Updates in the Management of HER2 Positive Breast Cancer

Hope S. Rugo, MDProfessor of Medicine

Director, Breast Oncology and Clinical Trials EducationUniversity of California San Francisco Comprehensive Cancer Center

ER+

Breast Cancer Clinical Subsets

All Breast Cancer HER2+

Triple Neg

About 20% of incident cases

are HER2+

half ER+half ER-

HER2+ Breast Cancer 2017 We are still curing most women with early stage

HER2+ breast cancer Understanding subsets is increasingly important

We are over treating at least a subset of patients Its hard to ratchet back with success

Resistance is still a problem Effective new agents are on the horizon

Key Phase III Trials for the HER2+ MBC

Trastuzumab + pertuzumab +

docetaxel

Trastuzumab + docetaxel

T-DM1

Capecitabine + lapatinib Trastuzumab+

lapatinibLapatinib

1Swain NEJM 2015; 2Diéras Lancet Oncol 2017;3Krop Lancet Oncol 2017; 4Blackwell J Clin Oncol 2012

Physician’s choiceT-DM1

1st lineCleopatra(n=808)

2nd lineEmilia

(n=991)

3rd line +TH3RESA (n= 602)

3rd/4th lineEGF 104900

(n=291)Design THP vs TH T-DM1 vs XL T-DM1 vs TPC HL vs LGain in OS 15.7 mo

(40.8 vs 56.5)4 mo

(25.9 vs 29.9)6.9 mo

(15.8 vs 22.7)4.5 mos

Side effects Minimallyincreased

In favor of T-DM1

In favor of T-DM1

Minimallyincreased

Prior trastuzumab?

Minimal (10%)and interval of

≥12 mos required

100%[if adjuvant,

free int < 6m](= 16% of pts)

Prior Trastuzumab and Lapatinib

100%(≥ 3 regimens)

T=docetaxel, H=trastuzumab, P=pertuzumab, L=lapatinib, TPC=Rx of physicians choice

Overall survivalMedian FU 50 mo. (0-70)

CLEOPATRA1st-line Pertuzumab + Trastuzumab

(10% prior trastuzumab)

Median follow-up: 30 months. PFS, progression-free survival; OS, overall survival.

Progression-free survival (inv assessed)

Pertuzumab+trastuzumab+docetaxel

Placebo+trastuzumab+docetaxel

Hazard ratio P-value

ORR1 80.2% 69.3% 0.0001

PFS1 18.7 months 12.4 months 0.69 <0.0001

OS2 56.5 months 40.8 months 0.66 0.0001

Most common adverse events ≥Grade 3 in the pertuzumab+trastuzumab+docetaxel group:1 Neutropenia (48.9%), febrile neutropenia (13.8%), leukopenia (12.3%) and diarrhoea (7.9%)

1. Baselga et al. N Engl J Med 2012;366:109; 2. Swain et al. NEJM 2015;724:734.

PFS: HR HR+ 0.72 vs 0.55 in HR-OS: HR HR+ 0.71 vs 0.61 in HR-

TH3RESA Trial HER2+ MBC with >2 HER2 directed therapies in the

advanced stage setting (T and L) T-DM1 vs TPC 2:1 randomization; 47% xover to T-DM1 3 mo improvement in PFS, less toxicity overall

Krop et al, Lancet Oncol

2017

Further Explorations Marianne trial (Perez et al, JCO 2017) T-DM1 = T-DM1/pertuzumab =

trastuzumab/taxane PFS 14.1 vs 15.2 vs 13.7 mo. QOL maintained for longer, and toxicity lower

with T-DM1

Pherexa (Urruticoechea A et al, JCO 2017) Does pertuzumab improve outcome in the 2nd

line setting after trastuzumab/taxane? Capecitabine/trastuzumab +/- pertuzumab PFS equivalent, OS numerically improved but NS 28.1 vs 37.2 mos. (HR 0.76)

Urruticoechea A et al, ASCO 2018

ER+/HER2+ Metastatic Breast Cancer: Should Treatment Differ?

