The Expert Thoughts

The Expert Thoughts

Alessandra Fabi Oncologia Medica 1

My Thoughts

Neoadjuvant: from the lessons of the history Adjuvant: Escalation and De-escalation

Advanced and HER2+ : field for immunomodulation Brain metastases and outcome: what is changed?

Effect of NCT vs ACT

on recurrence and mortality

EBCTCG Lancet Oncology 2018

1998-2003

Dual Inhibition in Neoadjuvant Trials

Trial Experimental Anti-HER2

pCR with Trastuzumab

pCR with Dual inhibition

NeoSphere Pertuzumab 29% 46%

NeoALTTO Lapatinib 30% 51%

CALGB 40601 Lapatinib 40% 51%*

NSABP B41^# Lapatinib 52% 62%*

TRYPHAENA^$ Pertuzumab NA 55-64%

* Not statistically significant, # Received AC-T, $ No single anti-HER2 arm

Trial ^{Setting Anti}

HER2 therapy

Primary Endpoint

Dual therapy superior to single agents

ALTTO adj

T

T + L T ->L

DFS NO

APHINITY adj T

T + P DFS YES

(subtypes*)

Dual Inhibition in Adjuvant Trials

HR 0.81

Minimize chemotherapy Eliminate chemotherapy

De-Escalation Strategies in Oncogene Addicted

Cancers

Study ^Phase PT HER2- therapy

Endocrine therapy

Weeks

pCR pCR

ER+ pCR ER - TBCRC006 II 64 T+L Yes 12 27% 21% 36%

TBCRC023 II

33 T+L Yes 12 15% 9% 20%

61 T+L Yes 24 25% 33% 18%

PAMELA II 150 T+L Yes 18 31% 18% 43%

NeoSphere II 107 T+P No 16 17% 6% 29%

Neoadjuvant Trials of Dual targeted therapy without chemotherapy

Predictive Biomarkers

for a De-Escalation Approach

- Novel Anti-HER2 agents - Additional targets/pathways

Mechanisms of Resistance

- Dual HER2-targeted therapy with no chemo

- Blocking ER in HER2+/ER+

Challenges

Determinants of Response/Resistance to anti-HER2 therapy

1. ER

2. HER2 level (addiction)

3. PI3K pathway deregulation 4. HER2 mutations

5. Microenvironment/immune infiltrate 6. Adaptive or escape pathways: HER3,

metabolic (mevalonate), cell cycle

SA BC S 20 17

Are HER2+/ER+ the same tumors?

- We may overtreat a subgroup of ER+, HER+ BC in the (neo)-adjuv (enough anti HER2+OT??)

- This subgroup may suffer late recurrence

(similar to what we see with some HER2-/ER+

cancers)

- Can we identify this subgroup drived by ER?

🤔

SA BC S 20 17

SA BC S 20 17

intrinsic subtype differed between HR- and HR+

Wee

k 1 W 3 W 2

W 4

W 5

W 6

W 7

W 9

W 1 0

W 1 1 W

8

W 12

Biopsy Biopsy

LAPATINIB + TRASTUZUMAB +/- LETROZOLE

Biopsy

Stage II/III HER2+

Breast CA N=64

Baseline Biopsy

PTEN IHC

PIK3CA mutations

M Rimawi, JCO 2013

TBCRC 006 (HELP Study)

There was no correlation between PIK3CA mutation status, PTEN level, and ER.

pCR No pCR

Marker ^{n % n % P}

PTEN (n=59) 0.04

High (≥100) 12 32 25 68

Low (<100) 2 9 20 91

PIK3CA (n=46) 0.14

Wild type 7 28 23 72

Mutation 1 7 13 93

PTEN low or PIK3CA mutation (n=43) 0.006

No 7 39 11 61

Yes 1 4 24 96

Correlation with pCR

Neoadjuvant therapy in HER2+ EBC

LESSONS LEARNED FROM NEOADJUVANT TRIALS I. First generation

Trastuzumab + chemo > chemo alone

Trastuzumab and chemotherapy

†No evidence of residual invasive cancer, both in breast and axilla

‡No evidence of residual disease in breast tissue

pCR, pathological complete response; H, trastuzumab; T, taxane FEC, 5-fluorouracil+epirubicin+cyclophosphamide; AT,

doxorubicin+paclitaxel

CMF, cyclophosphamide+methotrexate+5-fluorouracil; EC, epirubicin+cyclophosphamide

