract #S1-04

• Toxicity:

– 2 symptomatic CHF (resolved on stopping trastuzumab)

– 13 asymptomatic declines in LVEF (able to resume trastuzumab in 11)

• Conclusion: Paclitaxel plus trastuzumab can be considered a reasonable approach for majority of patients with small, lymph node negative, HER2+ breast cancer

HER2 Therapy CombinationsHER2 Therapy CombinationsNeo ALTTO: Preop HER2+Neo ALTTO: Preop HER2+

Baselga J et al, Lancet 379:633-640, 2012Baselga J et al, Lancet 379:633-640, 2012

Invasive, operable

HER2+ breast cancer

T > 2 cm

N=450

lapatiniblapatinib

trastuzumabtrastuzumab

lapatiniblapatinibtrastuzumabtrastuzumab

FEC

X

3

SURGERY

RANDOMIZE

Lapatinib 1500 mg/d Lapatinib 1500 mg/d

Trastuzumab weeklyTrastuzumab weekly

Lapatinib 1000 to 750Lapatinib 1000 to 750trastuzumabtrastuzumab

paclitaxel paclitaxel 80 mg/m2 80 mg/m2

paclitaxel paclitaxel

paclitaxelpaclitaxel

pCR

Neo ALTTO: Survival Follow-up AnalysisNeo ALTTO: Survival Follow-up AnalysisPiccart M et al, SABCS 2013 abstract #S1-01Piccart M et al, SABCS 2013 abstract #S1-01

Lapatanib + Lapatanib + TrastuzumabTrastuzumab

TrastuzumabTrastuzumab LapatinibLapatinib

3 yr EFS (all) 84% 78% 78%

HR+ 83% 80% 86%

HR- 86% 72% 70%

3 yr OS (all) 95% 90% 93%

HR+ 97% 94% 93%

HR- 93% 87% 93%

None statistically significantNone statistically significant

Neo ALTTO: EFS and OS by pCRNeo ALTTO: EFS and OS by pCRPiccart M et al, SABCS 2013 abstract #S1-01Piccart M et al, SABCS 2013 abstract #S1-01

Neo ALTTO Survival Follow-up Neo ALTTO Survival Follow-up Analysis: ConclusionsAnalysis: Conclusions

• Underpowered to detect moderate EFS and OS Underpowered to detect moderate EFS and OS differences, await results of ALTTO adjuvant trialdifferences, await results of ALTTO adjuvant trial

• Patients who achieved pCR had significantly better Patients who achieved pCR had significantly better EFS and OS compared with no pCREFS and OS compared with no pCR

• HER2+/ER- disease different from HER2/ER+ diseaseHER2+/ER- disease different from HER2/ER+ disease

Combined HER-2 Targeted TherapyCombined HER-2 Targeted Therapy

BIG 2.06/N063D Adjuvant HER2+ Trial BIG 2.06/N063D Adjuvant HER2+ Trial (ALTTO) – Soon to Report(ALTTO) – Soon to Report

PIs: M Piccart, E PerezPIs: M Piccart, E Perez

HER2+ BC Tumors 1 cm after completion of anthracycline based therapy with LVEF 50%

RANDOMIZE

(paclitaxel) trastuzumab (trast for 1 yr)

(paclitaxel) lapatinib (lap for 1 yr)

(paclitaxel) trastuzumab+ lapatinib(trast + lap for 1 yr)

(paclitaxel) trastuzumab (12 weeks),6-week wash out , lapatinib (34 weeks)

N= 8,000N= 8,000

TRIO Trial: Phase II Trial of Preoperative TRIO Trial: Phase II Trial of Preoperative Trastuzumab, Lapatinib or CombinationTrastuzumab, Lapatinib or Combination

Hurvitz S et al, SABCS 2013, abstract #S1-02Hurvitz S et al, SABCS 2013, abstract #S1-02

LapatinibLapatinib21 days21 days

TrastuzumabTrastuzumab1 dose1 dose

LapatinibLapatinib21 days21 days

Trastuzumab Trastuzumab 1 dose1 dose

TCH x 6 cyclesTCH x 6 cycles

TCL x 6 cyclesTCL x 6 cycles

TCHL x 6 cyclesTCHL x 6 cycles

surgery

biopsy

HER2+ invasive breast cancer

Stage I-III

N=130





• pCR similar in TCH and TCHL arms pCR similar in TCH and TCHL arms

– Differs from other preop studiesDiffers from other preop studies

– Numbers in each arm very smallNumbers in each arm very small

• Addition of lapatinib increased toxicity, limiting ability Addition of lapatinib increased toxicity, limiting ability of patients to receive planned therapyof patients to receive planned therapy

• Molecular analyses ongoing Molecular analyses ongoing to evaluate profiles of non-to evaluate profiles of non-respondersresponders

BETH: Randomized Phase III Trial of BETH: Randomized Phase III Trial of Adjuvant Bevacizumab in HER2+ Breast Adjuvant Bevacizumab in HER2+ Breast

CancerCancerSlamon D et al, SABCS 2-13, abstract #S1-03Slamon D et al, SABCS 2-13, abstract #S1-03

Cohort 1Non-Anthracycline

TCH H

Cohort 2Anthracycline

TH FEC H

Node positive or high-risk node negativeNode positive or high-risk node negativeHER2+HER2+

Arm 1A

TCH HArm 1B

TCHBev HBev

Arm 2A

TH FEC H

Arm 2B

THBev FEC HBev

N= 3231 N= 278



IDFS OS

No Bevacizumab 92% 96%

+ Bevacizumab 92% 97%

Median Follow-up 38 monthsMedian Follow-up 38 months

1 year of adjuvant bevacizumab added to chemo and 1 year of adjuvant bevacizumab added to chemo and trastuzumab does not improve IDFS or OStrastuzumab does not improve IDFS or OS