Luminal intrinsic subtype more commen HER2 amplification results in relative resistance to

hormone therapy Improved PFS when hormone therapy combined with

HER2 targeted therapy, no impact on OS Tandem trial N=207 Median PFS 2.4 → 4.8 mos, HR 0.63; p=.0016

Lapatinib plus letrozole N=1286, 219 HER2+ Median PFS 3.0 → 8.2 months, HR = 0.71; P=0.019

Kaufman, JCO 2009, Johnston JCO 2009

Alternative Trial: De-Escalating Therapy in HR+ Disease (Johnston et al, JCO 2018)

355 women, HR+/HER2+ MBC, prior rx with trastuzumab/chemo, hormone therapy Randomized to L/T/AI vs T/AI vs L/AI

Grade 3 diarrhea 13 vs 6%

Clinical Pathway HER2+ MBC: 2015

First-line: Add hormone therapy to HP after response, and stop chemotherapyPertain trial (Rimawi, SABCS 2016)

2018

Targeting HER2: New Directions

Antibody-drug conjugate

(maytansineanalogue conjugated

to trastuzumab)

Small molecule kinase inhibitors

Humanized monoclonal Ab to HER2 extracellular domain

Neratinib

Humanized monoclonal Ab, blocks heterodimerization

Agents Antibody drug conjugates

Trastuzumab DS-8201

SYD 985

Novel antibodies Margetuximab

Bispecific antibodies: ZW25

Oral tyrosine kinase inhibitors Tucatinib

Neratinib

Pyrotinib

Poziotinib

Checkpoint inhibition

Biosimilars! Multiple approved in US and EU

Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing advanced solid tumors: Long-term efficacy and safety

from a first-in-human phase 1 study with multiple expansion cohorts

DS-8201a was designed with the goal of improving critical attributes of an ADCIwata et al, ASCO 2018

Phase I Trial Design

*Subjects in part 1 were not required to have HER2-positive (IHC 3+ or IHC2+/ISH+) tumors.HER2, human epidermal growth factor receptor 2; HNSTD, highest non-severely toxic dose; IHC, immunohistochemistry; ISH, in situ hybridization; IV, intravenous; PK, pharmacokinetic; Q3W, once every 3 weeks; RD, recommended dose for dose expansion; T-DM1, trastuzumab emtansine.

Response Across Tumor TypesHER2 low=1/2+ by IHC and FISH neg

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

Chan

ge fr

om b

asel

ine

(%) HER2-Positive Breast

Cancer N = 104

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

Chan

ge fr

om b

asel

ine

(%) HER2-Low Breast

Cancer N = 33

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

Chan

ge fr

om b

asel

ine

(%) HER2-Positive Gastric

Cancer N = 44

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

Chan

ge fr

om b

asel

ine

(%)

C o lo re c ta l

N S C L C

O th e r

Other CancersN = 37

• Overall, 86.3% of subjects experienced tumor shrinkage• Confirmed ORR* in the overall population is 49.3%• Median PFS in HER2+ NR, and in HER2 low is 12.9 months

Toxicity 10 (4.1%) TEAEs

leading to death

23 (9.5%) leading to Rx discontinuation

Events of ILD/pneumonitis including 5 fatal cases were observed

All grades Grade ≥3Nausea 166 (68.9) 6 (2.5)Vomiting 84 (34.9) 4 (1.7)Diarrhea 64 (26.6) 2 (0.8)Constipation 51 (21.2) 0 (0.0)Stomatitis 43 (17.8) 0 (0.0)Decreased appetite 134 (55.6) 8 (3.3)Anemia 77 (32.0) 36 (14.9)Platelet count decreased 69 (28.6) 25 (10.4)Neutrophil count decreased

61 (25.3)37 (15.4)

White blood cell count decreased58 (24.1) 30 (12.4)

Alopecia 87 (36.1) 0 (0.0)Fatigue 67 (27.8) 4 (1.7)Malaise 50 (20.7) 1 (0.4)Pyrexia 25 (10.4) 1 (0.4)Dysgeusia 24 (10.0) 0 (0.0)

Phase II Destiny Trial

Baselga et al, ASCO 2018

SYD 985 Phase I Expansion Study Trastuzumab duocarmazine

Pro-drug (seco-DUBA) of DNA alkylating agent

Responses HER2+: 24% (TDM1 rxd, 9/38) HER2 low/HR+: 20% (6/30)