1. Buzdar AU, et al. 2007,2. Gianni L, et al. 2010

n=45 n=19

n=117

n=118 22^‡ 26^†

43^‡

60^†

0 20 40 60

NOAH²

MD Anderson¹

pCR (%) Chemotherapy alone Trastuzumab + chemotherapy

T →FEC H+(T →FEC)

AT→T→CMF H+(AT→T→CMF)

P<0.0007 P=NR

Improved pCR rate translates into improved outcome with Trastuzumab

*EFS, Event –free survival; HR, Hazard ratio;

OS, Overall survival.

Gianni L, et al. 2014

5-year event-free survival 5-year overall survival

Dual HER2 blockade

LESSONS LEARNED FROM NEOADJUVANT TRIALS

II. Second generation

Dual HER2 blockade + chemo > single HER2 blockade + chemo

Pertuzumab and trastuzumab

Gianni L, et al. Lancet Oncol 2011

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)

T H

TH P

H P

TP 50

40 30 20 10 0

pCR, %  95% CI

2 9

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

Beyond dual blockade

LESSONS LEARNED FROM NEOADJUVANT TRIALS

III. Third generation

Identify the subset which can benefit from a chemo-sparing regimen

HER2+ /HR- disease

Dual HER2 blockade

+ taxane

62%

20 40 60 80 100

Dual HER2 blockade

alone 29%

Dual HER2 blockade

+ taxane

+

other agent (anthrac.,

carbo) 73 - 80%

% PCR rates

Based on NeoSphere, NeoAltto, Tryphaena

Who are these patients with HER2+ HR- disease

who perhaps do not need chemo ?

HER2+ /HR- disease

PIK3CA mutations/

PTEN loss

TIL’s Immune signatures

Improved tailoring

?

ADAPT study in HER2+/HR+

• International, prospective, randomized phase II trial

• Primary endpoint: pCR (no invasive carcinoma in breast/nodes)

• Secondary endpoints: dynamic testing evaluation, EFS, OS, safety

Pts with ER+ and/or PgR+, HER2+, cT1c - cT4a-c, cN,

cM0 BC and adequate organ function, LVEF ≥

50%, normal ECG (N = 375)

T-DM1 3.6 mg/kg Q3W (n = 119)

Trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W + ET*

(n = 129)

T-DM1 3.6 mg/kg Q3W + ET*

(n = 127)

1. Harbeck N, et al. SABCS 2015. Abstract S5-03.

2. Hofmann D, et al. Trials. 2013;14:261.

Surgery^† Wk 12

*Tamoxifen if premenopausal; aromatase inhibitor (of investigator’s choice) if postmenopausal.

†Standard chemotherapy (1-yr trastuzumab) recommended after surgery or 12-wk biopsy (if clinical non-pCR).

ADAPT Trial

Harbeck N, et al. SABCS 2015. Abstract S5-03.

Outcome, n/N (%) T-DM1 T-DM1 + ET Trastuzumab + ET

pCR (ypT0 or ypT0/is, ypN0)

 All pts*

 Premenopausal women

 Postmenopausal women

48/117 (41.0) 22/58 (37.9) 26/59 (44.1)

51/123 (41.5) 24/63 (38.1) 27/60 (45.0)

18/119 (15.1) 8/59 (13.6) 10/60 (16.7)

Near pCR (ypT1a) 14/117 (12.0) 14/123 (11.4) 5/119 (4.2) Early response^†

 Nonresponders

 Responders

9/36 (25.0) 24/61 (39.3)

6/25 (24.0) 36/76 (47.4)

5/40 (12.5) 11/62 (17.7)

*P < .001 for comparison between each T-DM1 arm vs trastuzumab + ET.

†Low cellularity (< 500 tumor cells) or Ki67 decline ≥ 30%in 3-wk biopsy.

