Malattia HER2 positiva

(1)

Novità e sequenze

terapeutiche nel carcinoma mammario HER2 positivo

Terapia neoadiuvante

Claudio Zamagni

Direttore SSD Oncologia Medica Addarii Policlinico S.Orsola-Malpighi

Bologna

(2)

Claudio Zamagni Pisa 30 settembre 2017

Anthra/taxane vs taxane alone Dual blockade vs single

Long vs short pCR vs no pCR ER+ vs ER-

Open questions in HER2+ eBC

(3)

pCR as a surrogate endpoint

Open questions in HER2+ eBC

(4)

Cortazar P et al, Lancet 2014

(5)

NSABP B-41 RFI by Breast pCR and Hormone Receptor Status

Presented By Andre Robidoux at 2016 ASCO Annual Meeting

(6)

Claudio Zamagni Pisa 30 settembre 2017 Cortazar P et al, Lancet 2014

(7)

De-escalating treatment

Open questions in HER2+ eBC

(8)

3-y failure rate 1.3% (95% CI 0.2-2.4)

Sequential Poisson test p<0.001

3-year DFS 98.7% (95% CI 97.6-99.8)

APT Trial

Disease-Free Survival

Tolaney SM et al NEJM 2015 Median follow-up 4.0 y (max 6.2 y)

(9)

ADAPT HER2+/HR+

Neoadjuvant Phase 2 Trial

*Standard chemo recommended after surgery

Trastuzumab to be completed, for total of one year

(10)

Claudio Zamagni Pisa 30 settembre 2017 Harbeck N et al J Clin Oncol 2017

pCR superior in TDM1 arms

(11)

0 10 20 30 40 50

TBCRC 006⁴ TBCRC 023⁵

12 wks 24 wks

NeoSphere¹ ADAPT³ PerELISA⁶

* Breast pCR

pCR rate (breast and axilla)

*

1. Gianni L, et al. Lancet Oncol 2012; 2. Hurvitz s, et al. ASCO 2016; 3. Harbeck N, et al. ASCO 2015; 4. Rimawi M, et al. J Clin Oncol 3013; 5. Rimawi M, et al. SABCS 2014; 6. Guarneri V, personal communication

Neoadjuvant chemo-free regimens in HER2+ BC

60

Kristine²

T+P

T-DM1+P

HT+T

T-DM1

T-DM1+HT

T + L + HT T+P+HT HER2+/ER- HER2+/ER+

(12)

The unmet need for HER2+ eBC

is treatment tailoring

Open questions in HER2+ eBC

(13)

NeoSphere

Gianni L, et al. Lancet Oncol 2012; 13:25–32

S U R G E R Y

Study dosing: q3w x 4 THP (n=107)

docetaxel (75100 mg/m²) trastuzumab (86 mg/kg) pertuzumab (840420 mg)

HP (n=107)

trastuzumab (86 mg/kg) pertuzumab (840420 mg) TP (n=96)

docetaxel (75100 mg/m²) pertuzumab (840420 mg) TH (n=107)

docetaxel (75100 mg/m²) trastuzumab (86 mg/kg)

HER2 Tumour Heterogeneity

(14)

NeoSphere: Study

design and main results

S U R G E R Y

HP (n=107)

TH THP HP TP

50 40 30 20 10 0

pCR, % 95% CI

29

46

17

24

HER2 Tumour Heterogeneity

(15)

NeoSphere: Study

design and main results

S U R G E R Y

HP (n=107)

TH THP HP TP

50 40 30 20 10 0

pCR, % 95% CI

29

46

17

24

0 10 20 30 40 50 60 70

TH THP HP TP

ER- or PR-positive ER- and PR-negative

20 26

17 37

29 30

63

6

pCR, % 95% CI

As in all other neoadjuvant trials, probability of pCR is significantly

higher for hormone receptor- negative tumours

HER2 Tumour Heterogeneity

(16)

HER2+ eBC is a heterogeneous disease

Intrinsic subtypes in CALGB 40601

Carey LA, et al., J Clin Oncol 2016; 34:542–549.

