Biomarkers for HER2-directed Therapies : Past Failures and Future

Perspectives

Ian KropDana-Farber Cancer Institute

Harvard Medical SchoolInchon 2018

Adjuvant Trastuzumab Improves Outcomes

in HER2+ Breast Cancer

(N9831 and NSABP B-31)

Perez E A et al. JCO 2014;32:3744-3752

Why do we need

predictive biomarkers?

• Identify patients whose cancer is likely to be particularly

sensitive to targeted therapy (and can be spared

chemotherapy)

• Identify patients who are not likely to do well on standard

HER2-directed therapy

• Rationally select between multiple second-generation

anti-HER2 agents

• Provide potential insight into potential mechanisms of

resistance

TAILORx: chemotherapy not needed in

patients with very low Oncotype RS

Adapted from: Sparano JA et al. NEJM 2015

Secondary Group

RS <11

Assigned to Hormonal

Therapy Only

Distant Relapse Free

Survival

99.3%

Invasive Disease Free

Survival

93.8%

Overall Survival 98.0%

5 Year Results

Why do we need

predictive biomarkers?

• Identify patients whose cancer is likely to be particularly

sensitive to targeted therapy (and can be spared

chemotherapy)

• Identify patients who are not likely to do well on standard

HER2-directed therapy

• Rationally select between multiple second-generation

anti-HER2 agents

• Provide potential insight into potential mechanisms of

resistance

Why do we need

predictive biomarkers?

• Identify patients whose cancer is likely to be particularly

sensitive to targeted therapy (and can be spared

chemotherapy)

• Identify patients who are not likely to do well on standard

HER2-directed therapy

• Rationally select between multiple second-generation

anti-HER2 agents

• Provide insight into potential mechanisms of resistance

Proliferation

HER2

PI3K

AKT

HER2 signaling pathway (simplified)

Adapted from Gluck, Clin Breast Cancer 2016

HER2 as a biomarker?

CALGB 9840: (paclitaxel ± trastuzumab):

No benefit to trastuzumab in HER2-negative

MBC

Seidman et al, JCO 2008, 26, 1642-1649

B-47 Adjuvant Trastuzumab in Patients with

Normal/Low HER2 Expression Breast Cancer

High Risk Primary Breast Cancer

IHC 1+ or 2+ for HER2

FISH Negative

(and HER2 copy number<4)

Anthracycline/taxane

chemotherapy

Randomization

Anthracycline/taxane

chemotherapy

+Trastuzumab x 1 yr

N=3260

B-47: Invasive Disease-Free Survival

No. at Risk

ChemoRx

ChemoRx+Trast1558

1528

1423

1403

1003

1009

595

591

140

117

1603

1599

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60

% D

ise

as

e-F

ree

Time Since Randomization (months)

ChemoRx

ChemoRx+Trast

1603

1599

134 89.2%

130 89.6%

HR 0.98 (95% CI 0.77-1.26) P=0.90

Treatment N Events 5 year EFS

San Antonio Breast Cancer Symposium, December 5-9, 2017

This presentation is the intellectual property of the presenter. Contact them at Lou.Fehrenbacher@kp.org for permission to reprint and/or distribute

Level of HER2 amplification associated with pCR

in TAXHER01 and GETNA01 studies

Arnould et al, Clin Cancer Res 2007;13(21)

LA: low amplification (mean, 6-10 signals)

HA: high amplification (mean, >10 signals/nuclei)

Level of HER2 mRNA and protein

associated with pCR in TRYPHAENA(Chemo + trastuzumab+pertuzumab; All arms pooled)

Schneeweiss et al. Breast Cancer Research 2014, 16:R73

*Biomarkers high vs. low with cut point at median value

HER2 FISH ratios are not associated with

trastuzumab benefit (DFS) in NCCTG N9831

Perez et al. JCO 28:4307 2010

HER2/

CEP17 n HR 95% CI P

NSABP-B-31: no significant association between

HER2 copy number and benefit (P = 0.60)