Adjuvant therapy in HER2 positive EBC

Optimal Adjuvant Therapy in 2018 for the ‘average’

patient with HER2-positive

breast cancer

Long-term DFS benefit with adjuvant Trastuzumab for 1 year

HR, hazard ratio

1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007; 3. Gianni L, et al. 2011, 4. Goldhirsch A, et al 2013 5. Slamon D, et al. 2011; 6. Romond EH, et al. 2005; 7. Perez EA, et al. 2011; 8. Perez EA, et al. 2014

1 3387 0.54

2 3401 0.64

4 3401 0.76

5 0.75

0.64 3222

Study Follow-up ^HR

(years)

N

Combined analysis^6-8 (NCCTG N9831/

NSABP B-31)

ACTHH vs. ACT

2 3351 0.48

4 4045 0.52

1

0 ^Favours 2

Trastuzumab

Favours observation HR (95% CI)

BCIRG 006⁵

ACTHH vs. ACT TCH vs. ACT

HERA^1–4

CT+/-RTH vs.

CT+/-RT

8 3401 0.76

8 4046 0.60

1. Longer trastuzumab duration (Hera 2y arm 😞) 2. Adding bevacizumab to trastuzumab (Beth😞) 3. Dual HER2 blockade

- Lapatinib + trastuzumab (ALTTO🤔)

- Pertuzumab + trastuzumab (APHINITY😊) 4. T-DM1 after neoadjuvant CT + trastuzumab in case of residual disease (Katherine ?)

5. Extended neratinib (😁)

Escalation: where do we start from?

Extended Neratinib

Neratinib

240 mg orally daily for 1 year

Placebo

Orally daily for 1 year HER2+

Stage II-IIIC node positive BC

following CT + 12 months of trastuzumab (adj)

(N=2821)

DFS

DFS

CT, chemotherapy; adj, adjuvant; DFS, disease-free survival; BC, breast cancer.

Press release - Puma Biotechnology July 22nd, 2014

Extended DFS by 33% compared with placebo (HR = 0.67; P = .0046) R

Martin et al Lancet 2017

ITT

ER+

ER-

Impact of Hormonal Therapy?

HER2+/HT+ different tumors?

Katherine

Neoadjuvant CT +

trastuzumab

Residual invasive

cancer

R

T-DM1

Trastuzumab

Primary endpoint : IDFS

≈ 900/1400 patients recruited as of today

KAITLIN

35

HER2+

Node+

or Node-, ER- and T>2cm

R

AC x 4 or FEC x3

AC x 4 or FEC x3

TAXANE

TRASTUZUMAB PERTUZUMAB

T-DM1 PERTUZUMAB

IDFS

HO 89,5%

93,1%

1300/2500 women recruited…

Worrysome : taxane + trastuzumab = T-DM1 = T-DM1 + pertuzumab in the first line metastatic MARIANNE trial !

SA BC S 20 17

5 studies

SA BC S 20 17

SA BC S 20 17

SA

B C S 20 17

SA BC S 20 17

Sold

STANDARD TREATMENT:

TRASUZUMAB FOR 1 YR

1. Tumor size

2. Age

3. Response to preoperative therapy

De-Escalation treatment in HER2+:

from where?

HER2+

Node Negative

< 3 cm N=406

Enroll

T P

T P

T P

T P T P T P T P T P T

P T P

T P

T P

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

T

T T T T T T T T T T T T

FOLLOWED BY 13 EVERY 3 WEEK DOSES OF TRASTUZUMAB (6 mg/kg)

Tolaney et al, NEJM 2015

APT Trial

3-year DFS

95% Conf.

Interval

98.7% 97.6% to 99.8%

Poisson p-value:

<0.0001

Point 1

SA BC S 20 17

SA BC S 20 17

SABCS 2017

ATEMPT trial

(randomized phase II)

T-DM1 Stage I R(3:1)

Trastuzumab + Paclitaxel

Objectives: Primary DFS

Secondary Outcome Measures :DFS in Patient

Groups Defined by Tumor Size < 1cm or >/= 1 cm and HR

Percentage of participants with Grade 3-4 Cardiac Dysfunction

Recruitment ongoing from 2013

Age and adj therapy

ATOP trial (phase II)

age > 60 yrs

stage I–III HER2+

T-DM1 for 1 yr

RESPECT trial (randomized phase II)

age 69–81

Trastuzumab alone

stage I–IIIA HER2+

Trastuzumab plus chemotherapy.

Recruitment ongoing

Point 2

We consider using escalation of biologic therapy as a mechanism to de-escalate chemotherapy. If adding pertuzumab to trastuzumab-based chemotherapy is found to improve long-term outcomes in the APHINITY trial, perhaps patients may achieve similar outcomes with less chemotherapy and highly effective biologic

therapy

Question:

EC/taxane + trastuzumab and pertuzumab vs with a taxane + trastuzumab and pertuzumab

?