Pre-therapy tumours

Hormone receptor-positive

Hormone receptor-negative

(17)

HER2+ eBC is a heterogeneous disease:

Subtypes have different pCR rates with neoadjuvant therapy

(18)

Intrinsic sub-types in CALGB 40601 are different after neoadjuvant therapy

HER2 enriched

Luminal A Luminal B

Basal like

Claudin low Normal-like

Pre-Treatment

HER2-E

Lum A Lum B

Basal-like Claudin low

Normal Like

Residual Disease

(19)

Less than 20% concordance between intrinsic

sub-types of primary biopsy and residual disease

Post-treatment

pre-treat HER2-E Lum A Lum B Basal-like Claudin low Normal-like

HER2-E 3 20 0 0 1 0

Lum A 6 1 12 0 0 0

Lum B 0 0 3 0 0 0

Basal-like 0 0 0 3 0 0

Claudin low 0 0 2 0 1 0

Normal-like 3 7 9 1 1 2

NA 13 22 25 5 0 1

(20)

Intrinsic sub-types in residual disease after neoadjuvant therapy – the CALGB 40601 data

Post-treatment

pre-treat HER2-E Lum A Lum B Basal-like Claudin low Normal-like

HER2-E 3 20 0 0 1 0

Lum A 6 1 12 0 0 0

Lum B 0 0 3 0 0 0

Basal-like 0 0 0 3 0 0

Claudin low 0 0 2 0 1 0

Normal-like 3 7 9 1 1 2

NA 13 22 25 5 0 1

Most residual tumours

are made up of luminal subtypes

(21)

Residual disease after neoadjuvant therapy

= micrometastasis

Primary tumour bulk

Drug(s) Surgery

Micrometastasis

Recurrence

Residual disease

(22)

A different way to test treatment according to pCR vs not

S U R G E R Y

pCR

RD

R

control

standard adjuvant HER2-therapy

HER2-directed neoadjuvant

as in the main design

standard adjuvant HER2-therapy experimental treatment

(23)

Slide 19

(24)

New therapies

Open questions in HER2+ eBC

(25)

Murine models show CDK4/6 implicated in anti-HER2 therapy resistance

• Following anti-HER2 therapy,

survival of resistant HER2+ model tumours was dependent on

expression of cyclin D1

• CDK4/6 inhibitors resensitised tumours to HER2-targeted agents

• Anti-HER2 therapy + CDK4/6 inhibition reduced tumour proliferation more than either therapy alone

Goel S, et al. Cancer Cell. 2016; 29;255–269

(26)

• Convergence at cyclin D to drive BC cell proliferation¹

– Nuclear hormone, PI3K/AKT/mTOR, MAPK, Wnt/β-catenin, JAK- STAT, and NF-κB pathways^1,2

• Mitogenic signals via ER and HER2 require Cyclin D1

– Cyclin D1 direct ER-target gene required for estrogen-dependent cell proliferation^4,5

– Cyclin D1-deficient mice are resistant to HER2-induced BCs⁶ – ER+/HER2+ cell lines are most sensitive to CDK4/6 inhibition⁷

• Cyclin D–CDK4/6–INK4–Rb pathway also disrupted in breast cancer through:

– CCND1 (cyclin D1) amplification – 35%³ – CDK4 amplification – 16%³

– CDK6 amplification – 17%³ – Loss of p16 – 49%⁸

– Inactivating alterations of TP53 (p21 activator) – 84% of basal and 27% of non-basal tumours³

• Cyclin D–CDK4/6–INK4–Rb pathway activation is associated with poor response of BC cells to endocrine therapy⁹

Convergence of multiple signals on Rb checkpoint in breast cancer

1. Lange CA, et al. Endocrine-related Cancer 2011;18:C18–C24; 2. Witzel II, et al. Biochem Soc Trans 2010;38:217–222; 3. TCGA, Nature 2012;490:61–70;

4. Lukas J, et al. Mol Cell Biol 1996;16:6917–6925; 5. Prall OW, et al. J Steroid Biochem Mol Biol 1998;65:169-74; 6. Yu Q, et al. Nature 2001;411:1017–1021;

7. Finn RS, et al. Breast Cancer Res 2009;11:R77; 8. Geradts J, Wilson PA. Am J Pathol 1996:149:15–20; 9. Thangavel C, et al. Endocr Relat Cancer 2011;18:333–345.