HER2 FISH ratios are not associated with

trastuzumab benefit (DFS) in HERA

Dowsett et al. JCO 27:2962 2009

Very high HER2 protein expression not associated

with trastuzumab benefit (DFS) in FinHer

Joensuu et al. Annals of Oncology 22:2007 2011

Very high HER2 protein

( log H2T ≥ 2.1)*

Moderate HER2 protein

( log H2T <2.1)

*Log H2T =2.1 HER2 protein expression is

22-fold the median of HER2-negative

cancers

HER2 FISH ratios are not associated with

trastuzumab benefit (DFS) in NCCTG N9831

Perez et al. JCO 28:4307 2010

HER2/

CEP17 n HR 95% CI P

NSABP-B-31: no significant association between

HER2 copy number and benefit (P = 0.60)

HER2 FISH ratios are not associated with

trastuzumab benefit (DFS) in HERA

Dowsett et al. JCO 27:2962 2009

Cleopatra: Prognostic effects independent of

treatment arm (both arms pooled)

Baselga SABCS 20129;

Cleopatra: Prognostic effects independent of

treatment arm (both arms pooled)

Baselga SABCS 20129;

Biomarkers to predict benefit of T-DM1:

Improved outcomes with high HER2 mRNA levels

Krop et al ASCO 2009, Burris, et al. JCO. 2011;

TH3RESA (T-DM1 vs Treatment of Physicians Choice):

Increased Benefit of T-DM1 in Cancers with HER2 mRNA Level?

aHazard ratios are based on unstratified analyses. Kim et al, Int. J. Cancer: 139, 2336–2342 (2016)

EMILIA Biomarker Analysis:

PFS by HER2 mRNA Level and Treatment Arm

Pro

po

rtio

n p

rog

res

sio

n-f

ree

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)No. at risk:

Lap + Cap (≤ Median) 204 164 119 74 47 21 14 9 5 2 1 0 0 0 0 0 0

Lap + Cap (> Median) 235 190 151 80 66 44 35 22 18 11 7 7 5 1 0 0 0

T-DM1 (≤ Median) 230 186 146 99 79 55 44 31 23 19 12 7 5 1 0 0 0

T-DM1 (> Median) 197 175 146 103 78 58 47 33 23 18 13 9 3 2 1 0 0

Lap + Cap (≤ Median)

Lap + Cap (> Median)

T-DM1 (≤ Median)

T-DM1 (> Median)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

aHazard ratios are based on unstratified analyses.

Lap + Cap T-DM1

HER2 median

mRNA conc.

ratio = 13.3 n

Median

(months) n

Median

(months)

Hazard

ratioa 95% CI

≤ Median 204 6.4 230 8.2 0.64 0.50–0.82

> Median 235 6.9 197 10.6 0.65 0.50–0.85

HER2 as biomarker

• HER2 levels (mRNA, FISH, protein) are associated with higher pCR in neoadjuvant trials

• HER2 levels do not predict benefit of adjuvant trastuzumab

• Very high HER2 levels may predict be associated with resistance to adjuvant trastuzumab

– Needs further validation

• HER2 mRNA levels are associated with response to T-DM1 in MBC

Proliferation

HER2

PI3K

AKT

HER2 signaling pathway (simplified)

Adapted from Gluck, Clin Breast Cancer 2016

PIK3CA_MUT

PIK3CA_WT

N=1,324

23%

All patients

PIK3CA mutations within HER2+ disease

HR+24%

22%HR-

TCGA Nature 2012; Ferrari et al. Nat Com 2015; Loibl et al. Annals Oncol 2016(adapted from A Prat SABCS 2016)

Loibl et al, Annals of Oncology 27: 1519–1525, 2016

PIK3CA mutations are associated with reduced pCR rates in pooled analysis of neoadjuvant studies

PI3-KINASE

Alterations in the PI3K/PTEN pathway are not associated with resistance to trastuzumab in NSABP B-31 (8 year DFS)

Pogue et al, JCO 33:1340-1347. 2015

WT Hazard ratio: 0.51MT Hazard ratio: 0.44

PTEN loss had no influence on trastuzumab benefit in N9831

Lap + Cap T-DM1

PIK3CA

mutation

status n

Median

(months) n

Median

(months)

Hazard

ratioa 95% CI

Mutated 39 17.3 40 NE 0.26 0.12–0.57

Wild type 87 27.8 93 NE 0.68 0.40–1.15

aHazard ratios are based on unstratified analyses

NE, not estimable.