TNBC: 27% (4/15)

Toxicity (grade 3) Neutropenia: 6% Conjunctivitis/keratitis: 5%

All grade ocular toxicities up to 29%

Phase III TULIP trial (vs TPC)

Saura et al, ASCO 2018

Synthon Pharmaceuticals

Margetuximab: Fc-Optimized anti-HER2 Monoclonal Antibody

Margetuximab (MGAH22) Derived from 4D5 with Fc domain engineered to

increase binding to isoforms of the activating Fcγreceptor CD16A

Antiproliferative in cell lines resistant to anti-HER2 ab

More potent than trastuzumab surrogate in ADCC assays

Phase I data encouraging Safety similar to trastuzumab Of 27 with breast cancer: 4 Partial Responses, 2 each in low affinity

CD16 F/F and F/V genotypes 3 ongoing on single agent study therapy at

41, 47, and 56 months (F/V, F/F, F/F)Bang et al, Ann Oncol 2017

SOPHIA Study to Establish Superiority Over Trastuzumab

1:1 Randomization(n = 530)

HER2+ mBC, 1-3 anti-HER2 lines in metastatic setting,

including pertuzumab

Arm 1margetuximab + chemotherapy

Arm 2trastuzumab + chemotherapy

PI Choice of Chemotherapy(capecitabine, eribulin,

gemcitabine or vinorelbine)R

Sequential Primary Endpoints: Progression-Free Survival (PFS, N=257, HR=0.67, α=0.05, power=90%) then Overall Survival (OS, N=385, HR=0.75, α=0.05, power=80%)

Phase 3 – Randomized Trial of Margetuximab in Third-Line Metastatic Breast Cancer

Stratification:• Type of chemotherapy• Lines of prior chemotherapy (≤2 vs >2)• Metastatic sites (≤2 vs >2)

ONT-380 (Tucatinib) Selective small molecule TKI more selective for

HER2 than EGFR Primary toxicity is elevation of transaminases 11% grade 3 diarrhea

With cape only

Treatment ONT-380/capecitabine/trastuzumab

HER2Climb Ongoing randomized phase II trial: cape/trast +/- ONT

Murthy et al, Lancet Oncol 2018

Her2-Directed Tyrosine Kinase Inhibitors: Activity in the CNS

Agent Target Phase of Development CNS ORR (Monotherapy) CNS ORR in combination with capecitabine

Lapatinib HER1/HER2 FDA Approved 6%1 20%2, 66%3

Neratinib HER1/HER2/HER4 FDA Approved(Adjuvant)Phase 3 (Metasatic)

8%4 49%5

Tucatinib HER2 Phase 3 5-9%6 (+ trastuzumab) 42%7 (+trastuzumab) 1

Pyrotinib HER1/HER2 Phase 3 NA NA

Poziotinib HER1/HER2/HER4 Phase 2 NA NA

Afatinib Phase 3 negative– No further development in breast

0%8 NA

1Lin et al, CCR 2009, 2Lin et al, CCR 2009, 3Bachelot et al, Lancet Oncol 2013, 4Freedman et al, JCO 2016, 5Freedman et al, ASCO 2017, 6Metzger et al, SABCS 2016, 7Hamilton et al, SABCS 2016, 8Cortes et al, Lancet Oncol 2015

Preclinical synergy with IO and HER2-directed agents A single dose of pre-operative trastuzumab can

change the immune profile within a tumor JAVELIN 3.8% ORR with avelumab1

Metastatic PANACEA 15% ORR with trastuzumab + pembrolizumab2

Numerous IO studies are planned or underway

Checkpoint Blockade in HER2-Positive Disease

1Dirix SABCS 2016; 2Loi SABCS 2017

PD-L1 positive (n=44)

• Median PFS 2.7(+) vs 2.5 mo(-)• Mean DOR: 10 months • 5 patients (10.8%) continue with no

progression at time of reporting• Higher TILS correlated with response

and DOR• Higher in PD-L1+ and in lung and

nodes

PD-L1 +Phase Ib,

n=6

PD-L1 +Phase II,

n=40

PD-L1 -Phase II,

n=12

ORR n (%) [90%CI]