(27)

MonarcHER: Phase Ib study of abemaciclib in

combination with therapies for patients with mBC

HR, hormone receptor; mBC, metastatic breast cancer

Part A: abemaciclib + letrozole Part B: abemaciclib + anastrozole

Part C: abemaciclib + tamoxifen Part D: abemaciclib + exemestane Part E: abemaciclib + exemestane + everolimus HR+/HER2- mBC

Part F: abemaciclib + trastuzumab HER2+ mBC

Key eligibility criteria:

• HR+/HER2- mBC (Parts A-E) or HER2+ (both HR+ and HR-) mBC (Part F)

• Post-menopausal status (natural, surgical, or medical; Parts A-E) or any menopausal status (Part F)

• Parts A-E: no prior systemic chemotherapy for metastatic disease Part F: ≥1 chemotherapy regimen for metastatic disease

• Patients receiving exemestane-based therapy must have received ≥1 nonsteroidal aromatase inhibitor for metastatic disease

Objectives:

•The primary objective was to evaluate safety and tolerability of abemaciclib in combination with endocrine therapies for HR+ HER2- mBC or

trastuzumab for HER2+ mBC

•The secondary objectives were to assess pharmacokinetics and anti- tumour activity

(28)

MonarcHER: anti-tumour activity

Beeram M, et al. ESMO 2016; abstract LBA18

Change in tumour size for patients with measurable disease

HER2+ mBC

Abemaciclib combinations show clinical activity in HR+

mBC, including HR+/HER2+

tumours

(29)

NA-PHER2: Phase II trial of neo-adjuvant treatment with palbociclib in HR+/HER2+

eBC

ORR, objective response rate; pCR, pathological complete response defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery

Patients with early and locally advanced HER2+

and ER+ (>10%) BC; chemo-naïve

HPPF x 6 4-weekly cycles Herceptin + pertuzumab +

palbociclib + fulvestrant

H = Trastuzumab, 8 mg/kg on first dose, 6 mg/kg thereafter x 6;

P = Pertuzumab, 840 mg on first dose, 420 mg thereafter x 6;

Palbociclib 125 mg orally QD. x 21 q. 4 wks. x 5

Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with an additional 500 mg dose given two weeks after the initial dose

The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and fulvestrant (5 administrations every 4 weeks plus the additional dose given two weeks after the initial dose) was selected to match as closely as possible the total duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab

*HER-2, ER, PR and Ki67 centrally confirmed

Primary endpoints

• Ki67 changes

frombaseline before therapy, at 2 weeks, and at surgery

• Change in apoptosis from baseline before therapy and at

surgery

Secondary endpoints

• pCR

• ORR

• Tolerability

Palbociclib is not approved for use in HER2+ disease in Europe

(30)

-45 -35 -25 -15 -5

Reduction of % Ki67+ cells

NA-PHER2: Ki67 levels decreased following treatment

Gianni L, et al. SABCS 2016; Poster P4-21-39

Ki67 change

Baseline (n=27)

Week 2 (n=25)

Surgery (n=22) Geometric

mean (SD) 31.9 (15.7) 4.3 (15.0) 12.1 (20.0) Mean change

95% CI – –24.0

(–31.0; –7.1)

–10.9 (–19.3; –2.6) Paired T-test

P-value – –7.11

< 0.0001

–2.72 0.013

0 10 20 30 40 50 60 70 80

% Ki67+ cells

(31)

NA-PHER2: Pathological and clinical response rate

Gianni L, et al. SABCS 2016; Poster P4-21-39

ITT population (n=30) n (%)

pCR (no invasive cells in breast and axilla) pCR in breast only

8 (27%) 9 (30%) Overall clinical response

• Complete clinical response

• Partial response

• Stable disease

29 (97%) 15 (50%) 14 (47%)

3 (3%)

(32)

HER2+ BC is immunogenic

(33)

FcγR–mediated Antigen Presentation and CTL Response

Andre F et al. Clinical Cancer Res 2012 FcɣR

(34)

Differential Fc-receptor engagement drives an anti-tumour vaccinal effect

David JD & Jeffrey RV. Cell 2015; 161:1035–1045.

(35)

Must the tumour be present for an optimal “vaccine-like” effect?

