POETIC-APeri-Operative Endocrine Therapy for Individualised Care with Abemaciclib

Professor Stephen JohnstonProfessor Judith BlissProfessor Mitch Dowsett

Dr Alistair Ring

UK IBCS Birmingham, 27-28 January 2020

2

POETIC – successful delivery of complex trial

• Trial entry: Choice of patient pathways - flexible, pragmatic approach (Trials,2015)

• Pioneering PPI: recognised by NIHR & as exemplar (Clin Oncol, 2015 editorial)

130 UK centres

> 16,000 blood & >10,000 tumour samples collected

2000 staff atparticipating centres

4486 patients (>110 pts/mth at peak)

• Primary analysis presented by Robertson et al., SABCS 2017

POETIC

Baseline

2-week

Tumour - FFPE

100

75

50

25

0

% s

urv

ivin

g T

TR

event fr

ee

0 1 2 3 4 5Time post randomization (years)

3

H, L

H, H

100

75

50

25

0

% s

urv

ivin

g T

TR

event fr

ee

0 1 2 3 4 5Time post randomization (years)

L, L

Time To Recurrence (TTR) by baseline and 2-week Ki67 – Peri-op AI

100

75

50

25

0

% s

urv

ivin

g T

TR

event fr

ee

0 1 2 3 4 5Time post randomization (years)

In patients with Ki67B≥10%:

HR for Ki672W≥10% is 2.22 (95%CI: 1.68, 2.94; p<0.001)

Ki67B Ki672W TTR events/Total

5 year absolute risk,

% (95%CI)

L L 31 / 743 4.5 (3.1, 6.6)

H L 101 / 1202 8.9 (7.2, 11.0)

H H 96 / 551 19.6 (15.9, 24.1)

Robertson et al., SABCS 2017

100

75

50

25

0

% s

urv

ivin

g T

TR

event fr

ee

0 1 2 3 4 5Time post randomization (years)

4

H, L

H, H

100

75

50

25

0

% s

urv

ivin

g T

TR

event fr

ee

0 1 2 3 4 5Time post randomization (years)

L, L

Time To Recurrence (TTR) by baseline and 2-week Ki67 – Peri-op AI

100

75

50

25

0

% s

urv

ivin

g T

TR

event fr

ee

0 1 2 3 4 5Time post randomization (years)

Ki67B Ki672W TTR events/Total

5 year absolute risk,

% (95%CI)

L L 31 / 743 4.5 (3.1, 6.6)

H L 101 / 1202 8.9 (7.2, 11.0)

H H 96 / 551 19.6 (15.9, 24.1)

Robertson et al., SABCS 2017

Identify High

risk

target

population

5

N=5600*

Histologically Confirmed HR+ HER2-

Pre- post menopausal women w/ Stage III or Stage IIB Or Stage 2A*

No more than 12 mos since initial pathologic diagnosis

Prior chemo allowed

Arm A

Palbociclib (2

yrs)

+

ET (5-10 yrs)

Arm B

ET (5-10 yrs)

R

A

N

D

O

M

I

Z

A

T

I

O

N

1:1

Primary End Point: • iDFS (Invasive Disease Free Survival)

Secondary End Points:

• iDFS excluding secondary primary non-BC,

• OS, PROs, Safety

HR+,

HER2-,

Node+,

high-

risk,

early-

stage

breast

cancer

Long-term Follow-up

Period

On-Study

Treatment

Period

6-10 years3-5 years2 years

ARM A:

Standard

Endocrine

Therapy

(SOC) +

Abemaciclib

(150mg BID)

ARM B:

Standard

Endocrine

Therapy

(SOC) Alone

~4580 patients

1:1 randomization

PALLAS NCT02513394 (available from https://clinicaltrials.gov/ct2/show/NCT02513394)

MONARCH-E NCT03155997 (available from https://clinicaltrials.gov/ct2/show/NCT03155997