1 (17%) [1-58]

6 (15%) [7-29]

0 (0%) [0-18]

OS

Panacea: Phase Ib/II Trial of Pembrolizumaband Trastuzumab in HER2+ MBC

Loi et al, SABCS 2017

BCRF Funded AVIATOR Trial (TBCRC 045) Addition of a 4-1BB Agonist to a Trastuzumab/anti-PD-L1

Combination in HER2+ MBC

• Advanced HER2+ cancer

• No prior immunotherapy

• PD-L1 unselected

Vinorelbine +trastuzumab+ avelumab

Vinorelbine +trastuzumabN=20

Vinorelbine +trastuzumab+ avelumab +

Utomilumab

Trastuzumab + avelumab +Utomilumab

Tumor tissue

Fresh or ≤1y old

TumorTissue

N=40

N=40

Vinorelbine 25mg/m2 D1,D8,D15Trastuzumab D1, D15Avelumab D1, D15 10mg/kg IVUtomilumab D1 100mg IV28d cycle

TumorTissue

PI: Ian Krop

Advances in Adjuvant Therapy for HER2+ Disease: How Much, How

Long?

Have we reached the ceiling of incremental benefits?

How do we de-escalate?

Adjuvant Trastuzumab Improves DFS and OS

1. Piccart-Gebhart MJ, et al; N Engl J Med 2005; 353:1659-1672; 2. Smith I, et al. Lancet 2007; 369:29-36; 3. Gianni L, et al; Lancet Oncol 2011; 12:236-244; 4. Goldhirsch A, et al. Lancet 2013; 5.Cameron et al, Lancet 2017

6. Romond EH, et al. N Engl J Med 2005; 353:1673-1684; 7. Perez EA, et al. J Clin Oncol 2011; 29:3366-3373; 8. Romond EH, et al. SABCS 2012; 9. Slamon D, et al. N Engl J Med 2011; 365:1273-1283; 10. Slamon et al, SABCS 2015

DFS OS

StudyFollow-up

(years) N HR p value HR p value

HERA1–5

CT+/–RTH vs. CT+/–RT

1 3387 0.54 < 0.0001 0.76 0.26

2 3401 0.64 < 0.0001 0.66 0.0115

4 3401 0.76 < 0.0001 0.85 0.1087

8 3401 0.76 < 0.0001 0.76 0.0005

11 34010.76

∆ 6.8% 0.00010.74

∆ 6.5% <0.0001

NCCTG N9831/NSABP B-316–8

ACTHH vs. ACT

2 3351 0.48 < 0.0001 – –

4 4045 0.52 < 0.001 0.61 < 0.001

8.4 40460.60

∆ 11% < 0.00010.63∆ 9% < 0.0001

BCIRG 0068,9

ACTHH vs. ACT10 3222

0.72∆ 6.7 < 0.0001 0.63

∆ 7.2 < 0.0001

TCH vs. ACT 0.77∆ 5.1 0.0011 0.76

∆ 4.60.075

Optimal Duration of Adjuvant Trastuzumab?

HERA Trial: 2 vs 1 year Trastuzumab at 11 Years Median FU

Cameron et al, Lancet 2017; Joensuu et al, JCO 2009

Optimal Duration of Adjuvant Trastuzumab?Trial Duration Chemotherapy Start Accrual Status/Results

PHARE 6 vs 12 mos InvestigatorChoice (~90% anthracycline-based)

5/2006 3384 Published 20131

Non-inferiority not reached, cardiac toxbetter with shorter

Hellenic Oncology

6 vs 12 mos ddFEC/D 10/2004 481 Published 20152

Non-inferiority not reached

Short-HER 9 wks vs 1year

A=T vs T+FEC 12/2007 1253 Reported ASCO 20173

Non-inferiority not reached, cardiac toxbetter with shorter

SOLD 9 wks vs 1year

T+FEC 1/2008 2168 Reported SABCS 20174

Non-inferiority not reached, less cardiac tox with shorter

Persephone 6 vs 12 mos InvestigatorChoice

10/2007(over 8 yrs)