Kroemer G. Annu Rev Immunol 2013

(36)

Trastuzumab IV (8 mg/kg loading dose, followed by 6 mg/kg) plus

Pertuzumab IV (840 mg loading dose, followed by 420 mg) plus

Docetaxel IV (75→100 mg/m²), every 3 weeks for 4 cycles

Eligibility (n = 63) Women with

histologically confirmed HER2-positive breast cancer with locally

advanced, inflammatory, or early stage tumor

(either greater than 2 cm in diameter or node positive) with no

evidence of metastatic disease

Randomized Phase II Biomarker Study of Immune-mediated Mechanism of Action of Neoadjuvant Trastuzumab (either iv or sc) in Patients with HER2-

positive Breast Cancer (ImmunHER)

R

Pre-randomization phase:

FEC (5FU 500; epirubicin 75;

CTX 500) x 3 cycles

Trastuzumab SC

(fixed dose of 600 mg) plus

Pertuzumab IV (840 mg loading dose, followed by 420 mg) plus

Docetaxel IV (75→100 mg/m²), every 3 weeks for 4 cycles

Primary endpoint:

TIL rate on residual disease after either IV trastuzumab or SC trastuzumab

Primary Objective:

To evaluate variations of host immune response

parameters to either trastuzumab SC or trastuzumab IV given in combination with pertuzumab and

chemotherapy.st cancer.

ClinicalTrials.gov Identifier: NCT03144947

(37)

Interaction of pCR with treatment for EFS in HER2+ groups

Stratum Sample size EFS HR (95% CI) p

pCR 45 vs. 23 0.29 (0.11 – 0.78) 0.0135

non pCR 72 vs. 95 0.92 (0.61 – 1.39) NS

Stratum Sample size EFS HR (95% CI) p

Trastuzumab 45 vs. 72 0.17 (0.08 – 0.38) <.0001

no Trastuzumab 23 vs. 95 0.57 (0.29 – 1.13) NS

p-value for interaction

treatment*pCR effect = 0.037

• pCR vs. non pCR

• Trastuzumab vs. no Trastuzumab

quality of pCR different with ADCC competent

monoclonal antibodies

(38)

Neoadjuvant is more effective than adjuvant therapy with anti-PD-1+anti-CD137

Liu J Cancer Discovery 2016 NeoAdj -PD-1/ -CD137

or control IgG Surgery 4T1.2 orthotopic

injection

Day: 0 17 19 21 23

Surgery

Adj -PD-1/ -CD137 or control IgG

NeoAdj -PD-1/ -CD137 or control IgG

Surgery E0771 orthotopic

injection

Day: 0 16 18 20 22

Surgery

Adj -PD-1/ -CD137 or control IgG

100

50

0

0 50 100 150

Days after 4T1.2 tumour injection

Percent survival

NeoAdj control IgG

-PD-1/-CD137 – no surgery Adj control IgG

p<0.0001 NeoAdj -PD-1/ -CD137

Adj -PD-1/ -CD137

100

50

0

0 50 100 150 200

Days after E0771 tumour injection

Percent survival

NeoAdj control IgG Adj control IgG

p<0.0001 NeoAdj -PD-1/ -CD137

Adj -PD-1/ -CD137

(39)

Neoadjuvant anti-PD-1+anti-CD137 leads to

systemic expansion of tumor-specific CD8+ T cells

Liu J Cancer Discovery 2016

200

0 150

100

50

# gp70 Tetramer CD8 T cells/ml (x102)

Blood

p<0.0001

250

0 150 100 50 200

# gp70 Tetramer CD8 T cells (x102)

Liver

p = 0.0012

(40)

Tumour-free survivors after neoadjuvant

immunotherapy have immunological memory

Neoadjuvant modality is superior to adjuvant delivery of immunotherapy in model systems and may be the optimal approach to achieve

“vaccine-like” effects and permanent tumour eradication

Tumour-free survivors

Naive mice 150

0 100

50

Mean tumour size (mm2 )

0 10 20 30

Days after 4T1.2 tumour injection

Naive mice

Tumour-free survivors p = 0.0079

Liu J Cancer Discovery 2016

(41)

• There is evidence of anti-tumour immune response in HER2+ BC

• Preclinical synergistic activity is observed for checkpoint inhibitors combined with anti-HER2 therapies