Chemo/Trastuzumab Chemo/Trastuzumab/Bevacizumab

Hypertension 4% 19%

Thromboembolic event

2% 3%

Bleeding <1% 2%

CHF <1% 2.1%

GI perforation 1 event 11 events

Adverse Events (grade 3, 4)Adverse Events (grade 3, 4)

TH3RESA Trial: T-DM1 in Later Line TH3RESA Trial: T-DM1 in Later Line Metastatic DiseaseMetastatic Disease

Wildiers H et al, European Cancer Congress 2013, Wildiers H et al, European Cancer Congress 2013, Abstract LBA15 Abstract LBA15

T-DM1 q3wks

Physician’s Choice

• HER2+ MBCHER2+ MBC

• Prior anthracycline, Prior anthracycline, taxane, taxane,

capecitabine, capecitabine, lapatinib, lapatinib,

trastuzumabtrastuzumab

• Progression on at Progression on at least 2 HER2 Rxsleast 2 HER2 Rxs

• N=795N=795

• 2:1 randomization2:1 randomization

R

TH3RESA Trial: T-DM1 in Later Line TH3RESA Trial: T-DM1 in Later Line Metastatic DiseaseMetastatic Disease

Wildiers H et al, European Cancer Congress 2013, Abstract Wildiers H et al, European Cancer Congress 2013, Abstract LBA15LBA15

Metastatic T-DM1 and PertuzumabMetastatic T-DM1 and PertuzumabCLOSED: MARIANNE Phase III 1CLOSED: MARIANNE Phase III 1stst-Line -Line

HER2+ Metastatic Breast Cancer HER2+ Metastatic Breast Cancer

Trastuzumab + TaxaneTrastuzumab + Taxane

T-DM1 + PertuzumabT-DM1 + Pertuzumab

T-DM1 + PlaceboT-DM1 + Placebo

HER2+ recurrent locally HER2+ recurrent locally advanced or untreated advanced or untreated MBCMBC

n=1092n=1092

Primary endpoint: OSPrimary endpoint: OS

Rx until progressive diseaseRx until progressive disease

Adjuvant PertuzumabAdjuvant PertuzumabCLOSED: APHINITY Trial Phase III Trial of CLOSED: APHINITY Trial Phase III Trial of Adjuvant Pertuzumab added to Standard Adjuvant Pertuzumab added to Standard

Chemo and TrastuzumabChemo and Trastuzumab

• N=4800N=4800

• Operable Operable HER2+ HER2+ breast breast cancercancer

• Primary Primary endpoint: endpoint: IDFSIDFS

Standard chemotherapy (6-8 cycles) +

Trastuzumab q3 wks x 52 weeks

+ Pertuzumab q3 wks x 52 weeks

Standard chemotherapy (6-8 cycles) +

Trastuzumab q3 wks x 52 weeks

+ Placebo q3 wks x 52 weeks

R

Adjuvant Pertuzumab and T-DM1Adjuvant Pertuzumab and T-DM1SOON TO OPEN: KAITLIN StudySOON TO OPEN: KAITLIN Study

Phase III Trial of Adjuvant Trastuzumab + Phase III Trial of Adjuvant Trastuzumab + Pertuzumab + Taxane Pertuzumab + Taxane vs TDM1 + Pertuzumab in vs TDM1 + Pertuzumab in

HER2+ Breast CancerHER2+ Breast Cancer

T-DM1 + Pertuzumab

Taxane + Trastuzumab +

Pertuzumab

HER2+, non-HER2+, non-metastatic breast metastatic breast

cancer cancer

(n=2500)(n=2500)

Co-Primary Co-Primary endpoints: invasive endpoints: invasive

DFS & OSDFS & OS

Anthracycline-based regimen

Residual Disease after Preop TherapyResidual Disease after Preop TherapyOPEN KATHERINE Trial: Phase III Trial of T-DM1 OPEN KATHERINE Trial: Phase III Trial of T-DM1 vs Trastuzumab in Patients with HER2+ Breast vs Trastuzumab in Patients with HER2+ Breast

Cancer with Residual Disease after Preop TherapyCancer with Residual Disease after Preop Therapy

T-DM1 q3 wks x 14

Trastuzumab q3 wks x 14

HER2+, non-HER2+, non-metastatic metastatic

breast cancerbreast cancer

T1-4, N0-3 at T1-4, N0-3 at presentation presentation

(n=1484)(n=1484)

Primary Primary endpoints: endpoints:

invasive DFSinvasive DFS

Preop Therapy:At least 6

cycles, including at

least 9 weeks of taxane and trastuzumab

Surgery:Residual tumor in breast or

axilla

Adjuvant HER2 Therapy Low HER2 Expression TumorsAdjuvant HER2 Therapy Low HER2 Expression Tumors

ONGOING NSABP B-47: Adjuvant Trastuzumab in ONGOING NSABP B-47: Adjuvant Trastuzumab in Breast Cancer with Normal HER2 ExpressionBreast Cancer with Normal HER2 Expression

Primary Breast Cancer

HER2 IHC 1+ or 2+

FISH Negative

Docetaxel + Cyclophosphamide x 6

orAC x 4 + Paclitaxel x 12

(MD Choice)

RandomizationRandomization

Docetaxel + Cyclophosphamide x 6

orAC x 4 + Paclitaxel x 12

(MD Choice)+

Trastuzumab x 1 yr

N= 3,260N= 3,260

Documents

Updates from the San Antonio Breast Cancer Symposium 2013 HER2+ Breast Cancer