4000 Cardiac outcomes published 20165; DFS at ASCO 20186

1. Pivot X et al. Lancet Oncol 2013;14:741-8. 2. Mavroudis D et al. Ann Oncol 2015;26:1333-40 3. Conte PF et al. J Clin Oncol 2017;35(15s):Abs 501. 4. Joensuu et al, SABCS 2017 5. Earl HM et al. Br J Cancer 2016;115:1462-70. 6. Earl et al, ASCO 2018

Persephone Study Design

1O: DFS [Diagnosis to 1st relapse (local or distant) or death]2O: OS; Cost effectiveness; Cardiac function

Earl et al, ASCO 2017

Statistics and Patient Characteristics 4 year DFS with 12 months estimated at 80%

Non-inferiority defined as no worse than 3% below

69% hormone receptor positive

48% A/T based, 42% A based

53% sequential trastuzumab (after chemo)

67% > 50 yo

56% randomized after at least one dose of trastuzumab

59% node negative; 48% T<2cm; 67% grade III

Disease-free survival

#events HR 90% CI Non-inferiority p

12 months 247 1.07 0.93-1.24 0.01

6 months 265

96.1%95.7% 89.8%

89.4%

Non-inferiority limit

}0.4%

Pre-defined subgroup analysis

Interaction between 2 groups χ21=2.3; p=0.13

Heterogeneity between 4 groups χ23=11.1; p=0.01

Interaction between 2 groups χ21=3.2; p=0.07

Interaction between 2 groups χ21=10.8; p<0.001

Overall survival

#events HR 90% CI Non-inferiority p

12 months 156 1.14 0.95-1.37 0.0006

6 months 179

98.9%98.7% 94.8%

93.8%

Non-inferiority limit

}1.0%

Cardiotoxicity

• Cardiac function recovers post-trastuzumab (p<0.0001)

• 6-month patients had a more rapid recovery (p=0.02)

• Other toxicity was modest• 20% of sequential patients

reported G3/4 toxicity during trastuzumab (23% 12 month, 18% 6 month, p=0.004)

Random effects modelling predicted lines and 95%CIs

Stopped trastuzumab because of cardiotoxicity

- in 8% of 12-month patients - in 4% of 6-month patients(p<0.0001)

Ref: Earl et al. British Journal of Cancer (2016) 115, 1462–1470

Implications for Clinical Practice The option for shorter trastuzumab has the potential to

increase accessibility and reduce cost world-wide

In the U.S.? Is a 3% margin for non-inferiority sufficient? Pertuzumab, neratinib approved for overall differences of less

than 3% Subgroup analysis? Hard to interpret

Who is a candidate for shorter adjuvant trastuzumab? Smaller tumors, ER+, older age, cardiac risk factors

Neoadjuvant Trastuzumab Trastuzumab markedly increases pCR rates when

added to standard chemotherapy Noah trial: improved pCR translated into improved

DFS

Addition of lapatinib in multiple trials Increased toxicity, variable impact on pCR

No impact on DFS

Buzdar A, et al. JCO 2004, Gianni et al, Lancet 2010

Outcome Based on pCR: Impact of Receptor Subsets

Luminal AHR+, low grade

von Minckwitz G, et al. J Clin Oncol 2012

BasalER/PR/HER2-Neg HER2+

H, trastuzumab; P, pertuzumab; T, docetaxel given for 4 cycles, followed by surgery, then 3 cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) and H for a full year

Dual HER2 Blockade and pCR: Impact of Adding Pertuzumab NeoSphere Study

p = 0.014150

40

30

20

10

0TH THP HP TP

pC

R, %

±95%

C

I

p = 0.0198

p = 0.003

29.0

45.8

16.824.0

Gianni L et al. Lancet Oncol. 2012

TRYPHAENA Trial: Anthracycline and Non-AnthracyclineComparisons With Pertuzumab-Based Therapy in All Arms

Schneeweiss A, et al. Ann Oncol 2013

Pat

holo

gic

com

ple

te r

espon

se (

%)

FEC+H+P x3→ T+H+P x3

(n = 73)

FEC x3→ T+H+P x3

(n = 75)

TCH+P x6(n = 77)