Rationale exists for atezolizumab combinations in HER2+ BC

Immune biomarkers at baseline have similarities to

TNBC

Immune (Teff) signature PD-L1 expression TILs and CD8 prevalence

TILs are associated with better outcomes for HER2

regimens

pCR and DFS (EBC), OS (CLEO MBC)

Immune effects of HER2 therapies are observed Neoadjuvant H/K increases PD-L1 and CD8+ TILS that are associated

with higher pCR (ADAPT HR+)

* αPD-1

** αPD-L1

Internal preclinical data

• K(A) consistent with published data

• A with (T)HP pending

APTneo phase III trial

(42)

pCR predittiva di prognosi

(fino al 73% di pCR in ER- HER2+)

Malattia HER2 positiva

Novità e sequenze

terapeutiche nel carcinoma mammario HER2 positivo

Terapia neoadiuvante

Anthra/taxane vs taxane alone Dual blockade vs single

Long vs short pCR vs no pCR ER+ vs ER-

Open questions in HER2+ eBC

pCR as a surrogate endpoint

Open questions in HER2+ eBC

De-escalating treatment

Open questions in HER2+ eBC

APT Trial

Disease-Free Survival

ADAPT HER2+/HR+

Neoadjuvant Phase 2 Trial

pCR superior in TDM1 arms

Neoadjuvant chemo-free regimens in HER2+ BC

The unmet need for HER2+ eBC

is treatment tailoring

Open questions in HER2+ eBC

NeoSphere

HER2 Tumour Heterogeneity

NeoSphere: Study

design and main results

HER2 Tumour Heterogeneity

NeoSphere: Study

design and main results

HER2 Tumour Heterogeneity

HER2+ eBC is a heterogeneous disease

HER2+ eBC is a heterogeneous disease:

Intrinsic sub-types in CALGB 40601 are different after neoadjuvant therapy

Less than 20% concordance between intrinsic

sub-types of primary biopsy and residual disease

Intrinsic sub-types in residual disease after neoadjuvant therapy – the CALGB 40601 data

Most residual tumours

are made up of luminal subtypes

Residual disease after neoadjuvant therapy

= micrometastasis

Drug(s) Surgery

A different way to test treatment according to pCR vs not

New therapies

Open questions in HER2+ eBC

Murine models show CDK4/6 implicated in anti-HER2 therapy resistance

Convergence of multiple signals on Rb checkpoint in breast cancer

MonarcHER: Phase Ib study of abemaciclib in

combination with therapies for patients with mBC

MonarcHER: anti-tumour activity

NA-PHER2: Phase II trial of neo-adjuvant treatment with palbociclib in HR+/HER2+

eBC

NA-PHER2: Ki67 levels decreased following treatment

NA-PHER2: Pathological and clinical response rate

pCR (no invasive cells in breast and axilla) pCR in breast only

8 (27%) 9 (30%) Overall clinical response

• Complete clinical response

• Partial response

• Stable disease

29 (97%) 15 (50%) 14 (47%)

3 (3%)

HER2+ BC is immunogenic

FcγR–mediated Antigen Presentation and CTL Response

Differential Fc-receptor engagement drives an anti-tumour vaccinal effect

Must the tumour be present for an optimal “vaccine-like” effect?

R

Interaction of pCR with treatment for EFS in HER2+ groups

quality of pCR different with ADCC competent

monoclonal antibodies

Neoadjuvant is more effective than adjuvant therapy with anti-PD-1+anti-CD137

Neoadjuvant anti-PD-1+anti-CD137 leads to

systemic expansion of tumor-specific CD8+ T cells

Tumour-free survivors after neoadjuvant

immunotherapy have immunological memory

Rationale exists for atezolizumab combinations in HER2+ BC

pCR predittiva di prognosi

Neoadiuvante fondamentale per selezionare pazienti a prognosi peggiore (no pCR) per nuovi studi

Trattamento di scelta nei T2-3 e/o N+, ma proponibile anche in stadio 1

Lo standard*: CHT + trastuzumab + pertuzumab

In attesa di CDK4-6i e anti PD1 – PDL1i

Terapia neoadiuvante tumori HER2+

Take Home message

**Lo standard*: CHT + trastuzumab + pertuzumab**