Malattia HER2 positiva

(1)

Claudio Zamagni Pisa 19 settembre 2019

Novità e sequenze

terapeutiche nel carcinoma mammario

Terapia neoadiuvante Malattia HER2 positiva

Claudio Zamagni

Direttore SSD Oncologia Medica Addarii Policlinico S.Orsola-Malpighi

Bologna

(2)

(3)

Efficacy in NSABP B-18 and B-27 after a longer follow-up

Rastogi P et al, JCO 2008

(4)

(5)

Lo standard: CHT + trastuzumab + pertuzumab

La modulazione del trattamento in funzione della risposta patologica comincia ad entrare nella

pratica clinica

Persiste la necessità di migliorare la selezione delle Pazienti (TILs, PI3K,…)

L’immunoterapia neoadiuvante è in fase III di sperimentazione anche nella malattia HER2+

Terapia neoadiuvante tumori HER2+

Take Home messages 2018

(6)

(7)

At presentation cT1-4 cN0-3

Excluding cT1a-b N0

At surgery

Invasive disease in breast and/or axilla

(no gross residual after mastectomy or positive margins after BCS)

HER2 +ve centrally confirmed (diagnostic biopsy or surgical specimen)

At least 6 courses of NACT

Including at least 9 w of taxane-based and 9 w of trastuzumab Additional HER2-targeted agents allowed

KATHERINE Eligibility Criteria

von Minckwitz G et al NEJM 2019

(8)

Claudio Zamagni Pisa 19 settembre 2019 Slide 19

≤ 12 wks after surgery

(9)

von Minckwitz G et al NEJM 2019

(10)

von Minckwitz G et al NEJM 2019

(11)

Primary Endpoint iDFS

von Minckwitz G et al NEJM 2019

(12)

Subgroup Analysis of iDFS

HR

HER2 agents

single/combo

ypN ypT

von Minckwitz G et al NEJM 2019

(13)

Distant DFS OS

Secondary Endpoint iDFS

von Minckwitz G et al NEJM 2019

(14)

TDM1 nuovo standard* nelle pazienti HER2+

con residuo post-neoadiuvante

(Programma di uso compassionevole approvato ieri da AIFA)

Implicazioni dello studio Katherine

La terapia neoadiuvante è lo standard nella malattia HER2 positiva

(escluso pT1a-b….forse)

(15)

Tutta la chemioterapia neoadiuvante prima dell’intervento

Implicazioni dello studio Katherine

- EC/AC taxani?

- Platino/taxani?

- Solo taxani?

(16)

NeoSphere: Study

design and main results

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/m

²

) 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/m

²

) pertuzumab (840→420 mg) TH (n=107)

docetaxel (75→100 mg/m

²

) trastuzumab (8→6 mg/kg)

TH THP HP TP

50 40 30 20 10 0

pC R, %  9 5 % CI

29

46

17

24 CHT + trastuzumab + pertuzumab

(17)

FE ₉₀ C x 3 Cb AUC6 q3w (or AUC 3 d1-8) + Pac80 d1-8 x 6

Cb AUC6 q3w (or AUC 3 d1-8) + Pac80 d1-8 x 9

Trastuzumab + Pertuzumab at standard doses q 3w x 9 in both arms

Stage II-III HER2+

Surgery within 6 weeks

R

(18)

TRAIN-2 Trial: pCR (ypT0/is ypN0) according to treatment and ER-PR status

van Ramshorst MS et al Lancet Oncol 2018

(19)

Disease-Free Survival

Tolaney SM et al ASCO 2018

APT trial

(wPaclitaxel x 12 + trastuzumab x 1y)

(20)

The unmet need for HER2+ eBC

is still treatment tailoring

Open questions in HER2+ eBC

(21)

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

(22)

Less than 20% concordance between intrinsic

sub-types of primary biopsy and residual disease

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

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

(23)

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

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

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

(24)

Total pCR (ypT0/is ypN0) by core biopsy

intrinsic subtype (PAM50) and by treatment in NSABP B-41

Swain S et al Breast Cancer Res Treat 2019 HER2+ eBC is a heterogeneous disease:

Subtypes have different pCR rates

with neoadjuvant therapy

(25)

Caswell-Jin JL et al Nature Communications, 2019

(26)

Can we avoid chemotherapy in HER2+ ER+ eBC?

Open questions in HER2+ eBC

(27)

• Convergence at cyclin D to drive BC cell proliferation

¹

– 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 BCs

⁶

– ER+/HER2+ cell lines are most sensitive to CDK4/6 inhibition

⁷

• 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 tumours

³

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

⁹

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.