39 34 32 31 28 27 22 17 14 10 8 6 4 3 2 0 0 0 0Lap + Cap (Mutated)

87 83 77 74 68 66 57 44 38 32 28 26 20 14 11 6 4 3 2Lap + Cap (Wild type)

40 40 40 40 38 37 36 34 27 25 21 14 12 7 4 4 3 2 2T-DM1 (Mutated)

93 91 89 86 82 78 69 52 44 37 30 27 21 17 12 7 5 3 2T-DM1 (Wild type)

Pro

po

rtio

n s

urv

ivin

g

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

Lap + Cap (PIK3CA mutated)

Lap + Cap (PIK3CA wild type)

T-DM1 (PIK3CA mutated)T-DM1 (PIK3CA wild type)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

No. at risk:

EMILIA Biomarker Analysis:

OS by PIK3CA Mutation Status and Treatment Arm

TH3RESA Biomarker Analysis:

PFS by PIK3CA mutation status and Treatment Arm

aHazard ratios are based on unstratified analyses. Kim et al, Int. J. Cancer: 139, 2336–2342 (2016)

PI3-kinase as biomarker

• Mutations in PIK3CA are associated with lower pCR across many in neoadjuvant trials of HER2-directed therapy

• PIK3CA mutations or PTEN loss do not predict benefit of adjuvant trastuzumab

• PIK3CA mutations do not predict benefit of T-DM1 or pertuzumab in HER2+ MBC

Proliferation

HER2

PI3K

AKT

HER2 signaling pathway (simplified)

Adapted from Gluck, Clin Breast Cancer 2016

Proliferation

HER2

PI3K

AKT

HER2 signaling pathway: cross-talk with ER

Adapted from Gluck, Clin Breast Cancer 2016

mTOR

ER ER

S6KER

ER

P

Estradiol

Copyrights for this presentation are held by the author/presenter. Contact them at gianni.luca@hsr.it for permission to reprint and/or distribute..

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6‒10, 2011

Hormone receptor status and pCR in NeoSphere

7

0

10

20

30

40

50

60

70

TH THP HP TP

ER or PR positiveER and PR negative

20.026.0

17.4

36.8

29.1 30.0

63.2

5.9

pC

R, %

9

5%

CI

p=0.005

p=0.478

ER, estrogen receptor; PR, progesterone receptorH, trastuzumab; P, pertuzumab; T, docetaxel (study dosing: q3w x 4 cycles)

Gianni L, et al. Lancet Oncol 2011 DOI:10.1016/S1470-2045(11)70336-9

Effect of Hormone Receptor expression on trastuzumab benefit in B-31/N9831

Perez et al, JCO 22:3744 2014

Effect of Hormone Receptor expression on trastuzumab benefit in BCIRG-006

Slamon D, N Engl J Med 2011;365:1273-83.

Effect of Hormone Receptor expression and HER2 copy number on trastuzumab benefit in

HERA

Loi et al JAMA Oncol. 2016;2(8):1040

Nonlinear interaction between expression levels

of ESR1 and ERBB2 and trastuzumab benefit in

NSABP B-31.