Pertuzumab is approved in the neoadjuvant setting for HER2+ breast cancer –

specifically for tumors > 2 cm and positive nodes

APHINITY: Randomized Adjuvant Phase 3 Trial

A=doxorubicin, E=epirubicin, C=cyclophosphamide, T=taxane (paclitaxel or docetaxel), F=5-fluorouracil, H=trastuzumab, P=pertuzumab

N=3800 planned (4800 enrolled)

trastuzumab + pertuzumab*x 1 year

SURGE

RY

Central confirmation

of HER2 status

ACT or TCH

trastuzumab + placebo*x 1 year

ACT or TCH

*antibody therapy starts with taxane

Node + orhigh risk node negative

Von Minckwitz et al. NEJM 2017

Demographics:• N0: 37% (25% N> 4+)• HR+: 64%• Anthracycline: 78%

APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival

Number needed to treat: 112

expected: 89.2%

4yr iDFS:HR = 0.81 (p = 0.045)

Absolute benefit = 1.7%

Δ %(H/P vs. H)

Absolute Δ

N0 96.7 v 96.2% 0.5%

N1 89.9 v 86.7% 3.2%

ER/PR+ 93 v 91.6% 1.4%

ER/PR- 91 v 88.7% 2.3%

iDFS subset analysis

*No difference in iDFS by type of chemotherapy

Additional Endpoints and Toxicity

Absolute difference in DRFI: 0.6%

Overall survival identical 97.7%

Toxicity Grade >3 diarrhea 9.8 vs 3.7% overall

18 vs 6.1% with TCH

Summary: Adjuvant Therapy

Anthracyline and non-anthracycline regimens are acceptable as (neo)adjuvant therapy Triage based on tumor and cardiac risk

12 months of trastuzumab remains the general standard 9 wks of tras in pts receiving anthracycline-based chemotherapy is

not equivalent to 12 months

Shorter duration associated with slightly less cardiac toxicity

Overall benefit from addition of pertuzumab modest at best Not surprising given huge impact of trastuzumab and excellent

outcome for patients with early stage HER2+ breast cancer

Clinical Implications Pertuzumab use should be restricted to those with high risk

cancer Definition complex: N+, ER neg – but what about N-/ER-? ER+

and one node? All neoadjuvant or just N+/HR-?

Is pertuzumab during chemotherapy enough? Do patients with moderate risk disease or pCR need one year of pertuzumab?

What about neratinib?

Neratinib as Extended Adjuvant Therapy: The ExteNET Trial

• Primary endpoint: invasive DFS (iDFS)• Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS metastases, OS, safety• Other: Biomarkers, QOL• Stratification: nodes 0, 1-3+, vs 4+, ER/PR status, concurrent vs sequential trastuzumab

• Median time from trastuzumab N vs P: 4.4 (0.2-30.9) vs 4.6 (0.3-40.6) months Chan et al, Lancet Oncology 2016

24% node negative, 47% 1-3+ nodes; 57% HR+

5 Year Analysis: IDFS

Martin et al, Lancet Oncology 2017

iDFS by hormone receptor status (exploratory analysis)

Martin et al, Lancet Oncology 2017

Antidiarrheal Prophylaxis Reduces the Incidence and Severity of Diarrhea. ExteNET and Study 6201 (CONTROL)

Hurvitzet al,

SABCS 2017

Less is More: De-escalating Therapy for HER2+ Breast Cancer

Heterogeneity of HER2+ Disease:Intrinsic subtype distribution based on HR status

HR+/HER2+N=1,648

HR-/HER2+N=1,213

36.0%

31.8%

30.0%

2.2%

75.1%

14.8%

7.4%2.7%

Courtesy Aleix Prat

Neoadjuvant Therapy for HER2+ Early Stage Breast Cancer: a Window into Best Therapy?