(28)

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

(29)

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

Gianni L, et al. SABCS 2016; Poster P4-21-39 e Lancet Oncol 2018

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 from baseline 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)

Gianni L, et al. Lancet Oncol 2018

NA-PHER2 Change In Ki67 Expression From Baseline

(31)

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 pC R, %  9 5 % CI

Gianni L, et al. Lancet Oncol 2018

NA-PHER2 Clinical And Pathological Response

(32)

Trastuzumab + Pertuzumab

0 10 20 30 40 50

TBCRC 006

⁴

TBCRC 023

⁵

12 wks 24 wks

NA-PHER2

¹

PerELISA

²

PAMELA

³

% pCR

*

1. Gianni L, et al. Lancet Oncol 2018; 2. Guarneri V, et al ASCO 2018 3. Llombart-Cusac A, et al Lancet Oncol 2017; 4. Rimawi M, et al. J Clin Oncol 2013; 5. Rimawi M, et al. SABCS 2014;

Neoadjuvant chemo-free regimens in HER2+ ER+ BC pCR rates (ypT0/Tis ypN0, ^except * ^yPT0/is )

60 Trastuzumab + Lapatinib

Fulvestrant + Palbociclib

Letrozole

(molecular selection under ET)

Letrozole or Tamoxifen

Letrozole Letrozole

18 wks 14 wks 18 wks 12 wks

(33)

Harbeck N et al J Clin Oncol 2017

ADAPT HER2+ HR+ trial

pCR (ypT0/Tis ypN0) superior in TDM1 arms

(34)

Can we de-escalate surgery in HER2+ ER+ eBC?

Open questions in HER2+ eBC

(35)

3062 HER2+ pts cT1-2 cN0 → NACT → breast pCR pN0 98.4% ¹

Previous similar small MDACC experience pN0 100%

²

1

Barron A et al JAMA Surg 2018

2

Tadros AB et al JAMA Surg 2017

(36)

(37)

Can we de-escalate surgery in HER2+ ER+ eBC?

Work in progress….

Open questions in HER2+ eBC

(38)

La terapia neoadiuvante è il nuovo standard di trattamento per (quasi) tutte le Pazienti con carcinoma mammario

HER2+

CHT (con o senza antra) + trastuzumab + pertuzumab Strategie di de-escalation (- chemio, - chirurgia) sono all’orizzonte (studi clinici)

Persiste la necessità di migliorare la selezione delle Pazienti (TILs, PI3K,…)

L’immunoterapia neoadiuvante è in fase III di sperimentazione anche nella malattia HER2+

Terapia neoadiuvante tumori HER2+

Take Home messages 2019

(39)

(40)

(41)

(42)

NeoSphere: Study

design and main results

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/m

²

) 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/m

²

) pertuzumab (840→420 mg) TH (n=107)

docetaxel (75→100 mg/m

²

) trastuzumab (8→6 mg/kg)

TH THP HP TP

50 40 30 20 10 0

pC R, %  9 5 % 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 pC R, %  9 5 % CI

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

higher for hormone receptor-

negative tumours

(43)

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

pCR – driven escalation/de-escalation

(44)

PerElisa Study plan

Presented By Valentina Guarneri at 2018 ASCO Annual Meeting

(45)

Outcomes: molecular responders

N=44

(46)

PAM50 and pCR: molecular responders

(47)

MonarcHER: Phase Ib study of abemaciclib in

combination with therapies for patients with mBC

HR, hormone receptor; mBC, metastatic breast cancer

Beeram M, et al. ESMO 2016; abstract LBA18

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

(48)

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

(49)

Gianni L, et al. Lancet Oncol 2018

NA-PHER2 Adverse Events

(50)

Harbeck N et al J Clin Oncol 2017

ADAPT HER2+/HR+

Neoadjuvant Phase 2 Trial

*Standard chemo recommended after surgery

Trastuzumab to be completed, for total of one year

(51)

Nitz UA et al Ann Oncol 2017

ADAPT HER2+ HR- trial Pathological Response

Clinical Stage at Baseline T+P

N 92

T+P+ Pac N 42

cT1 (%) 41.3 40.5

cT2 (%) 51.1 52.4

cN0 (%) 54.4 61.9

(52)

HER2+ BC is immunogenic

(53)

Overall Survival and TILs pCR and TILs

Denkert C et al Lancet Oncol 2018

(54)

FcγR–mediated Antigen Presentation and CTL Response

Andre F et al. Clinical Cancer Res 2012

FcɣR

(55)

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

treatmentpCR effect =* 0.037

• pCR vs. non pCR

• Trastuzumab vs. no Trastuzumab

Gianni L et al, Lancet Oncol 2014

quality of pCR different with ADCC competent

monoclonal antibodies

(56)

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 M e a n tu mour s ize (mm

2

)

0 10 20 30

Days after 4T1.2 tumour injection

Naive mice

Tumour-free survivors p = 0.0079

Liu J Cancer Discovery 2016

(57)

• 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

Courtesy L. Gianni

(58)