Point 3

Failed Succeeded

X

Trastuzumab x 2y

X

Trastuzumab + bevacizumab

X

Trastuzumab + lapatinib Trastuzumab followed by

neratinib

X

?

Trastuzumab + pertuzumab

?

?

T-DM1 after neoadj CT + trast

?

MY TOUGHTS

Escalation attempts : preliminary conclusions

Failed Succeeded

X

^{(so far…)} Shorten trastuzumab duration

Eliminate the anthracycline

component

X

(in selected pts !)

?

Use T-DM1 + pertuzumab instead of taxane +

trastuzumab + pertuzumab

?

?

Use of only trastuzumab

without CT in stage I older pts

?

MY THOUGHTS

De-Escalation attempts : preliminary conclusions

METASTATIC DISEASE

HER2+ Disease HER2 + no longer the only prognostic factor of disease and predictive of response

TILs come to stage

TILs associated with improved prognosis among patients with HER2-positive breast cancer

The TIL count predicts a pathologic complete response to neoadjuvant chemotherapy, trastuzumab, and lapatinib

Increased TIL count predicted better distant DFS in HER2+ early BC pts (FinHER, NeoALTTO)

higher TIL values are significantly associated with improved overall survival, suggesting that the effect of antitumour immunity extends to the advanced setting (Cleopatra data)

Ali HR, Ann Oncol 2014; Bianchini G, Lancet Oncol 2014; Denkert C, J Clin Oncol 2010; Dieci MV et al, Ann Oncol 2015;

Denkert C, J Clin Omncol 2015; Loi S, Ann Oncol 2014 ,

Stromal TILs and Survival in HER2+

Further clinical studies in this cancer subtype should

consider TILs as a stratification factor

Luen, Lancet Oncol 2016

Postulated mechanism of engagement of the innate and adaptive immune system through HER2-targeted monoclonal antibodies

MHC II

Tumor cell death

(immunogenic or not immunogenic)

Debris or dying cells

Coated debris

Tumor

NK

NK/DC crosstalk ADCC

DC CTL

Cross presentation

CTL

CD4 Th1 IFNγ

Tumor cell

NK

cell Cytotoxic

T-cell Dendritic

cells

MHC I TCR

CD4 (Th1)

Phagocytosis

Legend ^Activated Cytotoxic

T-cell

HER2 FcγR

IFNγ IL-2

Bianchini G & Gianni L. Lancet Oncol 2014

Trastuzumab/pertuzumab

Trastuzumab, rituximab and others

monoclonal antibodies have demonstrated to generate an “in vivo” vaccine-like effect

HER2 targeted monoclonals

combinations

Preclinical studies are supportive of benefit for combining anti- HER2 antibodies and immune checkpoints inhibitors

Stagg J et al PNAS 2011

Anti-HER2 mAb and Anti-PD1

TDM1

and Anti-PD1/Abti-CTLA4

Muller P et al Sci Transl Med 2015

SA BC S 20 17

Panacea Study

SA BC S 20 17

Loi 2017

SA BC S 20 17

Loi 2017

Immunotherapy excitement in breast cancer Trial ongoing with immunechekpoint inhibitors

Only breast cancer Multiple solid

77 41

ClinicalTrialsGov (updated 15-09-2017)

10 trials 67 trials

Phase I or II Phase III Marketed

38 TNBC (only)

12 ER+/HER2- (only) 6 HER2+ (only)

66 trials of combinations

who survives longer with brain metastases?

Martin, Jama 2017

HER2+ population

Mounsey, Clin Breast Cancer 2017

Survival

The HERBA trial

a retrospective study on pts with HER2+ BC and brain metastases 154 HER2+ve BC pts diagnosed with BMs from January 2005

to December 2014

Gori et al. 2017

Median OS from the diagnosis of BMs was 24.5 months, with no significant difference between pts diagnosed in period 2005-2009 (25.2 months) and those diagnosed in period 2010-2014 (21.5 months; p=0.42).

No significant difference in terms of mOS between pts with and those without previously diagnosed systemic metastases (23 vs 27 months;

p=0.469) and this data suggest that the occurrence of BMs is a predominant prognostic factor for HER2+ve BC pts

Grazie