Pogue-Geile K L et al. JNCI J Natl Cancer Inst 2013;105:1782-1788

Green = high trastuzumab benefit (HR 0.28)

Brown = moderate benefit (HR 0.60)

Red = no benefit (HR 1.58)

APHINITY: Trial Design

Presented By Gunter Von Minckwitz at 2017 ASCO Annual Meeting

Presented By Gunter Von Minckwitz at 2017 ASCO Annual Meeting

Neratinib Extended Study Design

• Primary endpoint: invasive disease-free survival (iDFS)

• Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS metastases, overall survival, safety

• Other analyses: biomarkers, health outcome assessment (FACT-B, EQ-5d)

• Stratified by: nodes 0, 1–3 vs 4+, ER/PR status, concurrent vs sequential trastuzumab

• HER2+ breast cancer (local)

• Prior adjuvant trastuzumab &

chemotherapy

• Lymph node –/+ or residual

invasive disease after

neoadjuvant therapy

• ER/PR + or –

1:1

ran

do

miz

atio

n

Neratinib x 1 year

240mg/day

Placebo x 1 year

2-y

ear

foll

ow

-up f

or

iDF

S

5-y

ear

foll

ow

-up f

or

iDF

S

5 +

yea

r s

urv

ival

Part A Part B Part C

Primary Endpoint: Invasive DFS (ITT)

0 3 6 9 12 15 18 21 24

Dis

ease-f

ree s

urv

ival (%

)

Months after randomization

1420

1420

1291

1367

1260

1324

1229

1292

1189

1243

1150

1209

1108

1163

1033

1090

No. at risk

Neratinib

Placebo662

704

100

60

50

80

90

0

70P-value = 0.009

HR (95% CI) = 0.67 (0.50–0.91)

97.8%

95.6%

93.9%

91.6%

Neratinib

Placebo

Chan et al, Lancet Oncology 2016

Dis

ea

se-f

ree

surv

ival (%

)

Months after randomization

384381

356373

352362

346351

337340

352333

313316

291293

No. at riskNeratinibPlacebo

198187

ER-positive:

HR (95% CI) = 0.25 (0.12–

0.48)

Events: Neratinib vs Placebo (10 vs 41)

98.6%

94.3%

97.0%

88.4%

iDFS centrally-confirmed HER2 positive & HR+

765 HR+ and centrally confirmed HER2 positive

HR+: estrogen and/or

progesterone positive

iDFS centrally-confirmed HR+ and HER2+ (ITT)

0 3 6 9 12 15 18 21 24

100

60

50

80

90

0

70

Neratinib

Placebo

8.6%

ER-negative:

HR (95% CI) = 0.96 (0.53–

1.74

Events: Neratinib vs Placebo (23 vs 22)

Adapted from A Chan et al, ASCO Breast 2015

Estrogen receptor as biomarker

• ER+ HER2+ breast cancers have markedly lower rates of pCR than ER-negative HER2+ cancer

• ER status alone does NOT predict benefit of adjuvant trastuzumab or pertuzumab

• In cancers with lower levels of HER2 expression and high ER expression, there are some data to suggest lower benefit of trastuzumab

– Needs validation

• ER status may predict benefit of neratinib

Intrinsic subtype as a biomarker?

17

1 P

rote

in/p

ho

sph

o-

Pro

tein

Exp

ress

ion

TCGA Nature 2012; N=403Groups based on Protein Expression

TCGA Nature 2012

• Among the different subtypes, the HER2-E is characterized by the highest expression of HER2/EGFR proteins and phospho(p)-HER2/p-EGFR.

• Thus, HER2+/HER2-E disease is likely to have the highest activation of the HER2/EGFR pathway.

Intrinsic subtypes: HER2-enriched by PAM50

TCGA Nature 2012

Protein Expression

Adapted from A Prat SABCS 2016

0%

20%

40%

60%

80%

100%

NeoALTTO (n=254)Fumagalli et al. JAMA Oncol 2016

HER2 enriched subtype has highest rate of pCR in HER2+ cancers treated with neoadjuvant anti-