APTneo: Phase III randomised study to test the benefit of adding atezolizumab to trastuzumab, pertuzumab and CT

L. Gianni for the Michelangelo Foundation, December 2016 A, doxorubicin, 60 mg/m

²

q 21 days; Cy, cyclophosphamide, 600 mg/m

²

q 21 days; C, carboplatin, AUC 2 d1&8 q 21 days; T, taxol, 90 mg/m

²

d1&8 q 21 days; H, trastuzumab, 8 mg/kg on first dose, 6 mg/kg thereafter; P, pertuzumab, 840 mg on first dose, 420 mg thereafter; atezolizumab, 1200 mg i.v. infusion q 3 wks, S, surgery; CBx, core biopsy; SN, sentinel node

ACy x 3 ➔ HPCT x 3 + atezolizumab Patients with S

operable or locally

advanced BC, HER2- positive

Chemo-naïve HPCT +

atezolizumab x 6 S

CBx SN Blood

CBx

Blood

Surgical Bx & SN

Blood Blood Blood

Before therapy Day 21 At surgery

HP + atezolizumab until 18 ^th q3 weeks dose 6 months End of therapy HPCT x 6

S

HP until 18 ^th q 3- weeks dose

HP + atezolizumab until 18 ^th q3 weeks dose

1° Pt enrolled July 30, 2018

(59)

(60)

KRISTINE Trial Pathological Complete Response

Overall (A) and by Hormone Receptor Status (B and C)

Hurvitz SA et al Lancet Oncol 2018

(61)

(62)

Malattia HER2 positiva

Novità e sequenze

terapeutiche nel carcinoma mammario

Terapia neoadiuvante Malattia HER2 positiva

Claudio Zamagni

Direttore SSD Oncologia Medica Addarii Policlinico S.Orsola-Malpighi

Bologna

Efficacy in NSABP B-18 and B-27 after a longer follow-up

Rastogi P et al, JCO 2008

Lo standard: CHT + trastuzumab + pertuzumab

La modulazione del trattamento in funzione della risposta patologica comincia ad entrare nella

pratica clinica

Persiste la necessità di migliorare la selezione delle Pazienti (TILs, PI3K,…)

L’immunoterapia neoadiuvante è in fase III di sperimentazione anche nella malattia HER2+

Terapia neoadiuvante tumori HER2+

Take Home messages 2018

At presentation cT1-4 cN0-3

Excluding cT1a-b N0

At surgery

Invasive disease in breast and/or axilla

(no gross residual after mastectomy or positive margins after BCS)

HER2 +ve centrally confirmed (diagnostic biopsy or surgical specimen)

At least 6 courses of NACT

Including at least 9 w of taxane-based and 9 w of trastuzumab Additional HER2-targeted agents allowed

KATHERINE Eligibility Criteria

von Minckwitz G et al NEJM 2019

≤ 12 wks after surgery

von Minckwitz G et al NEJM 2019

von Minckwitz G et al NEJM 2019

Primary Endpoint iDFS

von Minckwitz G et al NEJM 2019

Subgroup Analysis of iDFS

HR

HER2 agents

ypN ypT

von Minckwitz G et al NEJM 2019

Distant DFS OS

Secondary Endpoint iDFS

von Minckwitz G et al NEJM 2019

TDM1 nuovo standard* nelle pazienti HER2+

con residuo post-neoadiuvante

(Programma di uso compassionevole approvato ieri da AIFA)

Implicazioni dello studio Katherine

La terapia neoadiuvante è lo standard nella malattia HER2 positiva

(escluso pT1a-b….forse)

Tutta la chemioterapia neoadiuvante prima dell’intervento

Implicazioni dello studio Katherine

- EC/AC taxani?

- Platino/taxani?

- Solo taxani?

NeoSphere: Study

design and main results

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/m

) 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/m

) pertuzumab (840→420 mg) TH (n=107)

docetaxel (75→100 mg/m

) trastuzumab (8→6 mg/kg)

TH THP HP TP

50 40 30 20 10 0

pC R, %  9 5 % CI

29

46

17

24

CHT + trastuzumab + pertuzumab

FE 90 C x 3 Cb AUC6 q3w (or AUC 3 d1-8) + Pac80 d1-8 x 6

Cb AUC6 q3w (or AUC 3 d1-8) + Pac80 d1-8 x 9

Trastuzumab + Pertuzumab at standard doses q 3w x 9 in both arms

Stage II-III HER2+

Surgery within 6 weeks

R

TRAIN-2 Trial: pCR (ypT0/is ypN0) according to treatment and ER-PR status

van Ramshorst MS et al Lancet Oncol 2018

Tolaney SM et al ASCO 2018

APT trial

FE ₉₀ C x 3 Cb AUC6 q3w (or AUC 3 d1-8) + Pac80 d1-8 x 6