Cortazar P, FDA Neoadjuvant Breast Cancer Workshop 2013, Lancet 2014

pCR Rates:Impact of Receptor Subsets

WSG ADAPT-HER2

3 arm trial (n=375) T-DM1 x 4 T-DM1/endocrine therapy Trastuzumab/endocrine therapy

Association of pCR with early response (low Ki67/cellularity)

Harbeck et al, JCO 2017

Adjuvant Paclitaxel and Trastuzumab (APT) A New Standard of Care for Low Risk HER2+

HER2+ER+ or ER-Node Negative< 3 cm

EnrollTP

TP

TP

TP

TP

TP

TP

TP

TP

TP

TP

TP

PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12

TT T T T T T T T T T T TN = 410

Median FU 7 years

Tolaney et al. NEJM 2015, ASCO 2017

Point Est. 95% Conf. Interval No. of events

3-yr DFS 98.5% 97.2% to 99.7% 6

5-yr DFS 96.3% 94.4% to 98.2% 14

7-yr DFS 93.3% 90.4% to 96.2% 23

Point Est. 95% Conf. Interval

No. of events

3-yr BCSS - - 0

5-yr BCSS 99.7% 98.1% to >99.9 % 1

7-yr BCSS 98.6% 97.0% to >99.9% 3

2 ptts with CHF (0.5%), 4 distant recurrence events (1%)

ATEMPT Trial Schema

Stage IHER2+*ER+ or ER-PS 0-1Adequate organ fx

N=500

Trastuzumab-DM1 q3weeks X17

*HER2-positive defined as IHC 3+ or FISH≥2.0; will be confirmed by central HER2 testing prior to study enrollment

Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy

Adjuvant radiation therapy can be administered concurrently with study treatment.

Paclitaxel + Trastuzumab x12Trastuzumab q3weeks x13

N=375

N=125

R3

1

Accrual time: 30 months

PI: Sara Tolaney, MD, MPH

KRISTINE/TRIO-021 Neoadjuvant therapy: Is less good enough?

444 patients with centrally confirmed HER2+ breast cancer Randomized to TCH+P x 6 vs T-DM1+P x 6

Same treatment continued post-op Primary endpoint: pCR

Patients Median age 50, 62% ER pos, 83% stage IIA-IIIA Median FU 8.8 months

Results: toxicity and efficacy T-DM1+P: less decline in HRQoL and physical function TCH+P: more AEs and SAEs; superior pCR rate and higher BCS

Hurvitz et al, ASCO 2016

0

20

40

60

80

TCH+P T-DM1+P

pC

R (

%)a

Difference: -11.395% CI: -20.5, -2.0

Stratified 2-sided P−value: 0.0155b

Primary Endpoint: pCR (ypT0/is, ypN0)

Presented by: Dr Sara Hurvitz

123/221 99/223

apCR rate and 95% CI are shown. Patients with missing or unevaluable pCR status were considered nonresponders: TCH+P, 7 (3.2%); T-DM1+P, 18 (8.1%). Treatment discontinuation in the neoadjuvant phase for progressive disease: TCH+P, 0% of patients; T-DM1+P, 7% of patients.bCochran-Mantel-Haenszel Chi-square.

56%44%

Our challenge: to identify those who will do as well with less vs more

Reg

istr

atio

n THP x 4 cycles

Surg

ery

pCR: De-escalation: HP + ET only

No pCR

EligibilityHER2+

Stage II-IIIa(T2-3, N0-2)

Primary Aim: RFS

COMPASS: Concept in Development

ER+

ER-

R

R

SOC +CDK4/6i

Rational de-escalation and escalation in HER2+

SOC + IO?

Courtesy of Lisa Carey

Summary: Major Progress! New agents

Less is more Individualizing therapy for tumor biology and

response

More and smarter therapy for those with poorly responsive disease

Continued Progress in the Treatment of HER2+ BC

EGFR discovery

Cohen

FDA approves trastuzumab in

adjuvant setting

19851978 1998 2006 2007 2010

Her2 amplification in breast cancer

Aaronson

FDA approves trastuzumab alone for 2nd line and in with paclitaxel for

1st line MBC

FDA approves lapatinib +

letrozole for MBC

FDA approves lapatinib +

capecitabine for MBC

1987

Her2/neuamplification

correlates with shorter survival

Slamon

MBC : metastatic breast cancer; MoAb : monoclonal antibody

2012

FDA approves pertuzumab + trastuzumab +

docetaxel for MBC

2013

FDA approves trastuzumab

emtansine for MBC

Accelerated approval of

pertuzumab/ trastzumab as neoadjuvant

therapy

2017

Neratinib approved for extended

adjuvant therapy

Approval of pertuzumab/ trastzumabas adjuvant

therapy