HER2-based chemotherapy

pC

Rra

tein

th

eb

reas

t

0%

20%

40%

60%

80%

100%

CALGB40601 (n=262)Carey et al. J Clin Oncol 2016

pC

Rra

tein

th

eb

reas

t

59.4% HER2-E vs. 29.3% Others; p<0.00159.4% HER2-E vs. 36.8% Basal-like; p=0.011

Adapted from A Prat SABCS 2016

Intrinsic subtype does not predict trastuzumab benefit in

NSABP-B31

Pogue-Geile et al. JCO 33:1340 2015

HER2 Enriched Luminal ABasel Luminal B

Intrinsic subtype does not predict trastuzumab benefit in

NCCTG-N31

Pogue-Geile et al. JCO 33:1340 2015

HER2 Enriched Luminal A/B Basel

trastuzumab trastuzumab

trastuzumabNo trastuzumab No trastuzumab

No trastuzumab

Immune activation as a biomarker?

Tumor-infiltrating Lymphocytes are associated with pCR in cancers treated with HER2-directed therapy

NeoALTTO (n=387)Salgado et al. JAMA Oncol 2015

NeoSphere (n=243)Bianchini et al. Annals Oncol 2015

pC

Rra

te

Adapted from A Prat SABCS 2016

Activity of 5 immune

signatures tested:

• B-cell

• T-cell

• CD8 T-cell

• IgG

• “HER2+ immune cell”

All significantly

associated with pCR

Carey et al, ASCO 2014

61%

66%62%

50%

39%

53%

39%

17%

31%

40%

24% 25%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Overall THL TH TL

IgG SignatureHigh (n=109)

Int (n=76)

Low (n=80)P<0.001

CALGB 40601: Immune cell signatures are associated with pCR after treatment with HER2-directed

therapy

Loi et al, ASCO 2012

Tumor infiltrating lymphocytes predict trastuzumab benefit

in the FinHER trial

Lymphocyte Predominant Breast Cancer Phenotype (LPBC)

>50% infiltration

Years from Randomization0 2 4 6 8 100 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

% R

FS Chemo

Chemo+trastuzumab

Chemo

LPBC (N=94) non-LPBC (N=851)

Log Rank <0.0001Log Rank = 0.22

NCCTG-N31: No benefit of trastuzumab seen in lymphocyte predominant (LPBC) cancers (≥60% TILS)

Perez et al, SABCS 2014 Abstract S1-06

Chemo+trastuzumab

Immune signature predicts benefit of adjuvant trastuzumab in N9831

Not immune signature enriched Immune signature enriched

Perez E et al. JCO 2015. 33:701

Interaction term P < .001

Immune signature predicts benefit of the addition of lapatinib

San Antonio Breast Cancer Symposium, December 5-9, 2017

This presentation is the intellectual property of the author/presenter. Contact him at ikrop@partners.org for permission to reprint and/or distribute.

IgG Low IgG High

Krop et al SABCS 2017

Summary

• Predictive biomarkers to allow tailoring HER2-directed therapy to the appropriate patients are needed

• Multiple biomarkers are associated with rates of pCR in HER2+ cancers treated with HER2-directed therapy– HER2 levels (mRNA, FISH, protein); Higher pCR

– PI3-kinase (PIK3CA) mutation; Lower pCR

– ER positivity; Lower pCR

– HER2 enriched subtype; Higher pCR

• However, none of these biomarkers predict benefit of trastuzumab in adjuvant setting

60

What explains the difference in biomarker effects between the adjuvant and neoadjuvant settings?

• In most cases, all patients in neoadjuvant trials received at least one HER2-directed agent

– Thus generally evaluating prognostic effects of marker, not predictive effect

61

What explains the difference in biomarker effects between the adjuvant and neoadjuvant settings?

• Concurrent endocrine therapy in adjuvant setting

• Treatment effects on micrometastatic disease may differ from that of the primary cancer

– Different tumor microenvironment

• Immunomodulatory effects may differ in location and timeframe

62

Summary (2)

• Markers of immune activation (TILS and immune signatures) are associated with higher rates of pCR

• These immune markers also are associated with increased benefit from trastuzumab– Perez data from N9831 is exception

• If further validated, immune activation markers could identify patients who are candidates for de-escalation approaches.

63

Thank You