Phase III trials of adjuvant CDK 4/6 inhibitors in early breast cancer

PALLAS MONARCH-E

Presentation with Primary Breast Cancer

ER+ and HER2- andKi67>/= 20%

2 weeks’ AI

ER- orHER2+ or

Ki67 <20%ineligible

Ki67 < 8% ineligible

Ki67 >/= 8%

Complete standard of care treatment

Diagnostic biopsy

Clinical end-point: TTRHRs: 0.5 for profile +ve

0.9 for profile -ve

Core-cut at surgery

AIR-CIS positiveRANDOMISE

AIR-CIS negativeRANDOMISE

ET only ET onlyET + abemaciclib

ET + abemaciclib

POETIC-A Pre-Operative Endocrine Therapy for Individualised Care withAbemaciclib

Design: Prospective, multi‐centre, randomised, phase III

Primary Aim: To determine whether a molecular algorithm (AIR-CIS) can identify those postmenopausalwomen with ER+ HER2- primary breast cancer and poor antiproliferative response to an aromatase inhibitor(AI) who may derive greatest benefit from additional adjuvant endocrine therapy with abemaciclib.

Key Eligibility Criteria for registration:• ER+, HER2-• Postmenopausal• Palpable tumour of any size or ≥1.5cm by imaging

• Baseline Ki67 ≥ 20% measured at the local siteOR

• Presence of clinico-pathologic factors that predict (>50% chance) patients with Ki67 ≥ 8% after 2weeks’ AI:• grade 3• clinical/radiological tumour size > 5cm• PgR negative or PgR unknown AND evidence of vascular invasion.

POETIC-A Pre-Operative Endocrine Therapy for Individualised Care withAbemaciclib

Design: Prospective, multi‐centre, randomised, phase III

Primary Aim: To determine whether a molecular algorithm (AIR-CIS) can identify those postmenopausalwomen with ER+ HER2- primary breast cancer and poor antiproliferative response to an aromatase inhibitor(AI) who may derive greatest benefit from additional adjuvant endocrine therapy with abemaciclib.

Key Eligibility Criteria for registration:• ER+, HER2-• Postmenopausal• Palpable tumour of any size or ≥1.5cm by imaging

• Baseline Ki67 ≥ 20% measured at the local siteOR

• presence of clinico-pathologic factors that predict (>50% chance) patients with Ki67 ≥ 8% after 2weeks’ AI, i.e. grade 3; clinical/radiological tumour size > 5cm; PgR negative or PgR unknown ANDevidence of vascular invasion.

Eligibility for randomisation: 1. Centrally confirmed Ki67 >8% following 2 weeks of AI.

2. Completed surgery, chemotherapy and radiotherapy (if prescribed) with any previous toxicities resolved to grade 1 or 0.

POETIC-A Pre-Operative Endocrine Therapy for Individualised Care with Abemaciclib

Randomisation: Patients who remain eligible will be formally entered into the randomised trial

and allocated to ± abemaciclib (1:1 allocation ratio) with stratification by the AIR-CIS signature

(dichotomised). There will be no placebo control, consistent with Monarch-E. Treatment with

endocrine therapy (AI) will be given until evidence of disease recurrence or for planned duration of

therapy.

Treatment period: patients in the abemaciclib arm will receive abemaciclib 150mg for 2 years. All

patients will receive standard adjuvant endocrine therapy for a minimum of 5 years. Patients will

have on-treatment visits for 2 years and follow-up visits at 3, 4, and 5 years post-randomisation.

Sample size and recruitment period:

6000 early breast cancer patients registered from approx. 80 UK centres, 2500 randomised over 3

years.

POETIC-A Team

Chief Investigator: Professor Stephen Johnston Coordinating Investigator: Dr Alistair RingTranslational Study Lead: Prof Mitch DowsettScientific/Methodology Lead: Prof Judith BlissBioinformatics and Genomic Analysis Lead: Dr Maggie Cheang

Coordinating Clinical Trials Unit: ICR-CTSU• Clinical Trials Programme Manager: Hilda Tsang• Trial Manager: Peter Chatfield

Sponsor: The Institute of Cancer Research

POETIC-A-icrctsu@icr.ac.uk

Tel: +44 (0)208 722 4264